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Association of variants in MMEL1 and CTLA4 with rheumatoid arthritis in the Han Chinese population
  1. Patrick Danoy1,
  2. Meng Wei2,
  3. Hadler Johanna1,
  4. Lei Jiang2,
  5. Dongyi He3,
  6. Linyun Sun4,
  7. Xiaofeng Zeng5,
  8. Peter M Visscher6,
  9. Matthew A Brown1,
  10. Huji Xu2
  1. 1Human Genetics Group, The University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  2. 2Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China
  3. 3Department of Rheumatology, Shanghai Guanghua Hospital, Shanghai, China
  4. 4Department of Rheumatology and Immunology, Nanjing Gulou Hospital, Nanjing, China
  5. 5Department of Rheumatology and Immunology, Peking Union Medical College Hospital, Beijing, China
  6. 6Queensland Statistical Genetics Laboratory, Queensland Institute for Medical Research, Herston, Queensland, Australia
  1. Correspondence to Professor Matthew A Brown, The University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Ipswich Road, Brisbane, QLD 4102, Australia; matt.brown{at}uq.edu.au

Abstract

Background The genome-wide association study era has made great progress in identifying susceptibility genes and genetic loci for rheumatoid arthritis (RA) in populations of White European ancestry. However, few studies have tried to dissect disease aetiopathogenesis in other ethnic populations.

Objective To investigate these associations in the Han Chinese population.

Methods Haplotypes from the HapMap database Chinese population were used to select tag-single-nucleotide polymorphisms (SNPs) (r2=0.8) across 19 distinct RA genomic regions. A two phase case–control association study was performed, with 169 SNPs genotyped in phase I (n=571 cases, n=880 controls), and 64 SNPs achieving p<0.2 in the first phase being genotyped in phase II (n=464 cases, n=822 controls). Association statistics were calculated using permutation tests both unadjusted and adjusted for the number of markers studied.

Results Robust association was detected for MMEL1 and CTLA4, and modest association was identified for another six loci: PADI4, STAT4, PRDM1, CDK6, TRAF1-C5 and KIF5A-PIP4K2C. All three markers genotyped in MMEL1 demonstrated association, with peak signal for rs3890745 (p=2.6×10−5 unadjusted, p=0.003 adjusted, OR=0.79). For CTLA4, significance was detected for three of five variants showing association, with peak association for marker rs12992492 (p=4.3×10−5 unadjusted, p=0.0021 adjusted, OR=0.77). Lack of association of common variants in PTPN22 with RA in Han Chinese was confirmed.

Conclusion This study identifies MMEL1 and CTLA4 as RA susceptibility genes, provides suggestive evidence of association for a further six loci in the Han Chinese population and confirms lack of PTPN22 association in Asian populations. It also confirms the value of multiethnic population studies to help dissect disease aetiopathogenesis.

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Footnotes

  • Patrick Danoy, Meng Wei, Matthew A Brown and Huji Xu contributed equally to the work.

  • Funding HX was funded by the National Natural Science Foundation of China grant 30972339, 30728008 and the Science and Technology Commission of Shanghai Municipality grants 08XD1400400, 074107021, 08JC1413300 and 08DZ2293100. MAB and PVM are supported by fellowships from the National Health and Medical Research Council (NHMRC) (Australia). Support was also received from a NHMRC Program Grant (reference 569938). This study was also supported by Arthritis Australia.

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the Second Military Medical University Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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