Lay Kim Tan1,2,3, Chun Lai Too4,5, Lina Marcela Diaz-Gallo6, Sulaiman Wahinuddin7,8, Ing Soo Lau9, Hussein Heselynn10, Shahril Nor-Shuhaila10, Suk Chyn Gun11, Mageswaran Eashwary10, Mohamed Said Mohd-Shahrir12, Mohd Mokhtar Ainon13, Rosman Azmillah9, Othman Muhaini8, Murad Shahnaz14, Lars Alfredsson15, Lars Klareskog7, Leonid Padyukov16. 1. Immunogenetic Unit, Allergy and Immunology Research Center, Ministry of Health Malaysia, Institute for Medical Research, National Institutes of Health Complex, Shah Alam, Selangor, Malaysia. tanlk@moh.gov.my. 2. Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, Malaysia. tanlk@moh.gov.my. 3. Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. tanlk@moh.gov.my. 4. Immunogenetic Unit, Allergy and Immunology Research Center, Ministry of Health Malaysia, Institute for Medical Research, National Institutes of Health Complex, Shah Alam, Selangor, Malaysia. toocl@moh.gov.my. 5. Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. toocl@moh.gov.my. 6. Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. 7. Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak, Ipoh, Perak, Malaysia. 8. Department of Medicine, Ministry of Health Malaysia, Hospital Raja Perempuan Bainun, Ipoh, Perak, Malaysia. 9. Department of Medicine, Ministry of Health Malaysia, Selayang Hospital, Selayang, Selangor, Malaysia. 10. Department of Medicine, Ministry of Health Malaysia, Putrajaya Hospital, Putrajaya, Malaysia. 11. Department of Medicine, Ministry of Health Malaysia, Hospital Tuanku Ja'afar Seremban, Seremban, Negeri Sembilan, Malaysia. 12. Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia. 13. Department of Medicine, Ministry of Health Malaysia, Tengku Ampuan Afzan Hospital, Kuantan, Pahang, Malaysia. 14. Ministry of Health Malaysia, Federal Government Administrative Center, Putrajaya, Malaysia. 15. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 16. Department of Medicine, Division of Rheumatology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden. leonid.padyukov@ki.se.
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.
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.
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