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Salem DA, El-Ijla R, AbuMusameh RR, Zakout KA, Abu Halima AY, Abudiab MT, Banat YM, Alqeeq BF, Al-Tawil M, Matar K. Sex-related differences in profiles and clinical outcomes of Inflammatory bowel disease: a systematic review and meta-analysis. BMC Gastroenterol 2024; 24:425. [PMID: 39580396 PMCID: PMC11585250 DOI: 10.1186/s12876-024-03514-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/12/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic and idiopathic condition that includes both Crohn's disease (CD) and ulcerative colitis (UC). The impact of sex on the disease course and the clinical outcomes not fully understood. Our systematic review and meta-analysis aims to explore the differences in the clinical outcomes in IBD. METHOD A systematic review and meta-analysis was done by searching in the PubMed /MEDLINE, Embase, and Scopus databases. We used the Random-Effects model to estimate risk ratios (RR) for binary outcomes and mean difference and hedges' g for continuous outcomes. RESULT A total of 44 unique studies were included. Our analysis revealed distinct sex differences in various outcomes of IBD. Anxiety was more prevalent in females (RR: 0.73; 95% CI [0.64, 0.82]) and females in the CD subgroup (RR: 0.76; 95% CI [0.62, 0.93]; p = 0.01. While depression was diagnosed more frequently in females (RR: 0.80; 95% CI [0.66, 0.97] in the total population of the study, subgroup analysis showed no sex difference. Additionally, quality of life scores were worse in females in the total population (Hedges' g: 0.24; 95% CI [0.05, 0.42]) with no significant difference in subgroup analyses. A significantly higher mortality risk was estimated in males (RR: 1.26; 95% CI [1.07, 1.48]) and in subgroup analysis for males with UC (RR: 1.48; 95% CI [1.19, 1.84]; p = 0.00) with no significant difference in CD. Regarding disease location, male patients were less likely to present with proctitis (RR: 0.67; 95% CI [0.50, 0.91]) when compared to females. Males had more frequent indications for surgery (RR: 1.10; 95% CI [1.01, 1.20]), however, no significant difference was found in subgroup analyses for CD or UC. Also, males were older at the time of admission (MD: 1.39 years; 95% CI [0.10, 2.68]). No significant sex differences were found in terms of hospitalization rates or disease behavior. CONCLUSION In conclusion, our meta-analysis shows that males face higher risks of early mortality and require more IBD surgeries, whereas females experience greater levels of anxiety and depression. These findings emphasize the need to consider sex disparities in IBD management.
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Affiliation(s)
- Dana A Salem
- Faculty of Medicine, Al-Quds University, Jerusalem, Palestine.
| | - Rawan El-Ijla
- Faculty of Medicine, Al-Quds University, Jerusalem, Palestine
| | | | - Khaled A Zakout
- Faculty of Medicine, Al-Quds University, Jerusalem, Palestine
| | | | | | - Yahya M Banat
- Faculty of Medicine, Al-Quds University, Jerusalem, Palestine
| | - Basel F Alqeeq
- Faculty of Medicine, Islamic University of Gaza, Gaza, Palestine
| | | | - Khaled Matar
- Consultant Internal Medicine and Gastroenterology, European Gaza Hospital, Gaza, Palestine
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Khrom M, Li D, Naito T, Lee HS, Botwin GJ, Potdar AA, Boucher G, NIDDK Inflammatory Bowel Disease Genetics Consortium, International Inflammatory Bowel Disease Genetics Consortium, Yang S, Mengesha E, Dube S, Song K, McGovern DPB, Haritunians T. Sex-Dimorphic Analyses Identify Novel and Sex-Specific Genetic Associations in Inflammatory Bowel Disease. Inflamm Bowel Dis 2023; 29:1622-1632. [PMID: 37262302 PMCID: PMC10547236 DOI: 10.1093/ibd/izad089] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Indexed: 06/03/2023]
Abstract
BACKGROUND Sex is an integral variable often overlooked in complex disease genetics. Differences between sexes have been reported in natural history, disease complications, and age of onset in inflammatory bowel disease (IBD). While association studies have identified >230 IBD loci, there have been a limited number of studies investigating sex differences underlying these genetic associations. METHODS We report the first investigation of sex-dimorphic associations via meta-analysis of a sex-stratified association study (34 579 IBD cases, 39 125 controls). In addition, we performed chromosome (chr) X-specific analyses, considering models of X inactivation (XCI) and XCI escape. Demographic and clinical characteristics were also compared between sexes. RESULTS We identified significant differences between sexes for disease location and perianal complication in Crohn's disease and disease extent in ulcerative colitis. We observed genome-wide-significant sex-dimorphic associations (P < 5 × 10-8) at loci not previously reported in large-scale IBD genetic studies, including at chr9q22, CARMIL1, and UBASH3A. We identified variants in known IBD loci, including in chr2p15 and within the major histocompatibility complex on chr6, exhibiting sex-specific patterns of association (P < 5 × 10-7 in one sex only). We identified 3 chrX associations with IBD, including a novel Crohn's disease susceptibility locus at Xp22. CONCLUSIONS These analyses identified novel IBD loci, in addition to characterizing sex-specific patterns of associations underlying sex-dimorphic associations. By elucidating the role of sex in IBD genetics, our study will help enhance our understanding of the differences between the sexes in IBD biology and underscores a need to move beyond conventional sex-combined analyses to appreciate the genetic architecture of IBD more comprehensively.
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Affiliation(s)
- Michelle Khrom
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dalin Li
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Takeo Naito
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ho-Su Lee
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Gregory J Botwin
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Alka A Potdar
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | | | | | - Shaohong Yang
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Emebet Mengesha
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Shishir Dube
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Dermot P B McGovern
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Talin Haritunians
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Song XQ, Li Q, Zhang J. A double-edged sword: DLG5 in diseases. Biomed Pharmacother 2023; 162:114611. [PMID: 37001186 DOI: 10.1016/j.biopha.2023.114611] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/22/2023] [Accepted: 03/24/2023] [Indexed: 03/31/2023] Open
Abstract
Discs large homolog 5 (DLG5), a key member of the membrane-associated guanylate kinase (MAGUKs) family, is a scaffold molecule for signal transduction complexes and is responsible for assembling receptors and adapters. This scaffold protein stabilizes adhesion and tight bonding complexes in many organs and tissues, and is involved of maintaining epithelial polarity. Although DLG5 plays a role in normal development in mice, it has also been linked to the onset and development of several diseases, particularly Crohn's disease and various malignancies. DLG5 has been shown to impact the progression of cancer through direct or indirect interactions with H-catenin, E-cadherin, Vimentin, p53, P21, Cyclin D1, TGF-β1, AKT, Hippo, and classic G protein signaling pathways. DLG5 and DLG5 variants has been found to have a dual role in human diseases. Although it is overexpressed in pancreatic adenocarcinoma, its expression is reduced in lung, liver, breast, prostate, and bladder cancers. However, two independent studies on glioblastoma (GBM) have shown the opposite effects of DLG5. Our study evaluates the existing literature on the role of DLG5 and DLG5 variants in disease processes, and summarizes the available data on the role of DLG5 in disease based on cell experiments, clinical samples, and animal models, while highlighting its future potential in disease treatment.
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Impact of Female Gender in Inflammatory Bowel Diseases: A Narrative Review. J Pers Med 2023; 13:jpm13020165. [PMID: 36836400 PMCID: PMC9958616 DOI: 10.3390/jpm13020165] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 01/05/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
Inflammatory bowel diseases show a gender bias, as reported for several other immune-mediated diseases. Female-specific differences influence disease presentation and activity, leading to a different progression between males and females. Women show a genetic predisposition to develop inflammatory bowel disease related to the X chromosome. Female hormone fluctuation influences gastrointestinal symptoms, pain perception, and the state of active disease at the time of conception could negatively affect the pregnancy. Women with inflammatory bowel disease report a worse quality of life, higher psychological distress, and reduced sexual activity than male patients. This narrative review aims to resume the current knowledge of female-related features in clinical manifestations, development, and therapy, as well as sexual and psychological implications related to inflammatory bowel disease. The final attempt is to provide gastroenterologists with a roadmap of female-specific differences, to improve patients' diagnosis, management, and treatment.
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Rustgi SD, Kayal M, Shah SC. Sex-based differences in inflammatory bowel diseases: a review. Therap Adv Gastroenterol 2020; 13:1756284820915043. [PMID: 32523620 PMCID: PMC7236567 DOI: 10.1177/1756284820915043] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Accepted: 03/03/2020] [Indexed: 02/04/2023] Open
Abstract
Sex-based differences in inflammatory bowel disease (IBD) pathogenesis, disease course, and response to therapy have been increasingly recognized, however, not fully understood. Experimental and translational models have been leveraged to investigate hypothesized mechanisms for these observed differences, including the potential modifying role of sex hormones and sex-dependent (epi)genetic and gut microbiome changes. The primary objective of this review is to comprehensively describe sex-based differences in IBD including epidemiology, pathogenesis, phenotypic differences, therapeutic response, and outcomes.
