Association of HLA-B and HLA-DR gene polymorphisms with rheumatoid arthritis: A cross-sectional study in Yunnan Chinese Han population

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease characterized by symmetrical polyarthritis and systemic complications involving the lungs, vasculature, and other organs mediated by cytokines, immune complexes, and autoantibodies.^[1,2] It affects 0.5% to 1% of the global adult population, with an incidence ranging from 0.18% to 1.07% across different demographics and a female-to-male ratio of approximately 3: 1.^[3,4] The etiology of RA is unclear, but its pathogenesis is likely driven by a complex interplay of genetic, immunological, and environmental factors, leading to significant clinical and prognostic heterogeneity.^[5,6] Studies show that HLA-DRB1*04 and *10 are more frequent in RA patients than controls, while HLA-DRB1*14 is less frequent in RA patients.^[7]

HLA-DRB1*04:05:01, DRB1*10:01:01, DQB1*04:01:01, and DPB1*02:01:02 alleles have been identified as RA risk alleles in Chinese Han patients, with specific haplotypes like HLA-DRB1*04:05:01 ~ DQB1*04:01:01 also present.^[8] Additionally, the HLA-DRB1*04 allele is associated with anti-citrullinated protein antibody (ACPA)-positive RA in Malaysian Chinese individuals.^[9] These findings suggest that relying solely on data from one Han subgroup can significantly underestimate the genetic heterogeneity of RA risk factors. Research on HLA polymorphisms in Nanning City, Guangxi Province, revealed that the local Han population has a closer genetic relationship with the Zhuang population than with northern Han populations, likely due to historical migration, environmental selection, and varying degrees of ethnic integration.^[10] Yunnan Province is a prime example of China’s ethnic diversity, situated at the core of a multi-ethnic convergence zone in southwest China. Since the Nanzhao Kingdom era, Yunnan’s Han population has extensively interacted with local ethnic groups, exchanged genetic material with Southeast Asian border communities, and coexisted with over 50 ethnic minorities. This complex ethnic blending suggests that Yunnan’s Han people may have unique genetic imprints, including gene traces from neighboring minorities like the Miao and Hani.^[11] These insights highlight the importance of detailed genetic research on Yunnan’s Han population and offer a unique model for analyzing the evolutionary trajectory of HLA molecules in cross-ethnic antigen responses.

Consequently, this study focuses on the Han population in Yunnan, China, systematically analyzing the association between HLA-B and HLA-DR gene co-polymorphisms and susceptibility to RA through a cross-sectional design for the first time. We hypothesize that there exists a specific relationship between the pathogenesis of RA in patients of the Yunnan Han nationality and HLA-B/DRB1. This relationship not only encompasses common susceptible genotypes found in RA patients but also includes unique genotypes. The objective is to elucidate the unique genetic risk profile of this population, provide region-specific data support for accurate typing and personalized treatment of RA, and establish critical benchmarks for assessing genetic risk related to RA among cross-border ethnic groups in Southeast Asia, such as Kokang in Myanmar and Daiyi in Vietnam.

Patients and Methods

This study utilized a retrospective cross-sectional research design to include patients of Yunnan Han nationality diagnosed with RA who were admitted to the Department of Rheumatology and Immunology at the First Affiliated Hospital of Kunming Medical University between June 2017 and December 2018. Health controls (HCs) were recruited from the Health Management Center. All participants fulfilled the criteria related to regional genetic background, specifically having three generations of direct relatives belonging to the Han nationality. The ethical review was conducted in accordance with the principles set forth in the ‘Helsinki Declaration’. Furthermore, the research protocol received approval from the Ethics Committee of the First Affiliated Hospital of Kunming Medical University. All participants provided written informed consent.

Result

Discussion

In this study, we found that the proportion of women among Han RA patients in Yunnan was significantly higher, consistent with global trends showing increased female susceptibility to RA.^[5] The female-to-male ratio in our sample was similar to the prevalence in China.^[14] This higher prevalence in women may reflect regional differences or sample selection biases. The higher incidence of RA in females is likely due to interactions between X-linked chromosomes and hormonal factors, as seen in other autoimmune diseases.^[15]

In our study, we identified risk associations with HLA-DRB1*04:05:01, *04:10:01, and *10:01:02 alleles in Yunnan Han Chinese RA patients. These alleles are all SE-encoded variants.^[16] Our findings are consistent with previous studies on RA patients from East China Han,^[8] Northern Han,^[17] and other East Asian regions ^[8] confirming the universality of the SE hypothesis across different ethnic groups. They also suggest that Yunnan Han RA patients share genetic features with the Han population in eastern China. However, unlike the DRB1*04:01/*04:04-dominant model in Caucasian populations.^[9,18] Our results show that the frequency of certain SE-encoding alleles varies among different populations.

