Revisiting HLA-DQA1*05 in Asian inflammatory bowel disease cohorts: Ethnic variations in genetic susceptibility to immunogenicity

Abstract

We read with great interest the article by Weng et al, wherein the authors investigated human leukocyte antigen (HLA) alleles linked to anti-drug antibody (ADA) formation in Taiwanese patients with inflammatory bowel disease. They reported that HLA-DQA1*05, a major risk allele in European cohorts, demonstrated no association with ADA development in Taiwanese patients. Instead, novel alleles emerge: HLA-C*03:04:01 correlating strongly with anti-infliximab ADAs and HLA-B*15:18:01 with anti-adalimumab ADAs. However, this finding contrasts with evidence from large cohort studies, wherein HLA-DQA1*05 consistently predicted ADA formation, particularly for infliximab. This letter aimed to contextualize these findings within the broader literature and to lay the ground for further analysis of ethnic variations and the implications for personalized medicine in inflammatory bowel disease. This divergence may suggest how genetic architecture shapes immunogenicity risk across ethnicities.

Key Words: Inflammatory bowel disease; Anti-tumor necrosis factor therapy; Anti-drug antibodies; Human leukocyte antigen genotype; Ethnic variation

Core Tip: This letter builds upon Weng et al’s study in Taiwan that incorporated comparative evidence from Asia and Europe toward the investigation of racial disparities in human leukocyte antigen (HLA)-related immunogenicity of anti-tumor necrosis factor therapy. Although Weng et al did not identify an association between HLA-DQA1*05 and the development of anti-drug antibody against infliximab and adalimumab, other larger-scale studies across Chinese and European cohorts demonstrated a significant correlation between HLA-DQA1*05 and anti-drug antibody formation, particularly with infliximab, highlighting the genetic diversity within Asia. The novel alleles reported by Weng et al warrant further validation. Until further comprehensive, large-scale racial cohort data becomes available, clinicians should prioritize therapeutic drug monitoring and individualized treatment approaches. Furthermore, HLA allele screening for inflammatory bowel disease treatment decisions requires support from larger, genetically diverse cohort studies.

TO THE EDITOR

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis, impose a growing global burden, with East Asia experiencing the fastest annual incidence increase in IBD. Moreover, the existing epidemiological data suggest variation in the disease incidence rate in different regions[1,2]. Biological therapies, particularly those involving anti-tumor necrosis factor (TNF) agents such as infliximab and adalimumab, remain the cornerstone treatments for moderate-to-severe IBD[3]. However, immunogenicity, which is manifested as anti-drug antibodies (ADAs), compromises efficacy in up to 60% of the patients, contributing to secondary treatment failure[4]. Genetic factors, particularly human leukocyte antigen (HLA) alleles, play a key role in ADA development. Although European studies have highlighted HLA-DQA1*05 as a key genetic risk factor for ADA formation[5], its generalizability to non-European populations remains uncertain.

MAIN FINDINGS OF THIS STUDY

Ethnic-specific HLA associations challenge the existing models

The multicenter study of Weng et al[6] conducted in Taiwan (n = 95 IBD patients, including 58 receiving anti-TNF therapy: 38 infliximab, 20 adalimumab) and found no significant association between HLA-DQA1*05 and ADA formation (P > 0.05). Instead, novel alleles have emerged, namely, HLA-C*03:04:01 that correlate strongly with anti-infliximab ADAs (31.6% vs 0%, P = 0.02) and HLA-B*15:18:01 with anti-adalimumab ADAs (66.7% vs 0%, P = 0.016). These novel associations suggest potential ethnicity-specific mechanisms in Taiwanese patients. However, the small sample size enrolled in this study may limit the statistical power to detect associations for HLA-DQA1*05, which has a minor allele frequency of approximately 40% in Europeans, but may vary in Asians.