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Affiliation(s)
- Sheila D. Rustgi
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Maia Kayal
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, USA
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6
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Li Y, Chen P, Sun J, Huang J, Tie H, Li L, Li H, Ren G. Meta-analysis of associations between DLG5 R30Q and P1371Q polymorphisms and susceptibility to inflammatory bowel disease. Sci Rep 2016; 6:33550. [PMID: 27633114 PMCID: PMC5025715 DOI: 10.1038/srep33550] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 08/30/2016] [Indexed: 01/01/2023] Open
Abstract
Growing evidence from recent studies has demonstrated an association between inflammatory bowel disease (IBD) susceptibility and two polymorphisms of DLG5 R30Q (rs1248696) and P1371Q (rs2289310), but the results remain controversial. We conducted a meta-analysis including a total of 22 studies with 10,878 IBD patients and 7917 healthy controls for R30Q and 5277 IBD cases and 4367 controls for P1371Q in order to systematically assess their association with the disease. The results indicated that R30Q was significantly associated with reduced susceptibility to IBD in Europeans by allelic and dominant comparisons, but not in overall population. No significant association was found between R30Q and Crohn's disease (CD) or ulcerative colitis (UC). P1371Q was associated with increased risk of IBD in Europeans and Americans. On the contrary, a decreased risk of IBD was observed in Asian population for P1371Q. In disease subgroup analysis, we found that P1371Q was also significantly associated with CD, but this relationship was not present for UC. In conclusion, our results strongly suggest that the both polymorphisms of DLG5 are correlated with IBD susceptibility in an ethnic-specific manner. Additional well-designed studies with large and diverse cohorts are needed to further strengthen our findings.
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Affiliation(s)
- Yunhai Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ping Chen
- Department of Rheumatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Jiazheng Sun
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jing Huang
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hongtao Tie
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Liangliang Li
- Department of Rheumatology, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Hongzhong Li
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guosheng Ren
- Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Huang LO, Infante-Rivard C, Labbe A. Analysis of Case-Parent Trios Using a Loglinear Model with Adjustment for Transmission Ratio Distortion. Front Genet 2016; 7:155. [PMID: 27630667 PMCID: PMC5005337 DOI: 10.3389/fgene.2016.00155] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/16/2016] [Indexed: 01/16/2023] Open
Abstract
Transmission of the two parental alleles to offspring deviating from the Mendelian ratio is termed Transmission Ratio Distortion (TRD), occurs throughout gametic and embryonic development. TRD has been well-studied in animals, but remains largely unknown in humans. The Transmission Disequilibrium Test (TDT) was first proposed to test for association and linkage in case-trios (affected offspring and parents); adjusting for TRD using control-trios was recommended. However, the TDT does not provide risk parameter estimates for different genetic models. A loglinear model was later proposed to provide child and maternal relative risk (RR) estimates of disease, assuming Mendelian transmission. Results from our simulation study showed that case-trios RR estimates using this model are biased in the presence of TRD; power and Type 1 error are compromised. We propose an extended loglinear model adjusting for TRD. Under this extended model, RR estimates, power and Type 1 error are correctly restored. We applied this model to an intrauterine growth restriction dataset, and showed consistent results with a previous approach that adjusted for TRD using control-trios. Our findings suggested the need to adjust for TRD in avoiding spurious results. Documenting TRD in the population is therefore essential for the correct interpretation of genetic association studies.
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Affiliation(s)
- Lam O. Huang
- Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontréal, QC, Canada
| | - Claire Infante-Rivard
- Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontréal, QC, Canada
| | - Aurélie Labbe
- Department of Epidemiology, Biostatistics and Occupational Health, McGill UniversityMontréal, QC, Canada
- Department of Psychiatry, McGill UniversityMontréal, QC, Canada
- Douglas Mental Health University InstituteMontréal, QC, Canada
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Abstract
Current statistical approaches to investigate the nature and magnitude of transmission ratio distortion (TRD) are scarce and restricted to the most common experimental designs such as F2 populations and backcrosses. In this article, we describe a new Bayesian approach to check TRD within a given biallelic genetic marker in a diploid species, providing a highly flexible framework that can accommodate any kind of population structure. This model relies on the genotype of each offspring and thus integrates all available information from either the parents' genotypes or population-specific allele frequencies and yields TRD estimates that can be corroborated by the calculation of a Bayes factor (BF). This approach has been evaluated on simulated data sets with appealing statistical performance. As a proof of concept, we have also tested TRD in a porcine population with five half-sib families and 352 offspring. All boars and piglets were genotyped with the Porcine SNP60 BeadChip, whereas genotypes from the sows were not available. The SNP-by-SNP screening of the pig genome revealed 84 SNPs with decisive evidences of TRD (BF > 100) after accounting for multiple testing. Many of these regions contained genes related to biological processes (e.g., nucleosome assembly and co-organization, DNA conformation and packaging, and DNA complex assembly) that are critically associated with embryonic viability. The implementation of this method, which overcomes many of the limitations of previous approaches, should contribute to fostering research on TRD in both model and nonmodel organisms.
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Michail S, Bultron G, Depaolo RW. Genetic variants associated with Crohn's disease. APPLICATION OF CLINICAL GENETICS 2013; 6:25-32. [PMID: 23935379 PMCID: PMC3735034 DOI: 10.2147/tacg.s33966] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Crohn’s disease is an immune-related disorder characterized by inflammation of the gastrointestinal mucosa, which can occur in any area throughout the digestive tract. This life-long disease commonly presents with abdominal pain, diarrhea, vomiting, and weight loss. While the exact etiology of this disease is largely unknown, it is thought to arise from an interaction between microbial, immunological, and environmental factors in a genetically susceptible host, whereby the immune system attacks the intestine as it cross reacts against gut microbial antigens. The study of genetic variants associated with Crohn’s disease has shed light on our understanding of disease pathophysiology. A large number of genetic variants identified in Crohn’s disease are related to genes targeting microbial recognition and bacterial wall sensing, the most common being NOD2/CARD15 gene. This review will discuss the recent advance in our knowledge of genetic variants of this disease and how they influence the disease course and prognosis.
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Affiliation(s)
- Sonia Michail
- The University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA
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Liu Y, Zhang L, Xu S, Hu L, Hurst LD, Kong X. Identification of two maternal transmission ratio distortion loci in pedigrees of the Framingham heart study. Sci Rep 2013; 3:2147. [PMID: 23828458 PMCID: PMC3701898 DOI: 10.1038/srep02147] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 06/17/2013] [Indexed: 12/29/2022] Open
Abstract
Transmission ratio distortion (TRD) is indicated by the recovery of alleles in offspring in non-Mendelian proportions. An assumption of Mendelian proportion is central to many methods to identify disease-associated markers. This seems reasonable as, while TRD cases have been occasionally observed in various species few instances have been identified in humans. Here we search for evidence of paternal or maternal TRD with genome-wide SNP data of pedigrees from the Framingham Heart Study. After excluding many examples as better explained by genotyping errors we identified two maternal-specific TRD loci for autosomal SNPs rs6733122 and rs926716 (corrected P = 0.029 and P = 0.018) on LRP2 and ZNF133, respectively. The transmission ratios were as high as 1.7~1.8:1. Genotyping validation and further replication is still necessary to confirm the TRD. This study shows that there may be large-effect maternal-specific TRD loci of common SNPs in the human genome but that these are rare.
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Affiliation(s)
- Yang Liu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200025, China
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Transmission ratio distortion: review of concept and implications for genetic association studies. Hum Genet 2012; 132:245-63. [PMID: 23242375 DOI: 10.1007/s00439-012-1257-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 12/04/2012] [Indexed: 12/31/2022]
Abstract
Transmission ratio distortion (TRD) occurs when one of the two alleles from either parent is preferentially transmitted to the offspring. This leads to a statistical departure from the Mendelian law of inheritance, which states that each of the two parental alleles is transmitted to offspring with a probability of 0.5. A number of mechanisms are thought to induce TRD such as meiotic drive, gametic competition, and embryo lethality. TRD has been extensively studied in animals, but the prevalence of TRD in humans remains largely unknown. Nevertheless, understanding the TRD phenomenon and taking it into consideration in many aspects of human genetics has potential benefits that have not been sufficiently emphasized in the current literature. In this review, we discuss the importance of TRD in three distinct but related fields of genetics: developmental genetics which studies the genetic abnormalities in zygotic and embryonic development, statistical genetics/genetic epidemiology which utilizes population study designs and statistical models to interpret the role of genes in human health, and population genetics which is concerned with genetic diversity in populations in an evolutionary context. From the perspective of developmental genetics, studying TRD leads to the identification of the processes and mechanisms for differential survival observed in embryos. As a result, it is a genetic force which affects allele frequency at the population, as well as, at the organismal level. Therefore, it has implications on genetic diversity of the population over time. From the perspective of genetic epidemiology, the TRD influence on a marker locus is a confounding factor which has to be adequately dealt with to correctly interpret linkage or association study results. These aspects are developed in this review. In addition to these theoretical notions, a brief summary of the empirical evidence of the TRD phenomenon in human and mouse studies is provided. The objective of our paper is to show the potentially important role of TRD in many areas of genetics, and to create an incentive for future research.
