The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: evidence from the MyEIRA case-control study

Abstract

Background Fine-mapping of human leukocyte antigen (HLA) region for rheumatoid arthritis (RA) risk factors has identified several HLA alleles and its corresponding amino acid residues as independent signals (i.e., HLA-A, HLA-B, HLA-DPB1, and HLA-DQA1 genes), in addition to the well-established genetic factor in HLA-DRB1 gene. However, this was mainly performed in the Caucasian and East Asian populations, and data from different Asian regions is less represented. We aimed to evaluate whether there are independent RA risk variants in both anti-citrullinated protein antibody (ACPA)-positive and ACPA-negative RA patients from the multi-ethnic Malaysian population, using the fine-mapping of HLA region strategy. Methods We imputed the classical HLA alleles, amino acids, and haplotypes using the Immunochip genotyping data of 1260 RA cases (i.e., 530 Malays, 259 Chinese, 412 Indians, and 59 mixed ethnicities) and 1571 controls (i.e., 981 Malays, 205 Chinese, 297 Indians, and 87 mixed ethnicities) from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) population-based case-control study. Stepwise logistic regression was performed to identify the independent genetic risk factors for RA within the HLA region. Results We confirmed that the HLA-DRB1 amino acid at position 11 with valine residue conferred the strongest risk effect for ACPA-positive RA (OR = 4.26, 95% CI = 3.30–5.49, PGWAS = 7.22 × 10−29) in the Malays. Our study also revealed that HLA-DRB1 amino acid at position 96 with histidine residue was negatively associated with the risk of developing ACPA-positive RA in the Indians (OR = 0.48, 95% CI = 0.37–0.62, PGWAS = 2.58 × 10−08). Interestingly, we observed that HLA-DQB1*03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malays (OR = 0.17, 95% CI = 0.09–0.30, PGWAS = 1.60 × 10−09). No association was observed between the HLA variants and risk of developing ACPA-negative RA in any of the three major ethnic groups in Malaysia. Conclusions Our results demonstrate that the RA-associated genetic factors in the multi-ethnic Malaysian population are similar to those in the Caucasian population, despite significant differences in the genetic architecture of HLA region across populations. A novel and distinct independent association between the HLA-DQB1*03:02 allele and ACPA-positive RA was observed in the Malays. In common with the Caucasian population, there is little risk from HLA region for ACPA-negative RA.

Human leucocyte antigens profiling in Malay female patients with systemic lupus erythematosus: are we the same or different?

“…The details of the classical HLA imputation for the dataset were previously described. 26 Briefly, a total of 6125 single nucleotide polymorphisms (SNPs) between position 29 and 34 Mb in the HLA region on chromosome 6 (GRCh37) were extracted from the postquality control Immunochip dataset. We imputed the classical two-digit and four-digit HLA alleles by using the extracted SNP genotypes from the HLA region, along with SNPs from the Pan Asian reference panel.…”

“…In this study, we used the data from a large, well-characterised, population-based and ethnically matched normal controls for risk association testing with the SLE patient’s cohort 23 26. These normal individuals with Malay ethnicity were previously subjected to dense SNP genotyping using the Immunochip array (~196 000 SNP markers) 26. We then performed HLA imputation for classical HLA-DQA1, HLA-DPA1 and HLA-DPB1 genes for allelic association analysis.…”

“…Nevertheless, the MyEIRA study subjects were genotyped using the Illumina iSelect HD custom genotyping array designed by the Immunochip Consortium (Immunochip Illumina, San Diego, California, USA). The details of the classical HLA imputation for the dataset were previously described 26. Briefly, a total of 6125 single nucleotide polymorphisms (SNPs) between position 29 and 34 Mb in the HLA region on chromosome 6 (GRCh37) were extracted from the postquality control Immunochip dataset.…”

“…23 26 These normal individuals with Malay ethnicity were previously subjected to dense SNP genotyping using the Immunochip array (~196 000 SNP markers). 26 We then performed HLA imputation for classical HLA-DQA1, HLA-DPA1 and HLA-DPB1 genes for allelic association analysis. In our analysis, we convincingly validated DQA1*01:02 as a potential universal susceptibility risk factor for SLE development, consistent with the findings from Hungarian, Mexican, Han Chinese, Tunisian and Indian populations.…”

Genetics of rheumatoid arthritis

“…In a study of Han Chinese ACPA-positive RA patients, strong association with Asp at position 160 of the HLA-DQA1 gene was detected independent from the HLA-DRB1 *04:05 allele and several other alleles from the HLA locus [ 38 ]. In an analysis of a multiethnic Malaysian cohort, a strong risk of ACPA-positive RA was associated with Val at position 11 of HLA-DRB1 ; it was found that HLA-DQB1 *03:02 allele was inversely related to the risk of developing ACPA-positive RA in the Malay population [ 39 ].…”