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High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.


ABSTRACT: Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

SUBMITTER: Sun C 

PROVIDER: S-EPMC4767573 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

Sun Celi C   Molineros Julio E JE   Looger Loren L LL   Zhou Xu-Jie XJ   Kim Kwangwoo K   Okada Yukinori Y   Ma Jianyang J   Qi Yuan-Yuan YY   Kim-Howard Xana X   Motghare Prasenjeet P   Bhattarai Krishna K   Adler Adam A   Bang So-Young SY   Lee Hye-Soon HS   Kim Tae-Hwan TH   Kang Young Mo YM   Suh Chang-Hee CH   Chung Won Tae WT   Park Yong-Beom YB   Choe Jung-Yoon JY   Shim Seung Cheol SC   Kochi Yuta Y   Suzuki Akari A   Kubo Michiaki M   Sumida Takayuki T   Yamamoto Kazuhiko K   Lee Shin-Seok SS   Kim Young Jin YJ   Han Bok-Ghee BG   Dozmorov Mikhail M   Kaufman Kenneth M KM   Wren Jonathan D JD   Harley John B JB   Shen Nan N   Chua Kek Heng KH   Zhang Hong H   Bae Sang-Cheol SC   Nath Swapan K SK  

Nature genetics 20160125 3


Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio  ...[more]

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