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Zelinkova Z, Stokkers PC, van der Linde K, Kuipers EJ, Peppelenbosch MP, van der Woude CPJ. Maternal imprinting and female predominance in familial Crohn's disease. J Crohns Colitis 2012; 6:771-6. [PMID: 22398090 DOI: 10.1016/j.crohns.2012.01.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2011] [Revised: 12/20/2011] [Accepted: 01/02/2012] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Although the genetic risk factors for familial and sporadic inflammatory bowel disease (IBD) seem identical, the relative risk for contracting IBD in the familial setting is larger as that seen in the population at large, suggesting an important role of epi- and/or paragenetic factors in familial IBD. Epidemiological data indicate a female predominance in IBD, but how this relates to familial IBD has not been assessed. METHODS Familial IBD patients (N=608) were compared with a cohort of 415 sporadic IBD patients with regards to the patterns of sex and disease type distribution. The imprinting pattern in 87 families in which both a parent and a child had IBD was tested using Galton binominal statistics. RESULTS The percentage of females in familial IBD population was significantly higher (61%; female/male ratio 1.5) compared with sporadic IBD (54%; female/male ratio 1.2; p=0.011). The analysis of offspring sex distribution pattern revealed significantly higher female to female transmission compared with female to male transmission rate (36 vs. 18, respectively; p=0.02). A significantly higher number of mother to child transmissions (55 vs. 32 of father to child transmissions) was observed (p=0.018). The female imprinting was specifically related to Crohn's disease (31 vs. 14 mother vs. father to child transmissions, respectively; p=0.016). CONCLUSION We propose that a female sex-specific epigenetic inheritance pattern for Crohn's disease is a major contributing factor in the family-specific risk in Crohn's disease. Sex-specific manifestation of familial Crohn's disease can partly explain the epidemiologically observed increased relative risk for females for contracting IBD.
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Affiliation(s)
- Zuzana Zelinkova
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands.
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Ringelstein M, Jung A, Berger K, Stoll M, Madlener K, Klötzsch C, Schlachetzki F, Stolz E. Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. J Neurol 2012; 259:2287-92. [DOI: 10.1007/s00415-012-6477-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2012] [Revised: 03/04/2012] [Accepted: 03/05/2012] [Indexed: 01/21/2023]
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Abstract
Transmission ratio distortion (TRD) is the departure from the expected genotypic frequencies under Mendelian inheritance. This departure can be due to multiple physiological mechanisms during gametogenesis, fertilization, fetal and embryonic development, and early neonatal life. Although a few TRD loci have been reported in mouse, inheritance patterns have never been evaluated for TRD. In this article, we developed a Bayesian binomial model accounting for additive and dominant deviation TRD mechanisms. Moreover, this model was used to perform genome-wide scans for TRD quantitative trait loci (QTL) on six F2 mouse crosses involving between 296 and 541 mice and between 72 and 1854 genetic markers. Statistical significance of each model was checked at each genetic marker with Bayes factors. Genome scans revealed overdominance TRD QTL located in mouse chromosomes 1, 2, 12, 13, and 14 and additive TRD QTL in mouse chromosomes 2, 3, and 15, although these results did not replicate across mouse crosses. This research contributes new statistical tools for the analysis of specific genetic patterns involved in TRD in F2 populations, our results suggesting a relevant incidence of TRD phenomena in mouse with important implications for both statistical analyses and biological research.
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Liu LY, Schaub MA, Sirota M, Butte AJ. Transmission distortion in Crohn's disease risk gene ATG16L1 leads to sex difference in disease association. Inflamm Bowel Dis 2012; 18:312-22. [PMID: 21618365 PMCID: PMC3165065 DOI: 10.1002/ibd.21781] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2011] [Accepted: 04/25/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Crohn's disease (CD), an inflammatory disease of the bowel, affects millions of people around the world. Evidence suggests that disease onset and pathogenesis differ between males and females. Yet no comprehensive efforts exist to assess the sex-specific genetic architecture of CD. METHODS We used genotyping data from a cohort of 1748 CD cases and 2938 controls to investigate 71 meta-analysis-confirmed CD risk loci for sex differences in disease risk. We further validated the significant results in separate cohorts of 968 CD cases and 2809 controls, and performed a meta-analysis across datasets. RESULTS The single nucleotide polymorphism (SNP) rs3792106 (C/T) in ATG16L1 showed a significant sex effect with P-value 6.9 × 10(-13) and allelic odds ratio 1.48 in females, and P-value 0.013 and odds ratio 1.22 in males (odds ratio heterogeneity P-value 0.037). Surprisingly, the difference was found to arise from a discrepancy in allele frequencies between male and female controls (P-value 0.0045) rather than cases. We found similar results for this SNP in the separate validation datasets. Using 155 HapMap 3 trios, we detected significant maternal overtransmission of the T allele at rs3792106 (P-value 0.027). CONCLUSIONS Our results indicate that different transmission patterns between sexes may sustain the disparate allele frequencies at rs3792106 in healthy populations, and furthermore that a virus-risk variant mechanism implicated in CD alters the distribution in diseased patients. To our knowledge, this is the first report of sex-specific CD association in ATG16L1. The possible implications in CD and basic human biology present interesting areas for future investigation.
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Affiliation(s)
- Linda Y. Liu
- Stanford Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, California, United States of America, Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America, Lucile Packard Children’s Hospital, Palo Alto, California, United States of America
| | - Marc A. Schaub
- Computer Science Department, Stanford University, Stanford, California, United States of America
| | - Marina Sirota
- Stanford Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, California, United States of America, Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America, Lucile Packard Children’s Hospital, Palo Alto, California, United States of America
| | - Atul J. Butte
- Stanford Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, California, United States of America, Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, United States of America, Lucile Packard Children’s Hospital, Palo Alto, California, United States of America,Corresponding Author: Atul J. Butte, MD, PhD, Stanford University School of Medicine, 251 Campus Drive MS-5415, Room X-163 Stanford, CA 94305-5415, Phone: (650) 723-3465, Fax: (650) 723-7070,
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Age- and gender-specific epistasis between ADA and TNF-α influences human life-expectancy. Cytokine 2011; 56:481-8. [PMID: 21865054 DOI: 10.1016/j.cyto.2011.07.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 07/19/2011] [Accepted: 07/25/2011] [Indexed: 11/22/2022]
Abstract
Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-α) genes may influence human life-expectancy. ADA (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629; -238G>A, rs361525) functional SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes defined according to demographic information and accounting for the different survivals between sexes: for men (women), the first class consists of individuals<66 years old (<73 years old), the second class of individuals 66-88 years old (73-91 years old), and the third class of individuals>88 years old (>91 years old). Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males (comparison 1 (age class 2 vs. age class 1), O.R. 1.943, P=0.036; comparison 2 (age class 3 vs. age class 2), O.R. 0.320, P=0.0056). Age- and gender-specific patterns of epistasis between ADA and TNF-α were found using Generalized Multifactor Dimensionality Reduction (GMDR). In comparison 1, a significant two-loci interaction occurs in females between ADA 22G>A and TNF-α -238G>A (Sign Test P=0.011). In comparison 2, both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88 years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-α genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity.
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Napolioni V, Predazzi IM. Age- and gender-specific association between ADA (22G>A) and TNF-α (-308G>A) genetic polymorphisms. ACTA ACUST UNITED AC 2011; 76:311-4. [PMID: 20522203 DOI: 10.1111/j.1399-0039.2010.01510.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
During the last years, several investigations have been performed to examine the influence of the tumor necrosis factor alpha (TNF-α) -308G>A single nucleotide polymorphism (SNP) in the susceptibility or severity of diseases and in many inflammatory conditions. However, the results of these studies have been conflicting, suggesting that, under normal/physiologic conditions, important disturbances in expression of major physiologic components can be compensated by mediators of the same system. In the present study, we evaluated the genetic relationship between the functional adenosine deaminase (ADA) (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629) SNPs in a healthy population from central Italy. An association between ADA*2 and TNF-α*A was observed in males aged ≥ 50 [odds ratio (OR) = 5.16, P = 0.001]; a three-way contingency table analysis by a log-linear model shows a significant interaction between TNF-α genotype, ADA genotype, and age group (P = 0.012) for this gender. Overall, we may speculate that, in males, higher adenosine levels (conferred by ADA*2) may counteract the higher levels of TNF-α (conferred by TNF-α*A) in protective model of inheritance.
