Human leukocyte antigen variants and clinical features of primary biliary cholangitis: Cumulative contributions

Abstract

This letter to the editor highlights the importance of considering potential cumulative contributions among human leukocyte antigen (HLA) alleles in shaping the clinical manifestations of primary biliary cholangitis. Complementing the overview by Curto et al, which focused on non-HLA candidate genes, this paper emphasizes that specific haplotypes of HLA-DRB1, HLA-DQA1, and HLA-DQB1, as well as HLA-G*01:01:01:08/UTR-1, may modulate disease heterogeneity, predisposition to primary biliary cholangitis and autoimmune hepatitis overlap syndrome, disease progression, and poorer therapeutic response. A comprehensive understanding of these HLA polymorphisms and their interactive effects is essential for improving risk stratification and guiding personalized management of this complex autoimmune liver disease.

Key Words: Human leukocyte antigen class II; Human leukocyte antigen-G; Primary biliary cholangitis; Prognosis; Primary biliary cholangitis-autoimmune hepatitis overlap syndrome; Therapy response

Core Tip: Specific classical human leukocyte antigen (HLA) alleles and haplotypes may influence predisposition to primary biliary cholangitis (PBC), prognosis, and the development of PBC-autoimmune hepatitis overlap syndrome. Potential cumulative contributions between the non-classical HLA-G*01:01:01:08-UTR-1 haplotype and its soluble HLA-G molecules may predict a poor therapeutic response to ursodeoxycholic acid. Thus, soluble HLA-G molecules may serve as novel, non-invasive biomarkers to guide personalized PBC treatment.

TO THE EDITOR

Primary biliary cholangitis (PBC) is a chronic autoimmune (AI) liver disorder characterized by progressive intrahepatic bile duct damage and high titers of autoantibodies against mitochondrial components (AMAs). These autoantibodies are mainly directed against the immunodominant pyruvate dehydrogenase complex E2 subunit autoantigen. Immunoregulatory genes play a crucial role in PBC predisposition, as indicated by their high prevalence in relatives of affected patients. Among these, human leukocyte antigen (HLA) genes represent the primary genetic risk factor for PBC[1-4]. More recently, Curto et al[5] focused primarily on non-HLA candidate genes related to PBC. Because HLA presentation of the ubiquitous mitochondrial antigen is essential for AMA production and T-cell activation[6,7], HLA polymorphisms can modulate PBC susceptibility, clinical outcomes, and therapeutic responses. This paper highlights the cumulative contributions of HLA genes in influencing the susceptibility and outcome of PBC.

The relevance of HLA in PBC susceptibility has been reinforced by genome-wide association studies in populations of different backgrounds. These findings established that the HLA class II region remains the most significant immunogenetic determinant influencing PBC predisposition[1-4]. Notably, a recent meta-analysis of genome-wide association studies provides strong evidence that four HLA class II alleles, including HLA-DRB1*08, HLA-DRB1*08:03, HLA-DRB1*11:01, and HLA-DQB1*03:01, are associated with PBC[2].

The PBC-autoimmune hepatitis (PBC-AIH) overlap syndrome is a primary autoimmune liver disorder that shares pathogenic features of both conditions. Liver biopsy is indicated in the absence of AMA or when there is suspicion of PBC-AIH overlap[8]. Genetic susceptibility in PBC-AIH has been explored through HLA association studies, although evidence supporting PBC-AIH as a distinct genetic entity remains limited. High-resolution HLA typing and imputation methods in a large Japanese cohort identified specific class II haplotypes, notably HLA-DRB1*04:05:01-DQA1*03:03:01-DQB1*04:01:01 and HLA-DRB1*04:05:01-DQB1*04:01:01[9]. In contrast, a cross-sectional study from Germany involving 20 individuals with PBC-AIH overlap reported associations with HLA-DR3 and HLA-DR4, although HLA data were reported only at the antigen level using serological typing[10]. Similarly, a Mexican case-control study including 26 AIH patients, 15 overlap syndrome patients, and 99 healthy controls employed low-resolution polymerase chain reaction (PCR)-sequence-specific primer typing and identified a significant association with HLA-DRB1*07[11]. Collectively, these studies indicate that HLA polymorphisms contribute to shared or partially overlapping immunopathogenic mechanisms in PBC-AIH overlap. The observed heterogeneity across cohorts likely reflects differences in disease definitions and diagnostic criteria, population-specific HLA frequencies, methodological disparities, limited statistical power, and reliance on low-resolution or serological typing rather than high-resolution genotyping. These findings emphasize the need for high-resolution, population-specific genetic analyses to precisely define the immunogenetic contributions to PBC-AIH overlap. Moreover, they extend the conclusions of Curto et al[5], who focused on non-HLA candidate genes, by demonstrating the central role of HLA polymorphisms in modulating both disease susceptibility and progression.

