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, P_GWAS = 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, P_GWAS = 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, P_GWAS = 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.

Keywords: HLA amino acid residues; HLA fine-mapping; Multi-ethnic Malaysian population; Rheumatoid arthritis; Risk variants.

Fig. 1

Association plots of the tested variants in the HLA region to ACPA-positive RA in Malays. Legends: a Regional plot of stepwise logistic regression in ACPA-positive Malay RA patients, HLA-DRB1 Val11 mapped as the strongest association signal (P_GWAS = 2.4 × 10⁻³⁵). b Conditioning of HLA-DRB1 Val11, HLA-DQB1*03:02 alleles (P_GWAS = 1.57 × 10⁻⁹) were mapped as the second independent HLA risk variants with decreased risk of developing ACPA-positive RA. c No independent variants observed from conditioning the two most associated HLA variants, i.e., HLA-DRB1 Val11 and HLA-DQB1*03:02 allele. The red line represents the suggested significant threshold, i.e., genome-wide significant threshold of P_GWAS < 5 × 10⁻⁸

Fig. 2

The frequency spectra of amino acid variants at position 11 within HLA-DRB1 protein. Legends: The figure illustrates the frequency of amino acid residues at position 11 within the HLA-DRB1 protein for the Malay, Chinese, and Indian ethnic groups. The asterisk indicates the published data retrieved from Okada et al. (2014) [19], and the number sign indicates the published data retrieved from Raychaudhuri et al. [17]