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Affiliation(s)
- V Napolioni
- Laboratory of Human Genetics, Department of Molecular, Cellular and Animal Biology, University of Camerino, Camerino, Italy.
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18
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Intestinal cancer risk in Crohn's disease: a meta-analysis. J Gastrointest Surg 2011; 15:576-83. [PMID: 21152994 DOI: 10.1007/s11605-010-1402-9] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 11/22/2010] [Indexed: 02/07/2023]
Abstract
AIM OF THE STUDY To clarify the intestinal cancer risk in Crohn's disease (CD). METHODS 20 clinical studies (1965-2008) with a total of 40,547 patients with Crohn's disease-associated cancer (CDAC) were included in the meta-analysis ("inverse variance weighted" method). RESULTS The incidence of CDAC in any CD patient was 0.8/1,000 person years duration (pyd) (CI, 0.6-1.0). The incidences of different carcinomas were: colorectal cancer 0.5/1,000 pyd (CI, 0.3-0.6), small bowel carcinoma 0.3/1,000 pyd (CI, 0.1-0.5), and cancers arising from CD-associated fistulae 0.2/1,000 pyd (CI, 0.0-0.4). Compared to the incidence in an age-matched standard population, the risk of colorectal cancer was increased by factor 2-3 and of small bowel cancer by factor 18.75, respectively. Mean patient age at diagnosis of CD-associated colorectal cancer was 51.5 years, thus 20 years earlier than in a standard population. The mean duration of CD until diagnosis of CDAC was 18.3 years. Duration of CD, age at diagnosis of CD, and anatomical area of CD involvement had no significant influence on cancer incidence. CONCLUSIONS CD is a risk factor for colorectal cancer, small bowel cancer, and fistula cancer; however, compared to ulcerative colitis, cancer risk is moderate.
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Yamamoto-Furusho JK. Genetic Susceptibility in Inflammatory Bowel Disease. Clin Rev Bone Miner Metab 2010. [DOI: 10.1007/s12018-009-9068-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Dema B, Fernández-Arquero M, Maluenda C, Polanco I, Figueredo MA, De La Concha EG, Urcelay E, Núñez C. The R30Q DLG5 variant is not associated with celiac disease or inflammatory bowel disease in the Spanish population. ACTA ACUST UNITED AC 2010; 77:62-4. [PMID: 20796250 DOI: 10.1111/j.1399-0039.2010.01560.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Alterations in intestinal epithelial permeability could underlie inflammatory bowel disease (IBD) and celiac disease (CeD) etiology, as supported by previous association studies. One related gene, DLG5 [discs, large homologue 5 (Drosophila)], has been associated with IBD in several populations and with CeD in the Dutch population. We tried to confirm the involvement of DLG5 in CeD performing a case-control study (725 CeD patients and 803 controls) by analysing the R30Q variant (rs1248696). Genetic frequencies did not significantly differ between groups (P > 0.80) and the meta-analysis with the Dutch data did not show any association. Additionally, we evaluated the effect of R30Q in IBD risk (858 patients), as discordant results were previously obtained. No association was detected. Our study does not support the effect of the R30Q DLG5 variant in CeD or IBD predisposition in the Spanish population.
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Affiliation(s)
- B Dema
- Clinical Immunology Department, Hospital Clínico San Carlos, Madrid, Spain
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Cuffari C. The genetics of inflammatory bowel disease: diagnostic and therapeutic implications. World J Pediatr 2010; 6:203-9. [PMID: 20706819 DOI: 10.1007/s12519-010-0219-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2010] [Accepted: 06/13/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND The genetics of inflammatory bowel diseases (IBD) has brought new insight into the spectrum of disease phenotypes that are collectively labeled as either Crohn's disease or ulcerative colitis. In concert with the pharmacogenomics of drug therapy, it has led clinicians to develop the notion of a more tailored approach to therapy. DATA SOURCES Articles were searched from PubMed (1995-2010) with key words "inflammatory bowel diseases", "Genetics", "pharmacogenomics". RESULTS Among all the putative susceptibility loci, the NOD2 gene has been the most studied and linked to an aggressive form of stricturing and perforating disease of the ileum. Other potential gene polymorphisms, including those encoding for the interleukin-23 receptor, have lent themselves to the recent development of potential novel immunosuppressive therapies. While the linkage of a number of autophagy genes with either Crohn's disease or ulcerative colitis has provided insight into the innate adaptive immune pathway's response to commensual intestinal bacteria. Pharmacogenetic polymorphisms of azathioprine metabolism have been shown to predict toxicity to anti-metabolite therapy. Patients with absent thiopurine methyl transferase enzyme activity are at risk for irreversible bone marrow suppression, and are not considered good candidates for either 6-mercaptopurine (6-MP) or azathioprine therapy. CONCLUSIONS Ultimately, the correlation between these genotypes and clinical phenotype of disease will inevitably lead to an improved understanding of disease natural history and a more tailored approach to therapy. Although there is ongoing debate as to whether these inherent differences in enzyme activity can predict responsiveness to anti-metabolite therapy, some gastroenterologists do find value in 6-MP metabolite testing as a means of monitoring patient compliance and tailoring the dose of anti-metabolite therapy based on a perceived therapeutic window. In the future, patients with IBD will ultimately be categorized based on their genomic imprint to allow for a better delineation of disease phenotype. Furthermore, the application pharmacogenomics of drug therapy into clinical practice will be pivotal in maximizing treatment response while avoiding untoward side-effects.
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Affiliation(s)
- Carmen Cuffari
- Division of Pediatric Gastroenterology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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Henckaerts L, Vlietinck R, Derom C, Boonen S, Rutgeerts P, Vermeire S. Transmission ratio distortion of DLG5 R30Q: evidence for prenatal selection? Inflamm Bowel Dis 2010; 16:910-1. [PMID: 19774648 DOI: 10.1002/ibd.21109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Lin Z, Nelson L, Franke A, Poritz L, Li TY, Wu R, Wang Y, MacNeill C, Thomas NJ, Schreiber S, Koltun WA. OCTN1 variant L503F is associated with familial and sporadic inflammatory bowel disease. J Crohns Colitis 2010; 4:132-8. [PMID: 21122496 DOI: 10.1016/j.crohns.2009.09.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2009] [Revised: 09/07/2009] [Accepted: 09/08/2009] [Indexed: 02/07/2023]
Abstract
PURPOSE A two-allele haplotype of TC (OCTN1 rs1050152 and OCTN2 -207G→C) is associated with Crohn's disease (CD). The association has been replicated in different populations, but also failed in some studies. The present study is to replicate the association of OCTN1 rs1050152 and examine another variant rs272879 with familial and sporadic inflammatory bowel disease (IBD) in a cohort from central Pennsylvania, USA. METHODS The study samples (n=465) included 212 inflammatory bowel disease patients (CD=115, UC=97), including 103 familial (CD=55, UC=46) and 111 sporadic (CD=60, UC=51) IBD, 139 non-IBD family members from a familial IBD registry, and 114 unrelated healthy controls. A total of 12 OCTN1 variants within exonic sequences were examined. Two nonsynonymous SNPs, rs1050152 (L503F) and rs272879 (L395V) were genotyped by a PCR-based RFLP/cRFLP method and statistically analyzed. These samples with an additional 141 unrelated healthy samples were also genotyped for rs1050152 using the SNPlex™ Genotyping System. RESULTS The OCTN1 rs1050152 is associated with CD (OR=1.745, 95% CI=1.019-2.990, χ²=4.129, p=0.042) and with IBD (OR=1.68, 95% CI=1.052-2.676, χ²=4.732, p=0.030); while the variant rs272879 is not associated with IBD, CD or ulcerative colitis (UC). The distribution of the rs1050152 variant showed a high level of the T allele in male UC (OR=2.585, 95% CI=1.139-5.869, p=0.023) and IBD (OR=2.039, 95% CI=1.024-4.059, p=0.042) patients, and in female CD patients (OR=2.329, 95% CI=1.038-5.226, ρ value=0.039). CONCLUSION The present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.
