From the Department of Rheumatology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Human Genetics, Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore; The Jackson Laboratory, Farmington, Connecticut, USA; the Singapore Eye Research Institute (SERI); the Ophthalmology and Visual Sciences Academic Clinical Program (Eye ACP), the Health Systems and Services Research, Duke-National University of Singapore (NUS) Medical School; Departments of Ophthalmology and Pediatrics, 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, Singapore; the division of Cancer Control and Population Sciences, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou; Shandong Provincial Institute of Dermatology and Venereology and Hospital for Skin Diseases, Shandong First Medical University and Shandong Academy of Medical Sciences; National Clinical Key Project of Dermatology and Venereology, Jinan, Shandong; Institute of Dermatology and Department of Dermatology, Huashan Hospital of Fudan University, Guangzhou; Institute of Dermatology and Department of Dermatology, No. 1 Hospital, Anhui Medical University; Key Laboratory of Dermatology, Ministry of Education (Anhui Medical University), Hefei; National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China.
X. Zheng, PhD, Third Affiliated Hospital of Sun Yat-sen University; Q. Li, PhD, Third Affiliated Hospital of Sun Yat-sen University; X. Li, PhD, Third Affiliated Hospital of Sun Yat-sen University; Y. Zhang, PhD, Third Affiliated Hospital of Sun Yat-sen University; X. Wu, PhD, Third Affiliated Hospital of Sun Yat-sen University; Q. Wei, BD, Third Affiliated Hospital of Sun Yat-sen University; S. Cao, BD, Third Affiliated Hospital of Sun Yat-sen University; M. Yang, PhD, Third Affiliated Hospital of Sun Yat-sen University; Z. Lin, PhD, Third Affiliated Hospital of Sun Yat-sen University; Z. Liao, PhD, Third Affiliated Hospital of Sun Yat-sen University; J. Qi, PhD, Third Affiliated Hospital of Sun Yat-sen University; Q. Lv, PhD, Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University; L. Wang, MD, Human Genetics, Genome Institute of Singapore, A*STAR; Y. Li, PhD, Human Genetics, Genome Institute of Singapore, A*STAR, and The Jackson Laboratory; A. Irwanto, PhD, Human Genetics, Genome Institute of Singapore, A*STAR; C. Cheng, PhD, SERI, Singapore National Eye Centre, Ophthalmology and Visual Sciences, Eye ACP, Duke-NUS Medical School, Department of Ophthalmology, Yong Loo Lin School of Medicine; X. Chai, PhD, SERI, Singapore National Eye Centre; C. Khor, PhD, Human Genetics, Genome Institute of Singapore, A*STAR; C. Heng, PhD, Department of Pediatrics, Yong Loo Lin School of Medicine, Khoo Teck Puat-National University Children's Medical Institute, National University Health System; W. Koh, PhD, Saw Swee Hock School of Public Health, NUS, Health Systems and Services Research, Duke-NUS Medical School; J. Yuan, PhD, Division of Cancer Control and Population Sciences, UPMC Hillman Cancer Center, Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh; J. Bei, PhD, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center; F. Zhang, PhD, Shandong Provincial Institute of Dermatology and Venereology and Hospital for Skin Diseases, Shandong First Medical University and Shandong Academy of Medical Sciences; X. Zhang, PhD, Institute of Dermatology and Department of Dermatology, Huashan Hospital of Fudan University, Institute of Dermatology and Department of Dermatology at No. 1 Hospital, Anhui Medical University, Key Laboratory of Dermatology, Ministry of Education (Anhui Medical University); Y. Zeng, PhD, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center; Y. Shen, PhD, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College; J. Liu, PhD, Human Genetics, Genome Institute of Singapore, A*STAR, The Third Affiliated Hospital of Sun Yat-sen University; J. Gu, MD, Department of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University.
J Rheumatol. 2020 May 1;47(5):674-681. doi: 10.3899/jrheum.190184. Epub 2019 Sep 15.
To present a systematic evaluation of 47 non-MHC ankylosing spondylitis (AS) susceptibility loci that have been initially discovered through white genome-wide association studies in Han Chinese.
Originally, 10,743 samples representing north and south Chinese in 4 datasets were obtained. After data quality control and imputation, metaanalysis results of 94,621 variants within 47 loci were extracted. Four single-nucleotide polymorphisms (SNP) and tag SNP rs13202464 were used for interaction analysis. Population-attributable risk percentages of AS-associated variants were compared. Functional annotations of AS-associated variants were conducted using HaploReg, RegulomeDB, and rVarBase databases.
We revealed 16 AS-associated variants with nominal evidence in Han Chinese, including rs10865331 (p = 6.30 × 10), rs10050860 (p = 4.09 × 10) and rs8070463 (p = 1.03 × 10). Potential susceptible SNP within these 47 loci were also identified, such as rs13024541 (2p15), rs17401719 (5q15), and rs62074054 (17q21). Epistatic interactions between 3 SNP (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 in whites. Further genomic annotation pinpointed 35 candidate functional SNP, especially in the 2p15, , and regions.
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, , and NPEPPS-TBKBP1 regions may play a critical role in AS pathogenesis across diverse populations.
系统评价通过汉族人群全基因组关联研究首次发现的 47 个非 MHC 强直性脊柱炎（AS）易感位点。
最初获得了代表中国南北人群的 4 个数据集的 10743 个样本。经过数据质量控制和 imputation 后，提取了 47 个位点内 94621 个变异的荟萃分析结果。使用 4 个单核苷酸多态性（SNP）和标签 SNP rs13202464 进行了相互作用分析。比较了与 AS 相关的变异的人群归因风险百分比。使用 HaploReg、RegulomeDB 和 rVarBase 数据库对与 AS 相关的变异进行了功能注释。
我们在汉族人群中发现了 16 个具有名义证据的 AS 相关变异，包括 rs10865331（p=6.30×10）、rs10050860（p=4.09×10）和 rs8070463（p=1.03×10）。还确定了这些 47 个位点内的潜在易感 SNP，如 rs13024541（2p15）、rs17401719（5q15）和 rs62074054（17q21）。还证实了 3 个 SNP（rs17401719、rs30187 和 rs10050860）与 HLA-B27 之间的上位性相互作用。在 16 个 AS 相关变异中，rs30187 显示出较弱的风险效应，而 rs10050860 和 rs12504282 在中国汉族人群中似乎比在白人中具有更高的风险。进一步的基因组注释确定了 35 个候选功能 SNP，特别是在 2p15、、和 区域。
我们的结果提供了汉族人群中所有报道的非 MHC AS 易感位点的详细谱，全面展示了 AS 易感性的种族异质性，并强调 2p15、、和 NPEPPS-TBKBP1 区域可能在不同人群中发挥关键作用。