In contrast, three large studies from mainland China demonstrated a strong association between HLA-DQA1*05 and ADA formation in CD patients treated with infliximab: (1) Wang et al[7] studied 345 infliximab-exposed CD patients and reported that HLA-DQA1*05 carriage significantly increased the risk of ADA development [adjusted hazard ratio (HR) = 1.65, 95% confidence interval (CI): 1.18-2.30, P = 0.003] and the loss of response (HR = 2.55, 95%CI: 1.78-3.68, P < 0.0001); (2) Zhu et al[8] included 104 CD patients and reported that HLA-DQA1*05 variant carriers had a higher frequency of ADA formation (71.05% vs 43.94%, odds ratio = 2.94, P = 0.01); and (3) Wu et al[9] analyzed 106 CD patients with isolated small-bowel disease and confirmed that HLA-DQA1*05 carriage increased the risk of antibodies generation to infliximab (odds ratio = 2.337, P = 0.043). These studies, with sample sizes ranging from 104 to 345, provide relatively robust evidence suggesting that HLA-DQA1*05 is a relevant risk factor in Chinese CD patients, contradicting Weng et al’s findings[6]. Furthermore, this discrepancy may stem from the ethnic substructure within Asia, variations in study design (e.g., concomitant immunomodulator use was 83.2% in Weng et al’s cohort[6], potentially masking effects), or sample size limitations. European evidence from the recent PANTS extension study provides critical insights from a large European cohort[10]. This prospective study followed anti-TNF-naive CD patients for 3 years and found an association between the carriage of HLA-DQA1*05 risk variant with an increased risk of developing ADAs, leading to undetectable drug concentrations for infliximab (HR = 1.46, 95%CI: 1.13-1.88), but not for adalimumab (HR = 1.60, 95%CI: 0.92-2.77). The study also reported that the concomitant use of immunomodulators mitigated this risk for both drugs, emphasizing the importance of combination therapy. Notably, only about one-third of the patients were in remission after 3 years, and low drug concentrations at induction predicted the loss of response, supporting the use of therapeutic drug monitoring.

Mechanistic insights and clinical relevance

Weng et al[6] demonstrated a negative correlation between ADA titers and serum drug levels (r = -0.446 for infliximab, r = -0.455 for adalimumab), reinforcing ADA’s role in accelerating drug clearance. This finding aligns with the global evidence that therapeutic drug monitoring optimizes the dosing[11,12]. However, the newly identified alleles (HLA-C*03:04:01 and HLA-B*15:18:01) lack external validation. Their specific mechanistic roles in the context of IBD also warrant further investigation. Moreover, HLA-C*03:04:01 has been linked to autoimmune diseases such as myasthenia gravis[13], and HLA-B*15:18:01 has been associated with drug-induced liver injury[14].

Clinically, the conflicting evidence across Asia and Europe suggests that genetic risk stratification must be ethnicity- and drug-specific. In mainland China, HLA-DQA1*05 screening may identify infliximab-treated patients with a high risk for immunogenicity, whereas in Taiwan, other alleles may be more relevant. Considering the current uncertainty, routine HLA screening in Asian populations is premature.

LIMITATIONS AND FUTURE DIRECTIONS

The study by Weng et al[6] has several limitations that warrant careful consideration. First, the small sample size, particularly the subgroup of only 38 infliximab-treated patients and 20 adalimumab-treated patients, undermines the statistical power to detect associations for HLA-DQA1*05. Second, cohort heterogeneity, arising from the inclusion of both Crohn’s disease and ulcerative colitis patients alongside high immunomodulator usage, may confound the results by introducing uncontrolled variables. In addition, methodological differences exist; for example, they only detected free antibodies using a free ADA enzyme-linked immunosorbent assay, which failed to detect antibodies bound to the drug. Therefore, some ADAs could have gone undetected, potentially leading to an underestimation of immunogenicity, affecting the interpretation of genetic risk.

Looking ahead, future research should prioritize several key directions. Conducting the study in large, multi-center Asian cohorts is essential to validate HLA associations and enhance the generalizability. Exploring gene-environment interactions and the impact of concomitant medications on ADA formation could uncover modifiable risk factors. Finally, integrating pharmacogenetic data with therapeutic drug monitoring may facilitate the development of personalized dosing algorithms, optimizing long-term outcomes for patients undergoing anti-TNF therapy.

CONCLUSION

Weng et al[6] contributes to the growing literature on HLA variations in immunogenicity, albeit cautious interpretation is essential. Evidence from mainland China and Europe confirms that HLA-DQA1*05 remains a significant risk factor for infliximab immunogenicity in several populations, highlighting the genetic heterogeneity within Asia. For clinicians, therapeutic drug monitoring should be used as a universal tool for monitoring anti-TNF therapy until more ethnically diverse data becomes available. In regions such as mainland China, HLA-DQA1*05 testing may provide a reference value for infliximab treatment, albeit further research is needed on local alleles in Taiwan. New alleles should be validated in independent cohorts, and genetic risk models should be integrated with therapeutic drug monitoring to enable personalized therapy. In summary, the genetic susceptibility to immunogenicity is complex and influenced by factors such as the population, drug type, and local variables. To develop individualized treatment strategies for patients with IBD, larger cohort studies with diverse genetic backgrounds are needed.