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Affiliation(s)
- Zhenwu Lin
- Department of Surgery, The Pennsylvania State University, College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
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Lin Z, Poritz L, Franke A, Li TY, Ruether A, Byrnes KA, Wang Y, Gebhard AW, MacNeill C, Thomas NJ, Schreiber S, Koltun WA. Genetic association of nonsynonymous variants of the IL23R with familial and sporadic inflammatory bowel disease in women. Dig Dis Sci 2010; 55:739-46. [PMID: 19294505 DOI: 10.1007/s10620-009-0782-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Accepted: 02/26/2009] [Indexed: 12/15/2022]
Abstract
PURPOSE To replicate the association of IL23R R381Q (rs11209026) with inflammatory bowel disease (IBD), examine the effect of the two nonsynonymous variations, Q3H and L310P, on IBD, and to study gender distribution of these variants in IBD patients. RESULTS IL23R R381Q was associated with Crohn's disease (CD) (P = 0.010), but not with ulcerative colitis (UC); L310P was associated with UC (P = 0.004), but not with CD; no association was observed for Q3H with CD or UC. A female-specific association of R381Q with CD (P = 0.041), and of L310P with UC (P = 0.008) was observed. CONCLUSION We replicated the association of IL23R R381Q with CD but not UC, and we observed an association of L310P with UC, but not CD, in a central Pennsylvania population. Further analysis of the distribution of IL23R variants revealed that these effects were largely female-specific. The results suggest that IL23R R381Q confers protection against CD and that L310P confers protection against UC in females.
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Affiliation(s)
- Zhenwu Lin
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA 17033, USA.
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Abstract
Crohn's disease and ulcerative colitis are chronic inflammatory disorders caused by a disruptive interaction between the immune system and gut luminal factors. Although the exact aetiology of IBD remains unclear, accumulating data, including genome-wide association studies (GWAS), have advanced our understanding of the immunopathogenesis. This review highlights the role in gut homeostasis and IBD pathogenesis. It focuses on past and recent advances in our understanding of IBD, including genetics and immunobiology. Recently published GWAS have confirmed earlier findings related to the NOD2 gene and the IBD5 locus. In addition, over 30 novel loci have been identified. Several promising associations between Crohn's disease and gene variants have been identified and replicated, the two most widely replicated being variants in the IL23R and ATG16L1 genes. These findings highlight and further support the importance of the immune system and its interactions with the intestinal flora in the pathogenesis of inflammatory bowel disease.
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Affiliation(s)
- Casper G Noomen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, C4-12 Leiden, the Netherlands.
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Tedde A, Laura Putignano A, Bagnoli S, Congregati C, Milla M, Sorbi S, Genuardi M, Papi L. Interleukin-10 promoter polymorphisms influence susceptibility to ulcerative colitis in a gender-specific manner. Scand J Gastroenterol 2008; 43:712-8. [PMID: 18569989 DOI: 10.1080/00365520701885507] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Pathological evidence supports a potential role of the pro- and anti-inflammatory cytokine network in the pathogenesis of inflammatory bowel disease (IBD). Moreover, associated studies suggest a possible involvement of cytokine-related genes in IBD susceptibility. In this study, we evaluated the effect of the anti-inflammatory interleukin-10 (IL10) gene on ulcerative colitis (UC). MATERIAL AND METHODS Two functional single nucleotide polymorphisms (-1082 G/A, -819 T/C) in the IL10 promoter in 203 Italian sporadic UC patients and 391 controls were determined using high-resolution melting analysis. RESULTS The frequency of the -1082A allele was significantly higher in the UC patients than in controls (p=0.00003); -1082 genotype frequencies were also significantly different between UC patients and controls (p=0.0001). Allele and genotype frequencies of -819 T/C were not significantly associated with UC. Furthermore, the frequencies of haplotypes -1082A/-819C and -1082A/-819T, which have been reported to have a lower promoter activity, were significantly higher in UC patients than in controls (p=0.0004). After gender stratification, we found a significant difference in the -1082A allele (p=0.00004) and genotype (p=0.0002) frequencies only between female UC patients and controls; the same result was obtained for the -1082A/-819C and -1082A/-819T haplotypes (p=0.0006). CONCLUSIONS A gender effect is observed, with women of AG/AA IL10 genotypes and AC/AT haplotypes having a higher risk of developing UC at a younger age. This finding could be related to the previously documented lower IL10 production associated with the -1082A allele and to the IL10 down-regulating effect of estrogens.
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Affiliation(s)
- Andrea Tedde
- Neurogenetics Unit, Department of Neurological and Psychiatric Sciences, University of Florence, Italy
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Lappalainen M, Halme L, Turunen U, Saavalainen P, Einarsdottir E, Färkkilä M, Kontula K, Paavola-Sakki P, Lanchbury JS, Merriman TR, Barclay ML, Kennedy MA. Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish population. Inflamm Bowel Dis 2008; 14:1118-24. [PMID: 18338763 DOI: 10.1002/ibd.20431] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Crohn's disease (CD) and ulcerative colitis (UC), 2 major forms of inflammatory bowel disease (IBD), are complex disorders with significant genetic predisposition. The first CD-associated gene, CARD15/NOD2, was recently identified and since then several reports on novel IBD candidate genes have emerged. We investigated disease phenotype association to genetic variations in IL23R, ATG16L1, DLG5, ABCB1/MDR1, TLR4, TNFRSF1A, chromosome 5 risk haplotype including SLC22A4 and SLC22A5, and HLA-DRB1*0103 allele among Finnish IBD patients. METHODS A total of 699 IBD patients were genotyped for disease-associated variants by polymerase chain reaction (PCR) and restriction enzyme digestion or Sequenom iPLEX method. RESULTS Five markers spanning the IL23R gene were associated with CD. The SNP (single nucleotide polymorphism) rs2201841 gave the strongest association (P = 0.002). The rare HLA-DRB1*0103 allele was found to associate with UC (P = 0.008), and the TNFRSF1A A36G variant was associated with familial UC (P = 0.007). Upon phenotypic analysis we detected association between familial UC and rare TNFRSF1A alleles 36G and IVS6+10G (P = 0.001 and P = 0.042, respectively). In addition, IL23R markers were associated with stricturing CD (P = 0.010-0.017), and ileocolonic CD was more prevalent in the carriers of the same 2 TNFRSF1A variants (P = 0.021 and P = 0.028, respectively). Less significant genotype-phenotype associations were observed for the TLR4 and HLA variants. CONCLUSIONS We were able to replicate the association of the IL23R variants with CD as well as HLA-DRB1*0103 with UC; confirmation of TNFRSF1A association with UC needs additional studies. Our findings also suggest that polymorphisms at IL23R and TNFRSF1A, and possibly HLA and TLR4, loci may account for phenotypic variation in IBD.
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Murphy AM, Meade KG, Hayes PA, Park SDE, Evans ACO, Lonergan P, MacHugh DE. Transmission ratio distortion at the growth hormone gene (GH1) in bovine preimplantation embryos: An in vitro culture-induced phenomenon? Mol Reprod Dev 2008; 75:715-22. [PMID: 17948248 DOI: 10.1002/mrd.20813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The growth hormone gene (GH1) and its polypeptide product (GH) have a crucial role in reproduction, embryogenesis and general development. A polymorphism present in the fifth exon of the bovine GH1 gene (GH1 p.Leu127Val) has been associated with GH release and milk production in cattle. The objective of the present study was to examine the genotype frequencies of the GH1 p.Leu127Val polymorphism in bovine blastocysts produced in vitro and in vivo to determine if allelic variation of the GH1 gene affects embryo development and survival. A heterozygous (p.Leu127/Val127) sire was used for in vitro fertilization of oocytes of unknown maternal genotype (n = 104) and known maternal genotype (n = 115). PCR amplification and genotyping of the GH1 gene from Day 8 blastocysts derived from these fertilized oocytes demonstrated that there was significant over-representation from the expected Mendelian ratio of GH1 p.Leu127/Leu127 homozygotes from oocytes of known maternal genotype (P = 0.006). Contrary to this, analysis of in vivo-produced bovine blastocysts of known parental GH1 genotype (n = 69) did not reveal an overrepresentation of GH1 p.Leu127/Leu127 homozygotes. These results suggest that developing in vitro-produced embryos are exposed to a selection process, probably due to a less favorable culture environment, that acts to increase the number of GH1 p.Leu127/Leu127 homozygotes, thereby giving rise to the observed transmission ratio distortion (TRD) of GH1 genotypes when compared to in vivo produced embryos.