HLA-DRB1*07:01:01, *14:01:01, and *15:01:01 alleles have been identified as protective against RA in the Yunnan Han population. The protective efects of HLA-DRB1*07:01 and *14:01 align with findings from Asian meta-analyses, while results for *15:01 show heterogeneity.^[19] Additionally, the impact of DRB1*14 on RA susceptibility is inconsistent across studies. Although it is associated with severe RA in South India,^[20] recent research suggests that DRB1*14 and *15 may protect against RA in Northeast India.^[21] However, these Indian studies did not distinguish between subtypes, highlighting the need for further research across diverse populations to clarify the specific roles of DRB1*14 and *15 subtypes in RA susceptibility.

There are limited studies investigating the association between HLA class I genes and susceptibility to RA, with significant correlations identified specifically for HLA-B.^[22] Previous research has indicated that a single nucleotide polymorphism (SNP) in the HLA-B locus, located at amino acid position 9 within the peptide binding groove, is associated with RA.^[23] In this study, we report for the first time that alleles HLA-B*40:01:01G, *40:02:01G, *15:01:01G, and *54:01:01G are susceptible genes for RA in the Yunnan Han population. Conversely, alleles HLA-B*15:01:01, *15:02:01, and *38:02:01 have been identified as protective genes against RA.

Notably, this study identified that the haplotypes HLA-B*38:02/DRB1*08:03, B*15:01/DRB1* 09:01 and HLA-B*54:01/DRB1*04:05 exhibited weak protective factors within the Yunnan Han RA population. The influence of HLA-DRB1*08:03 on RA susceptibility appears to be neutral; however, the protective effect associated with HLA-B*38:02/DRB1*08:03 may be contingent upon the specific genotype of HLA-B* 38: 02. Interestingly, while genotypes such as HLA-B*15:01, HLA-B*54:01, and HLA-DRB1*04:05 are recognized as risk factors for RA, their combination into haplotypes demonstrates a protective effect. This suggests that RA susceptibility is not solely dictated by individual HLA genotypes. There are limited studies on this cross-category (I/II) haplotype, and the findings have been inconsistent. The haplotypes mentioned above have been identified in the Han population for the first time, potentially reflecting unique genetic recombination events occurring in Yunnan. However, it is important to emphasize that, in addition to the interactions between HLA class I and II genes, certain associations within the major histocompatibility complex (MHC) region—including those involving HLA class III genes-must be understood through the lens of how closely linked genes function together as haplotype blocks.^[24]

It is worth noting that this study did not find any significant differences between the SE allele carrying status and different anti-CCP antibody titers or disease activity (DAS28). This aligns with previous findings in China and reflects the relatively low prevalence of SE positivity in the Chinese RA population.^[25] Prior research has suggested that HLA-DRB1*04:05 may drive joint destruction by modulating the Th17/Treg balance rather than simply influencing ACPA production.^[26] This insight provides a novel perspective for understanding the clinical heterogeneity of RA.

The limitations of this study are as follows: (1) The detection efficiency is constrained by the sample size, particularly regarding low-frequency allele effects; (2) There is a lack of functional experiments to validate the biological mechanisms associated with key alleles; (3) The interaction analysis between HLA-DQ/DP alleles and non-MHC genes was not included. Future research should integrate high-depth HLA typing, epitope analysis, and organoid models to systematically investigate the molecular pathogenesis network of RA within the Chinese Han population. This is especially crucial for ACPA-negative subtypes, where it is necessary to explore the impacts of polymorphisms in HLA-C, MHC class I polypeptide-related sequence A (MICA), and other relevant genes.^[27]

Conclusion

This study reveals the unique HLA genetic profile of RA in Yunnan’s Han population, shaped by geography and historical migrations. It confirms race-adaptive variations linked to the SE hypothesis and identifies a new HLA-I risk model. The potential synergy between HLA-I and HLA-II could be a target for immune intervention, while functional analysis of protective alleles may inform precise prevention strategies. Compared to other regions, this research highlights regional differences in RA genetic susceptibility across China, enriching our understanding of RA’s genetic landscape. Comprehensive analysis of HLA-B and HLA-DR polymorphisms provides a complete picture of RA’s genetic factors. Correlating genetic findings with clinical outcomes via DAS28-ESR enhances the clinical relevance of this research. The study offers valuable references for future large-scale analyses and RA-targeted gene screening tools, and provides a basis for RA prevention and disease management strategies in Yunnan.