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J Rheumatol. 2019 Sep 15. pii: jrheum.190184. doi: 10.3899/jrheum.190184. [Epub ahead of print]

Analysis of 47 non-MHC Ankylosing Spondylitis Susceptibility Loci Reveals Shared Associated Variants across Caucasians and Han Chinese.

Author information

1
From the Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen Universiy; Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR);the Jackson Laboratory,USA; the Singapore Eye Research Institute (SERI);the Ophthalmology & Visual Sciences Academic Clinical Program (Eye ACP), the Health Systems and Services Research, Duke-NUS Medical School; the department of Ophthalmology, the department of Paediatrics,Yong Loo Lin School of Medicine;the Khoo Teck Puat - National University Children's Medical Institute; the Saw Swee Hock School of Public Health, National University of Singapore; the division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, the department of Epidemiology, Graduate School of Public Health, University of Pittsburgh; the State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center;the Shandong Provincial Institute of Dermatology and Venereology & Hospital for Skin Diseases, Shandong First Medical University & Shandong Academy of Medical Sciences; the National Clinical Key Project of Dermatology and Venereology;the Institute of Dermatology and Department of Dermatology, Huashan Hospital of Fudan University;the Institute of Dermatology and Department of Dermatology, No.1 Hospital, Anhui Medical University; the Key Laboratory of Dermatology, Ministry of Education (Anhui Medical University);the National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College. Supported by the Science and Technology Planning Project of Guangdong Province,China (2016A020216013),the Guangdong Natural Science Funds for Distinguished Young Scholar (Grant No.2014A030306039), the Municipal Healthcare Joint-Innovation Major Project of Guangzhou and High-level personnel of special support program for Technology Innovative Talents and the Top Young of Guangdong Province (Grant No.2015TQ01R516),the National Supercomputer Center in Guangzhou and the Agency of Science, Technology and Research (A*STAR) of Singapore, the HUJ-CREATE Programme of the National Research Foundation, Singapore (Project Number 370062002), the U.S. National Institutes of Health (Grant Numbers R01CA144034 and UM1 CA182876), the Singapore National Medical Research Council(Grant Number 1270/2010), the 5010 Project of Sun Yat-sen University(Grant No.2007023), Distinguished Young Scholar Candidates Programme for The Third Affiliated Hospital of Sun Yat-Sen University and Pearl River Nova Program of Guangzhou (Grant No. 201610010005). Address Correspondence to Prof. J Gu, Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen Universiy, Guangzhou 510630, China; Email:gujieruo@163.com or Prof. J. Liu, Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672; Email: liuj3@gis.a-star.edu.sg.

Abstract

OBJECTIVE:

We aimed to present a systematic evaluation of 47 non Major Histocompatibility Complex (MHC) Ankylosing Spondylitis (AS) susceptibility loci which have been initially discovered through Caucasian Genome-wide association studies (GWASs) in Han Chinese.

METHODS:

Totally 10,743 samples representing north and south Chinese in four datasets were obtained. After data quality control and imputation, meta-analysis results of 94,621 variants within 47 loci were extracted. Four ERAP1 single-nucleotide polymorphisms (SNPs) and HLA-B27 tag SNP rs13202464 were used for interaction analysis. Population-attributable risk percentages (PARPs) of AS-associated variants were compared. Functional annotation of AS-associated variants were conducted using HaploReg, RegulomeDB and rVarBase Database.

RESULTS:

We revealed 16 AS-associated variants with nominal evidence in Han Chinese, including rs10865331 (P=6.30×10-10), rs10050860 (P=4.09×10-5) and rs8070463 (P=1.03×10-4). Potential susceptible SNPs within these 47 loci were also identified, such as rs13024541 (2p15), rs17401719 (5q15) and rs62074054 (17q21). Epistatic ineractions between three ERAP1 SNPs (rs17401719, rs30187 and rs10050860) and HLA-B27 were confirmed. Among the 16 AS-associated variants, rs30187 showed weaker risk effect while rs10050860 and rs12504282 seemed to attribute more risk in Han Chinese than Caucasians. Further genomic annotation pinpointed 35 candidate functional SNPs, especially in 2p15, ERAP1 and NPEPPS-TBKBP1 region.

CONCLUSION:

Our results provided a detailed spectrum of all the reported non-MHC AS susceptibility loci in Han Chinese, which comprehensively exhibited the ethnic heterogeneity of AS susceptibility and highlighted that 2p15, ERAP1 and NPEPPS-TBKBP1 region may play a critical role in AS pathogenesis across diverse populations.

PMID:
31523044
DOI:
10.3899/jrheum.190184

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