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Affiliation(s)
- Angela M Murphy
- Animal Genomics Laboratory and Conway Institute for Biomolecular and Biomedical Research, School of Agriculture, Food Science and Veterinary Medicine, College of Life Sciences, University College Dublin, Belfield, Dublin 4, Ireland
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The Crohn's disease susceptibility gene DLG5 as a member of the CARD interaction network. J Mol Med (Berl) 2008; 86:423-32. [PMID: 18335190 DOI: 10.1007/s00109-008-0307-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2007] [Revised: 12/23/2007] [Accepted: 01/02/2008] [Indexed: 01/01/2023]
Abstract
Discs large homolog 5 (DLG5), a member of the membrane-associated guanylate kinase (MAGUK) family of scaffolding proteins, has been associated with Crohn's disease (CD), but its role in the pathogenesis of this inflammatory bowel disease is disputed. Here, we used sequence comparisons and phylogenies to analyse the DLG5 gene and its protein product. We identified a 5' exon, which codes for an N-terminal caspase recruitment domain (CARD) and experimentally confirmed its expression in colonic tissue. DLG5 shares this new domain with nucleotide-binding oligomerisation domain containing 2 (NOD2); the first CD susceptibility factor identified in genetic studies. An extensive phylogenetic analysis redefines the family organisation of the MAGUK proteins: DLG5 is closely related to CARD10, CARD11 and CARD14, CARD-containing proteins which initiate pro-inflammatory NFkappaB signalling, but not to DLG1-4, previously considered the closest related proteins. Therefore, we suggest renaming DLG5 to correctly annotate the gene in its phylogenetic and functional context. Our study provides evidence that the scaffolding protein DLG5 belongs to the CARD protein family. Thus, DLG5 likely acts in the regulation of NFkB activation or caspase activation as part of host defence mechanisms. As there is substantial crosstalk between CARD-mediated pathways, both CD susceptibility genes, NOD2 and DLG5, may interact functionally to contribute to CD risk.
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Abstract
Genome-wide association studies have firmly established that many genomic loci contribute to inflammatory bowel disease, especially in Crohn’s disease. These studies have newly-established the importance of the interleukin 23 and autophagy pathways in disease pathogenesis. Future challenges include: (1) the establishment of precisely causal alleles, (2) definition of altered functional outcomes of associated and causal alleles and (3) integration of genetic findings with environmental factors.
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Epidemiology, genes and inflammatory bowel diseases in childhood. Dig Liver Dis 2008; 40:3-11. [PMID: 17997369 DOI: 10.1016/j.dld.2007.07.165] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 07/26/2007] [Indexed: 12/11/2022]
Abstract
There is evidence that inflammatory bowel disease is immunologically mediated and that genetic factors play an important aetiological role. The identification of disease susceptibility genes has led to significant progress in our understanding of the pathogenesis of Crohn's disease. Genes linked to Crohn's disease play critical roles in the normal function of the innate immune system, and genes linked to epithelial integrity may play a role in the pathogenesis of inflammatory bowel disease as well. However, the dynamic epidemiology of both Crohn's disease and ulcerative colitis suggests that extrinsic environmental factors acting at the population level may be involved in their pathogenesis. These environmental factors may be responsible for the rising incidence of inflammatory bowel disease.
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Weersma RK, van Dullemen HM, van der Steege G, Nolte IM, Kleibeuker JH, Dijkstra G. Review article: Inflammatory bowel disease and genetics. Aliment Pharmacol Ther 2007; 26 Suppl 2:57-65. [PMID: 18081650 DOI: 10.1111/j.1365-2036.2007.03476.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Inflammatory bowel disease (IBD) comprising ulcerative colitis (UC) and Crohn's disease (CD) is multigenic disorder. Tremendous progress has been achieved in unravelling the genetic background of IBD. It has led to the discovery of mutations in NOD2 associated with ileal CD and numerous other genes have been found to be associated with IBD susceptibility. METHODS A review of the literature on the genetic background of IBD was performed. RESULTS It is only partially understood how mutations in NOD2 lead to CD. Mouse models, in vitro data and studies in humans offer conflicting data as regards whether there is a loss or gain of function of NOD2 in CD. Several additional genes have been identified of which only a few are currently being recognized as potential disease causing or disease modifying genes. Promising candidate genes include TLR4, MDR1, NOD1 (CARD4), DLG5 as well as the IBD5 locus including SLC22A4/5. CONCLUSIONS Although genetic research has not yet led to a better prediction of the disease course or patient selection for medical therapy, remarkable progress has been made in the understanding of the pathogenesis of IBD. For future genetic research, accurate phenotyping of patients is very important and large population-based cohorts are needed. Eventually, genetic research may be able to classify different disease phenotypes on a more detailed molecular basis and may provide important contributions in the development of new therapeutic approaches.
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Affiliation(s)
- R K Weersma
- Department of Gastroenterology and Hepatology, Section Medical Biology, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.
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Rodríguez-Bores L, Fonseca GC, Villeda MA, Yamamoto-Furusho JK. Novel genetic markers in inflammatory bowel disease. World J Gastroenterol 2007; 13:5560-70. [PMID: 17948929 PMCID: PMC4172734 DOI: 10.3748/wjg.v13.i42.5560] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Genetic factors play a significant role in determining inflammatory bowel disease (IBD) susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain (NOD2) and human leukocyte antigen (HLA) genes are the most extensively studied genetic regions (IBD1 and IBD3 respectively) in IBD. Mutations of the NOD2 gene are associated with Crohn's disease (CD) and several HLA genes are associated with ulcerative colitis (UC) and CD. Toll like receptors (TLRs) have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms (SNPs) in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD: NOD1/Caspase-activation recruitment domains 4 (CARD4), Chemokine ligand 20 (CCL20), IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.
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Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a clinically and, likely, genetically heterogeneous group of disorders. A recent report suggests that genetic variations in the TNFSF15 gene contribute to the susceptibility of IBD in both Japanese and Caucasian populations. The aim was to confirm the association between TNFSF15 high- and low-risk haplotypes and IBD in a Caucasian population. METHODS Five single-nucleotide polymorphisms (SNPs) that comprise the 2 common haplotypes were genotyped in 599 Caucasian patients with Crohn's disease (CD), 382 Caucasian patients with ulcerative colitis (UC), and 230 ethnically matched healthy controls, including both Jews and non-Jews. RESULTS The previously reported 'risk' haplotype was not associated with CD or UC (88.2% in CD cases versus 88.3% in controls, P = 0.96; 88.1% in UC cases versus 88.3% in controls, P = 0.78). We did, however, observe an increased frequency of the "protective" haplotype in non-Jewish controls for both CD and UC (38.8% CD cases versus 50% controls, P = 0.01; 37.3% UC cases versus 50% controls, P = 0.01) with no such effect observed in the Jewish samples. There was an interactive effect between ethnicity and the protective haplotype in CD (P = 0.04). CONCLUSIONS We observed a protective haplotype, consisting of the minor alleles for all 5 markers, to have a higher frequency in the non-Jewish controls than in CD and UC. Of further interest, the haplotype frequency was in the opposite direction in our Jewish case-control panels (both CD and UC), leading us to conclude 1) that TNFSF15 is indeed an IBD susceptibility gene, and 2) the disease susceptibility is ethnic-specific.
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Affiliation(s)
- Yoana Picornell
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Ling Mei
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Kent Taylor
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Huiying Yang
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
| | - Stephan R. Targan
- Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center Los Angeles, CA 90048
| | - Jerome I. Rotter
- Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048
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Bochud M, Chiolero A, Elston RC, Paccaud F. A cautionary note on the use of Mendelian randomization to infer causation in observational epidemiology. Int J Epidemiol 2007; 37:414-6; author reply 416-7. [PMID: 17881410 DOI: 10.1093/ije/dym186] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
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Browning BL, Huebner C, Petermann I, Demmers P, McCulloch A, Gearry RB, Barclay ML, Shelling AN, Ferguson LR. Association of DLG5 variants with inflammatory bowel disease in the New Zealand Caucasian population and meta-analysis of the DLG5 R30Q variant. Inflamm Bowel Dis 2007; 13:1069-76. [PMID: 17455201 DOI: 10.1002/ibd.20157] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Variants in the DLG5 gene have been associated with inflammatory bowel disease (IBD) in samples from some, but not all populations. In particular, 2 nonsynonymous single-nucleotide polymorphisms (SNPs), R30Q (rs1248696) and P1371Q (rs2289310), have been associated with an increased risk of IBD, and a common haplotype (called haplotype "A") has been associated with reduced risk. METHODS We genotyped R30Q, P1371Q, and a haplotype A tagging SNP (rs2289311) in a New Zealand Caucasian cohort of 389 Crohn's disease (CD) patients, 406 ulcerative colitis (UC) patients, and 416 population controls. Each SNP was tested for association with disease susceptibility and clinical phenotypes. We also performed a meta-analysis of R30Q data from published association studies. RESULTS The haplotype A tagging SNP was associated with reduced risk of IBD at the 0.05 significance level (P=0.036) with an allelic odds ratio of 0.83 (95% confidence interval [CI]: 0.69-0.99). Association with haplotype A was strongest (odds ratio approximately 0.57) in UC patients with familial IBD or extraintestinal manifestations. The R30Q and P1371Q polymorphisms were not significantly associated with UC, CD, or IBD. Analysis of male and female data did not find any gender-specific associations. Meta-analysis gave no evidence of association of R30Q with IBD. CONCLUSIONS Meta-analysis demonstrates that the minor allele of R30Q is not a risk factor for IBD across populations. This study provides some evidence that DLG5 haplotype A is associated with reduced risk of IBD in the New Zealand Caucasian population, but this association will need to be replicated in an independent sample.