PBC can progress to complications of end-stage liver disease, such as fibrosis and cirrhosis, if under-treated or untreated[12]. Assessment of disease severity and risk stratification is primarily based on biochemical markers, response to treatment, and liver imaging[12-14]. Furthermore, 5% of PBC patients are AMA-negative and exhibit a poorer prognosis compared to AMA-positive patients[15]. A case-control study conducted in the United Kingdom included 164 Northern European Caucasoid PBC patients and 102 healthy controls[16]. Using PCR-sequence-specific oligonucleotide typing, the study reported a significant association between the HLA-DRB1*08:01-DQA1*04:01-DQB1*04:02 haplotype and late-stage PBC as compared to early-stage disease[16]. These findings suggest that this haplotype influences disease progression rather than susceptibility, potentially explaining why some patients advance to end-stage liver disease, and highlighting the potential of HLA haplotypes to complement conventional risk markers. However, the study is limited by weak, progression-specific HLA associations driven predominantly by advanced cases, imperfect histological staging, referral and case-mix bias, low-resolution HLA typing, and its cross-sectional design.

Treatment of PBC mainly relies on ursodeoxycholic acid (UDCA)[17]. However, a substantial proportion of patients exhibit a suboptimal response. Several factors have been associated with poor UDCA response, including cirrhosis at diagnosis and elevated baseline alkaline phosphatase and γ-glutamyl transferase levels[18]. Recently, Miglianti et al[19] reported that non-classical HLA-G polymorphisms are significantly associated with poor UDCA response in PBC. Specifically, the HLA-G*01:01:01:08/UTR-1 haplotype is associated with the lowest levels of soluble HLA-G (sHLA-G) and poorer therapy outcomes[19]. These findings suggest that sHLA-G may serve as a novel, non-invasive biomarker for predicting suboptimal UDCA response in PBC. However, this preliminary observation requires validation in larger, ethnically diverse cohorts to confirm its clinical utility.

In conclusion, specific classical HLA haplotypes may influence PBC prognosis and the development of PBC-AIH overlap syndrome. Furthermore, the HLA-G gene and its sHLA-G molecules are associated with poor therapeutic response. Both classical HLA class II alleles and haplotypes, as well as sHLA-G molecules, may serve as novel non-invasive biomarkers to aid in risk stratification and guide personalized PBC therapy. Several critical steps are required before clinical implementation: (1) Standardization of sHLA-G assays across laboratories, given current inter-laboratory variability; (2) Validation of the HLA-G*01:01:01:08/UTR-1 haplotype associations in large, multi-ethnic prospective cohorts; (3) Demonstration that HLA-G biomarkers provide incremental value beyond established risk scores such as Global Primary Biliary Cholangitis Group Score and United Kingdom-Primary Biliary Cholangitis Score; and (4) Development of cost-effective algorithms integrating HLA markers with conventional predictors. Research on non-invasive biomarkers predicting poor response to UDCA remains limited, and HLA-G represents a promising but unvalidated candidate that requires rigorous assessment before clinical translation.