PMID- 33514426
OWN - NLM
STAT- MEDLINE
DCOM- 20210621
LR  - 20210621
IS  - 1478-6362 (Electronic)
IS  - 1478-6354 (Print)
IS  - 1478-6354 (Linking)
VI  - 23
IP  - 1
DP  - 2021 Jan 30
TI  - The spectrum of association in HLA region with rheumatoid arthritis in a diverse 
      Asian population: evidence from the MyEIRA case-control study.
PG  - 46
LID - 10.1186/s13075-021-02431-z [doi]
LID - 46
AB  - 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 x 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 x 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 x 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.
FAU - Tan, Lay Kim
AU  - Tan LK
AUID- ORCID: 0000-0001-5846-2783
AD  - 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.
AD  - Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak, 
      Ipoh, Perak, Malaysia. tanlk@moh.gov.my.
AD  - Department of Medicine, Division of Rheumatology, Karolinska Institutet and 
      Karolinska University Hospital, Stockholm, Sweden. tanlk@moh.gov.my.
FAU - Too, Chun Lai
AU  - Too CL
AD  - 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.
AD  - Department of Medicine, Division of Rheumatology, Karolinska Institutet and 
      Karolinska University Hospital, Stockholm, Sweden. toocl@moh.gov.my.
FAU - Diaz-Gallo, Lina Marcela
AU  - Diaz-Gallo LM
AD  - Department of Medicine, Division of Rheumatology, Karolinska Institutet and 
      Karolinska University Hospital, Stockholm, Sweden.
FAU - Wahinuddin, Sulaiman
AU  - Wahinuddin S
AD  - Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak, 
      Ipoh, Perak, Malaysia.
AD  - Department of Medicine, Ministry of Health Malaysia, Hospital Raja Perempuan 
      Bainun, Ipoh, Perak, Malaysia.
FAU - Lau, Ing Soo
AU  - Lau IS
AD  - Department of Medicine, Ministry of Health Malaysia, Selayang Hospital, Selayang, 
      Selangor, Malaysia.
FAU - Heselynn, Hussein
AU  - Heselynn H
AD  - Department of Medicine, Ministry of Health Malaysia, Putrajaya Hospital, 
      Putrajaya, Malaysia.
FAU - Nor-Shuhaila, Shahril
AU  - Nor-Shuhaila S
AD  - Department of Medicine, Ministry of Health Malaysia, Putrajaya Hospital, 
      Putrajaya, Malaysia.
FAU - Gun, Suk Chyn
AU  - Gun SC
AD  - Department of Medicine, Ministry of Health Malaysia, Hospital Tuanku Ja'afar 
      Seremban, Seremban, Negeri Sembilan, Malaysia.
FAU - Eashwary, Mageswaran
AU  - Eashwary M
AD  - Department of Medicine, Ministry of Health Malaysia, Putrajaya Hospital, 
      Putrajaya, Malaysia.
FAU - Mohd-Shahrir, Mohamed Said
AU  - Mohd-Shahrir MS
AD  - Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, 
      Malaysia.
FAU - Ainon, Mohd Mokhtar
AU  - Ainon MM
AD  - Department of Medicine, Ministry of Health Malaysia, Tengku Ampuan Afzan 
      Hospital, Kuantan, Pahang, Malaysia.
FAU - Azmillah, Rosman
AU  - Azmillah R
AD  - Department of Medicine, Ministry of Health Malaysia, Selayang Hospital, Selayang, 
      Selangor, Malaysia.
FAU - Muhaini, Othman
AU  - Muhaini O
AD  - Department of Medicine, Ministry of Health Malaysia, Hospital Raja Perempuan 
      Bainun, Ipoh, Perak, Malaysia.
FAU - Shahnaz, Murad
AU  - Shahnaz M
AD  - Ministry of Health Malaysia, Federal Government Administrative Center, Putrajaya, 
      Malaysia.
FAU - Alfredsson, Lars
AU  - Alfredsson L
AD  - Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
FAU - Klareskog, Lars
AU  - Klareskog L
AD  - Faculty of Medicine, Universiti Kuala Lumpur Royal College of Medicine Perak, 
      Ipoh, Perak, Malaysia.
FAU - Padyukov, Leonid
AU  - Padyukov L
AD  - Department of Medicine, Division of Rheumatology, Karolinska Institutet and 
      Karolinska University Hospital, Stockholm, Sweden. leonid.padyukov@ki.se.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210130
PL  - England
TA  - Arthritis Res Ther
JT  - Arthritis research & therapy
JID - 101154438
RN  - 0 (Autoantibodies)
RN  - 0 (HLA Antigens)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Alleles
MH  - *Arthritis, Rheumatoid/diagnosis/epidemiology/genetics
MH  - Autoantibodies/genetics
MH  - Case-Control Studies
MH  - Genetic Predisposition to Disease/genetics
MH  - HLA Antigens
MH  - HLA-DRB1 Chains/genetics
MH  - Humans
PMC - PMC7847037
OTO - NOTNLM
OT  - HLA amino acid residues
OT  - HLA fine-mapping
OT  - Multi-ethnic Malaysian population
OT  - Rheumatoid arthritis
OT  - Risk variants
COIS- The authors declare that they have no competing interests.
EDAT- 2021/01/31 06:00
MHDA- 2021/06/22 06:00
PMCR- 2021/01/30
CRDT- 2021/01/30 05:23
PHST- 2020/11/04 00:00 [received]
PHST- 2021/01/19 00:00 [accepted]
PHST- 2021/01/30 05:23 [entrez]
PHST- 2021/01/31 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2021/01/30 00:00 [pmc-release]
AID - 10.1186/s13075-021-02431-z [pii]
AID - 2431 [pii]
AID - 10.1186/s13075-021-02431-z [doi]
PST - epublish
SO  - Arthritis Res Ther. 2021 Jan 30;23(1):46. doi: 10.1186/s13075-021-02431-z.