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Affiliation(s)
- Brian L Browning
- Discipline of Nutrition, Department of Statistics, University of Auckland, New Zealand, and Department of Gastroenterology, Box Hill Hospital, Monash, Australia.
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de Ridder L, Weersma RK, Dijkstra G, van der Steege G, Benninga MA, Nolte IM, Taminiau JAJM, Hommes DW, Stokkers PCF. Genetic susceptibility has a more important role in pediatric-onset Crohn's disease than in adult-onset Crohn's disease. Inflamm Bowel Dis 2007; 13:1083-92. [PMID: 17476680 DOI: 10.1002/ibd.20171] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Genetic susceptibility may play a more important role in the etiology of early-onset inflammatory bowel disease (IBD) than in late-onset IBD, and therefore pediatric-onset IBD patients can be expected to have a higher frequency of gene mutations. We aimed to determine genotypes and phenotypes of patients with pediatric-onset IBD, to compare them with those of patients with adult-onset IBD and with controls, and to identify genotype-phenotype associations. METHODS Polymorphisms R702W, G908R, and 3020insC of CARD15 (caspase activating recruitment domain 15); Asp299Gly and Thr399Ile of TLR4; -207G-->C, 1672C-->T (L503F), rs3792876, rs274551, rs272893, and rs273900 of SLC22A4/5; and 113G-->A as well as rs2289311, rs1270912, and rs2165047 of DLG5 (Drosophila discs large homologue 5) were assessed in 103 pediatric-onset and 696 adult-onset IBD patients. Phenotypic classification was based on disease localization and behavior. RESULTS Homozygosity for 3020insC in CARD15 was significantly higher in patients with pediatric-onset Crohn's disease (CD) than in patients with adult-onset CD (4.2% versus 0.6%, 95% confidence interval [CI] 1.2-42.0). Homozygosity for single-nucleotide polymorphism (SNP) rs3792876 in SLC22A4/5 was significantly higher in patients with pediatric-onset CD than in patients with adult-onset CD (6.1% versus 1.1%, P=0.02). Polymorphism 3020insC in CARD15 was associated with ileal involvement (1.9% versus 13.3%, CI 1.0-53.8) and a positive family history (6.1% versus 20%, CI 1.2-9.0). DLG5 SNP rs2165047 was significantly associated with perianal disease (50% versus 21.2%, CI 1.4-4). CONCLUSIONS Polymorphisms 3020insC in CARD15 and SNP rs3792876 in SLC22A4/5 occurred statistically significantly more often in patients with pediatric-onset CD than in patients with adult-onset CD. Polymorphisms 3020insC in CARD15 and SNP rs2165047 in DLG5 were associated with specific phenotypes in this pediatric-onset CD cohort.
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Affiliation(s)
- Lissy de Ridder
- Department of Pediatric Gastroenterology, VU University Medical Center, and Department of Pediatric Gastroenterology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.
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Franke A, Hampe J, Rosenstiel P, Becker C, Wagner F, Häsler R, Little RD, Huse K, Ruether A, Balschun T, Wittig M, ElSharawy A, Mayr G, Albrecht M, Prescott NJ, Onnie CM, Fournier H, Keith T, Radelof U, Platzer M, Mathew CG, Stoll M, Krawczak M, Nürnberg P, Schreiber S. Systematic association mapping identifies NELL1 as a novel IBD disease gene. PLoS One 2007; 2:e691. [PMID: 17684544 PMCID: PMC1933598 DOI: 10.1371/journal.pone.0000691] [Citation(s) in RCA: 111] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2007] [Accepted: 06/20/2007] [Indexed: 12/14/2022] Open
Abstract
Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10(-6); OR = 1.66, 95% CI: 1.30-2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10(-6) for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).
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Affiliation(s)
- Andre Franke
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
| | - Jochen Hampe
- First Department of Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Philip Rosenstiel
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
| | - Christian Becker
- Cologne Center for Genomics, University of Cologne, Köln, Germany
- RZPD German Resource Center for Genome Research, Berlin, Germany
| | - Florian Wagner
- RZPD German Resource Center for Genome Research, Berlin, Germany
| | - Robert Häsler
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
| | | | - Klaus Huse
- Genome Analysis Group, Leibniz Institute for Age Research, Jena, Germany
| | - Andreas Ruether
- PopGen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
| | - Tobias Balschun
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
| | - Michael Wittig
- PopGen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
| | - Abdou ElSharawy
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
| | - Gabriele Mayr
- Max-Planck Institute for Informatics, Saarbrücken, Germany
| | - Mario Albrecht
- Max-Planck Institute for Informatics, Saarbrücken, Germany
| | - Natalie J. Prescott
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom
| | - Clive M. Onnie
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom
| | | | - Tim Keith
- Genizon BioSciences5, Québec, Canada
| | - Uwe Radelof
- RZPD German Resource Center for Genome Research, Berlin, Germany
| | - Matthias Platzer
- Genome Analysis Group, Leibniz Institute for Age Research, Jena, Germany
| | - Christopher G. Mathew
- Department of Medical and Molecular Genetics, King's College London School of Medicine, London, United Kingdom
| | - Monika Stoll
- Leibniz-Institute for Arteriosclerosis Research, University Münster, Münster, Germany
| | - Michael Krawczak
- PopGen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
- Institute of Medical Statistics and Informatics, Christian-Albrechts University Kiel, Kiel, Germany
| | - Peter Nürnberg
- Cologne Center for Genomics, University of Cologne, Köln, Germany
- Center for Molecular Medicine Cologne, University of Cologne, Köln, Germany
| | - Stefan Schreiber
- Institute for Clinical Molecular Biology, Christian-Albrechts University Kiel, Kiel, Germany
- First Department of Medicine, University Hospital Schleswig-Holstein, Kiel, Germany
- PopGen Biobank, Christian-Albrechts University Kiel, Kiel, Germany
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Latella G, Fiocchi C, Caprilli R. Late-breaking news from the "4th International Meeting on Inflammatory Bowel Diseases" Capri, 2006. Inflamm Bowel Dis 2007; 13:1031-50. [PMID: 17309072 DOI: 10.1002/ibd.20127] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
At the "4th International Meeting on Inflammatory Bowel Diseases: on the Way to New Therapies," Capri, 2006, genetics, bacteria-host interactions, immunomodulation, and tissue response were discussed deeply in order to understand, rationalize, and develop novel therapies. About genetics, the importance of a better understanding of the nature of known loci and of the putative associations was stressed. It was confirmed that genotype-phenotype associations in inflammatory bowel disease (IBD) have important clinical and therapeutic implications. The importance of the search for dominant bacterial antigens in chronic immune-mediated intestinal inflammation emerged, as well as knowledge of cellular and molecular mechanisms of bacterial-host interactions. It was discussed how innate and adaptive immunity signaling events can perpetuate chronic inflammation. Signal transduction pathways provide an intracellular mechanism by which cells respond and adapt to environmental stress. The identification of these signals have led to a greater understanding of the pathogenesis of IBD and pointed to potential therapeutic targets. It was shown that immune homeostasis is lost in IBD, resulting in a complex tissue response involving the action of immune and nonimmune cells. The nonimmune tissue response in IBD could be regarded as a new target for control of chronic intestinal inflammation. The changing role of biotherapy in IBD was widely discussed and in particular the anti-TNF-alpha monoclonal antibodies. Granulocyte-colony stimulating factor (GM-CSF) and stem cells therapies were also discussed. The risk-to-benefit ratio of the novel therapies was analyzed in detail. Finally, future directions for basic science and the unmet needs for clinical practice were presented.
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Affiliation(s)
- Giovanni Latella
- Department of Internal Medicine, GI Unit, University of L'Aquila, L'Aquila, Italy
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Abstract
A modern approach to inflammatory bowel disease (IBD) research has been under way for little over one-half century, but only during the last two decades has progress accelerated and finally generated tangible results that have been translated into practical and better therapeutic strategies. The areas where progress has been more evident are those currently believed to be the key components of IBD pathogenesis, and include the environment, genetics, enteric microbiology, and immune reactivity. Progress in these different areas has been somewhat uneven, yielding a better understanding of the mechanisms behind gut inflammation and tissue injury rather than of specific etiological agents or predisposing factors. However, with the rapidly increasing utilization of novel methodological approaches like genetics, genomics, proteomics, and pharmacogenomics, it is reasonable to anticipate that the etiopathogenesis of IBD will be unveiled in the next couple of decades and more definitive, perhaps disease-modifying, approaches will be uncovered and implemented.
