Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis.
Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran's homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10(-9) at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10(-13) in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Kwangwoo
K
Kim
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
So-Young
SY
Bang
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 162-0054, Japan.
Katsunori
K
Ikari
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Dae Hyun
DH
Yoo
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Soo-Kyung
SK
Cho
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Chan-Bum
CB
Choi
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Yoon-Kyoung
YK
Sung
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Tae-Hwan
TH
Kim
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Jae-Bum
JB
Jun
Division of Rheumatology, Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-721, Republic of Korea.
Young Mo
YM
Kang
Department of Rheumatology, Ajou University School of Medicine, Suwon 443-380, Republic of Korea.
Chang-Hee
CH
Suh
Division of Rheumatology, Daejeon Rheumatoid &Degenerative Arthritis Center, Chungnam National University Hospital, Daejeon 301-721, Republic of Korea.
Seung-Cheol
SC
Shim
Division of Rheumatology, Department of Internal Medicine, Chonnam National University Medical School and Hospital, Gwangju 501-757, Republic of Korea.
Shin-Seok
SS
Lee
Division of Rheumatology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul 158-710, Republic of Korea.
Jisoo
J
Lee
Division of Rheumatology, Department of internal medicine, Dong-A University, Busan 602-715, Republic of Korea.
Won Tae
WT
Chung
Division of Rheumatology, Department of Internal Medicine, Arthritis &Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Seong-Kyu
SK
Kim
Division of Rheumatology, Department of Internal Medicine, Arthritis &Autoimmunity Research Center, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Jung-Yoon
JY
Choe
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
Shigeki
S
Momohara
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
Atsuo
A
Taniguchi
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo 162-0054, Japan.
Hisashi
H
Yamanaka
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Swapan K
SK
Nath
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Hye-Soon
HS
Lee
Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul 133-792, Republic of Korea.
Sang-Cheol
SC
Bae
D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000473:pathology; D044466:Asian People / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D019473:Transcription Factors, TFII / Q000235:genetics*; D044465:White People / Q000235:genetics
C104259:GTF2I protein, human; D019473:Transcription Factors, TFII