Xu-Jie Zhou1,2,3,4, Lam C Tsoi5,6,7, Yong Hu8, Matthew T Patrick5, Kevin He9,10, Celine C Berthier11, Yanming Li12, Yan-Na Wang1,2,3,4, Yuan-Yuan Qi1,2,3,4, Yue-Miao Zhang1,2,3,4, Ting Gan1,2,3,4, Yang Li1,2,3,4, Ping Hou1,2,3,4, Li-Jun Liu1,2,3,4, Su-Fang Shi1,2,3,4, Ji-Cheng Lv1,2,3,4, Hu-Ji Xu12,13, Hong Zhang14,2,3,4. 1. Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People's Republic of China. 2. Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China. 3. Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China. 4. Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People's Republic of China. 5. Department of Dermatology, University of Michigan Medical School, Ann Arbor, Michigan. 6. Department of Biostatistics, Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan. 7. Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan. 8. Beijing Institute of Biotechnology, Beijing, People's Republic of China. 9. Department of Biostatistics, University of Michigan, Ann Arbor, Michigan. 10. Kidney Epidemiology and Cost Center, School of Public Health, University of Michigan, Ann Arbor, Michigan. 11. Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. 12. Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas. 13. Department of Rheumatology and Immunology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, People's Republic of China. 14. Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People's Republic of China hongzh@bjmu.edu.cn.
Abstract
BACKGROUND AND OBJECTIVES: IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a two-stage exome chip-based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored. RESULTS: We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (P meta <5×10-5) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy. CONCLUSIONS: Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.
BACKGROUND AND OBJECTIVES: IgA nephropathy is the most common form of primary GN worldwide. The evidence of geographic and ethnic differences, as well as familial aggregation of the disease, supports a strong genetic contribution to IgA nephropathy. Evidence for genetic factors in IgA nephropathy comes also from genome-wide association patient-control studies. However, few studies have systematically evaluated the contribution of coding variation in IgA nephropathy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a two-stage exome chip-based association study in 13,242 samples, including 3363 patients with IgA nephropathy and 9879 healthy controls of Han Chinese ancestry. Common variant functional annotation, gene-based low-frequency variants analysis, differential mRNA expression, and gene network integration were also explored. RESULTS: We identified three non-HLA gene regions (FBXL21, CCR6, and STAT3) and one HLA gene region (GABBR1) with suggestive significance (P meta <5×10-5) in single-variant associations. These novel non-HLA variants were annotated as expression-associated single-nucleotide polymorphisms and were located in enhancer regions enriched in histone marks H3K4me1 in primary B cells. Gene-based low-frequency variants analysis suggests CFB as another potential susceptibility gene. Further combined expression and network integration suggested that the five novel susceptibility genes, TGFBI, CCR6, STAT3, GABBR1, and CFB, were involved in IgA nephropathy. CONCLUSIONS: Five novel gene regions with suggestive significance for IgA nephropathy were identified and shed new light for further mechanism investigation.
Authors: Kar Neng Lai; Sydney C W Tang; Francesco Paolo Schena; Jan Novak; Yasuhiko Tomino; Agnes B Fogo; Richard J Glassock Journal: Nat Rev Dis Primers Date: 2016-02-11 Impact factor: 52.329
Authors: Jingyuan Xie; Krzysztof Kiryluk; Yifu Li; Nikol Mladkova; Li Zhu; Ping Hou; Hong Ren; Weiming Wang; Hong Zhang; Nan Chen; Ali G Gharavi Journal: J Am Soc Nephrol Date: 2016-03-03 Impact factor: 10.121
Authors: Loukas Moutsianas; Vineeta Agarwala; Christian Fuchsberger; Jason Flannick; Manuel A Rivas; Kyle J Gaulton; Patrick K Albers; Gil McVean; Michael Boehnke; David Altshuler; Mark I McCarthy Journal: PLoS Genet Date: 2015-04-23 Impact factor: 5.917