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Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
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Annese V, Latiano A, Palmieri O, Andriulli A. Dissecting genetic predisposition to inflammatory bowel disease: current progress and prospective application. Expert Rev Clin Immunol 2007; 3:287-298. [PMID: 20477673 DOI: 10.1586/1744666x.3.3.287] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Over the last 10 years, sensitive advancement has been made in the study of genetic susceptibility to inflammatory bowel disease (IBD). Complementary methodologies of linkage, fine-mapping and candidate-gene studies have led to the identification of a number of susceptibility genes and loci, including caspase activation and recruitment domain 15 (CARD15), major histocompatibility complex (MHC) and IBD5, whereas many other genes (nucleotide oligomerization domain 1 [NOD1], tumor-upregulated CARD-containing antagonist of caspase-9 [TUCAN], Toll-like receptors [TLR], interleukin 23 receptor [IL23R], multidrug resistance 1 [MDR1], myosin IXb [MYO9B], chemokine [C-Cmotif] ligand 20 [CCL20], human beta-defensin 2 [HBD-2], autophagy-related 16-like 1 [ATG16L1]) are still awaiting confirmation. The CARD15 gene is currently the most widely replicated and investigated gene. The exact sequence of events that link CARD15 variants to early pathogenetic changes is unknown. However, the role of the encoded protein confirms the relevance of appropriate responses by the innate immune system to intestinal bacteria, including the production of antimicrobial peptides (defensins). With the implementation of new genomics and proteomics methodologies, genetic research will advance our further understanding of the clinical heterogeneity of IBD and tackle the complex interactions between genetic and environmental risk factors.
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Affiliation(s)
- Vito Annese
- Unità e Laboratorio di Gastroenterologia ed Endoscopia, Ospedale I.R.C.C.S 'Casa Sollievo della Sofferenza', Viale Cappuccini, 1-71013 San Giovanni Rotondo (Fg), Italy.
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Van Limbergen J, Russell RK, Nimmo ER, Ho GT, Arnott ID, Wilson DC, Satsangi J. Genetics of the innate immune response in inflammatory bowel disease. Inflamm Bowel Dis 2007; 13:338-55. [PMID: 17206667 DOI: 10.1002/ibd.20096] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.
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Affiliation(s)
- Johan Van Limbergen
- Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, UK.
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Russell RK, Drummond HE, Nimmo ER, Anderson N, Wilson DC, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset WM, Mahdi G, Satsangi J. The contribution of the DLG5 113A variant in early-onset inflammatory bowel disease. J Pediatr 2007; 150:268-73. [PMID: 17307543 DOI: 10.1016/j.jpeds.2006.12.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 10/04/2006] [Accepted: 12/07/2006] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To assess the contribution of the 113 G-->A missense mutation within the discs, large homolog 5 (DLG5) gene in childhood-onset inflammatory bowel disease (IBD) in Scotland. STUDY DESIGN Two-hundred and ninety-six children with IBD were studied. Parental DNA was also collected for transmission disequilibrium testing (TDT) analysis. Genotyping was performed by TaqMan. Genotype-phenotype analysis was also undertaken. Socioeconomic status was assigned using a deprivation category (DepCat) score 1 through 7 (1 = most affluent). RESULTS TDT analysis demonstrated a significant association with IBD (P = .045). On unifactorial analysis, 113A carriage was associated with: (1) higher social class (DepCat 1 compared with 2-7, and 1-2 compared with 3-7) (66.7% vs 22.6%, P = .0005, OR 6.84 [1.99-23.55] and 37.2% vs 22.2%, P = .03, OR 2.08 [1.04-4.17], respectively); (2) higher height centile (>75th centile vs <75th centile) (42.9% vs 23.1%, P = .01, OR 2.50 [1.18-5.28]); and (3) male sex in Crohn's disease (CD) (29.3% vs 16.9%, P = .04, OR 2.04 [1.01-4.11]). Multifactorial analysis demonstrated that higher social class (DepCat 1) was independently associated with carriage of variants of 113A (P = .001, OR = 6.92 [2.24-21.33]). CONCLUSIONS DLG5 113A is associated with increased susceptibility to IBD in Scottish children. The effect may be most marked for those children living in relative affluence.
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Affiliation(s)
- R K Russell
- Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, United Kingdom.
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Cucchiara S, Latiano A, Palmieri O, Staiano AM, D'Incà R, Guariso G, Vieni G, Rutigliano V, Borrelli O, Valvano MR, Annese V. Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases. World J Gastroenterol 2007; 13:1221-1229. [PMID: 17451203 PMCID: PMC4146997 DOI: 10.3748/wjg.v13.i8.1221] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2006] [Revised: 12/01/2006] [Accepted: 01/12/2007] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric onset of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.
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Affiliation(s)
- S Cucchiara
- Clinica Pediatrica, Università L Sapienza, Roma, Italy
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Biank V, Friedrichs F, Babusukumar U, Wang T, Stoll M, Broeckel U, Kugathasan S. DLG5 R30Q variant is a female-specific protective factor in pediatric onset Crohn's disease. Am J Gastroenterol 2007; 102:391-8. [PMID: 17156146 DOI: 10.1111/j.1572-0241.2006.01011.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohn's disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort. DESIGN A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene-gene and gene-gender interactions, as well as genotype-phenotype correlations. RESULTS Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55-1.20, P= 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2-0.77, P= 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5. CONCLUSIONS DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.
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Affiliation(s)
- Vincent Biank
- Department of Pediatrics, Medical College Wisconsin, Milwaukee, Wisconsin 53226, USA
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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Török HP, Glas J, Lohse P, Folwaczny C. Genetic variants and the risk of Crohn's disease: what does it mean for future disease management? Expert Opin Pharmacother 2006; 7:1591-602. [PMID: 16872262 DOI: 10.1517/14656566.7.12.1591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Genetic research in inflammatory bowel disease, especially in Crohn's disease, has made significant progress during recent years. There have been > 10 total genome scans that have been performed, and susceptibility loci on several chromosomes have been identified. Together with candidate gene studies, these scans have led to the identification of several susceptibility genes, with CARD15 being the most important. These genetic data have already provided important insights into the pathophysiology of inflammatory bowel disease and are stimulating future research. On the other hand, genotype-phenotype associations have illustrated the heterogenic nature of the disease. Although the clinical application of this knowledge is so far limited, there is significant optimism that an individual management of patients based on genetic data will be possible in the near future.
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Affiliation(s)
- Helga-Paula Török
- Department of Surgery Innenstadt, Ludwig-Maximilians University, Nussbaumstrasse 20, D-80336 Munich, Germany.
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Abstract
Inflammatory bowel disease (IBD) is a complex disease, controlled by multiple risk factors that evolve and interact together. In a genetically susceptible host, there are multiple processing steps controlled by the host and the environment, from environmental exposure to the clinical and biological expression of IBD-related phenotypes. This article discusses the recent genetic discoveries, along with the proposed environmental risk factors that have been implicated in IBD. Technical advances of the HapMap project and the promise of whole genome association scans have given hopes for clarifying gene-environmental interactions in IBD that ultimately lead to a clearer understanding of the pathogenesis.
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Affiliation(s)
- Subra Kugathasan
- Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Evans DM, Morris AP, Cardon LR, Sham PC. A note on the power to detect transmission distortion in parent-child trios via the transmission disequilibrium test. Behav Genet 2006; 36:947-50. [PMID: 16804748 DOI: 10.1007/s10519-006-9087-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2006] [Accepted: 05/19/2006] [Indexed: 10/24/2022]
Abstract
Transmission distortion refers to deviation from the normal 50:50 transmission of alleles from parents to offspring. Identification of genomic regions which undergo distortion is necessary for the correct interpretation of linkage and association studies, since tests of linkage using affected relative pairs and family based tests of association will yield spurious results in the presence of transmission distortion. With the increasing availability of genome-wide high density SNP data (e.g. from the International HapMap project), identification of these loci is now a real possibility. Here we present an analytical formula which demonstrates that the power to detect transmission distortion is a simple function of the number of heterozygous parents in the sample and the level of distortion at the locus. Our results indicate that whilst it will be possible to identify loci undergoing major levels of distortion using tens or hundreds of trios, large sample sizes in the order of tens of thousands of trios will be necessary to detect minor levels of distortion with appreciable power. The corollary is that genome-wide searches are unlikely to identify loci where the level of distortion is small, although they may serve to identify interesting regions worthy of follow up.
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Affiliation(s)
- D M Evans
- Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
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