Background Genetic association studies using multiple ancestral cohorts have revealed a large overlap of rheumatoid arthritis (RA)-risk alleles among different ancestries, but there are some exceptional loci showing heterogenic association among populations.
Objectives Here we investigated genetic variants with distinct effects on the development of RA in Asian and European populations.
Methods Ancestry-related association heterogeneity was examined using the association data from large Korean (n=9,299) and European (n=45,790) rheumatoid arthritis cohorts with Immunochip and genome-wide SNP array data. Novel disease associations detected in Koreans were validated using two independent Asian cohorts (n=5,166) and a meta-analysis.
Results We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus and showed that this heterogeneity is due to an Asian-specific association effect (PHeterogeneity =9.6×10-9 at rs73366469 [ORMeta =1.37 and PMeta =4.2×10–13 in Asians; ORMeta =1.00 and PMeta =1.00 in Europeans]) in RA. Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal SNP (rs117026326; linked to rs73366469), whose minor allele is common in Asians but rare in Europeans.
Conclusions We identified the largest effect on Asian RA across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–81 (2014).
Kim, K. et al. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis 74, e13 (2015).
Acknowledgement This study was supported by the Korea Healthcare Technology R&D Project of the Ministry for Health & Welfare (HI13C2124), the Japanese Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research (15H04965) and the US National Institutes of Health (R01MD007909 and R01AR060366).
*Drs. Kwangwoo Kim and So-Young Bang contributed equally to this work.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.