title: Autophagy-related gene LRRK2 is likely a susceptibility gene for systemic lupus erythematosus in northern Han Chinese.
abstract: Autophagy is associated with various immune diseases, including systemic lupus erythematosus (SLE). Seven variants within autophagy-related genes previously reported to show top association signals by genome-wide association studies in immune diseases were selected for analysis. Initially, 510 SLE patients (631 controls) were enrolled in the study. An additional independent cohort of 511 SLE patients (687 controls) was included for replication. Polymorphism rs2638272 in LRRK2 gene showed significant association with susceptibility to SLE (P = 1.14 × 10-2) within the initial patient population. This was independently replicated (second patient cohort), and was reinforced with combination (P = 2.82 × 10-3). By combining multiple layers of regulatory effects, rs1491941 in high linkage disequilibrium with rs2638272 (r2 = 0.99) was regarded to have the strongest function in LRRK2. The rs1491941 protective A-allele exhibited an increase of nuclear protein binding, and an increase in LRRK2 transcription compared with G-allele. Furthermore, we observed increased transcription levels of LRRK2 in peripheral blood mononuclear cells from SLE patients compared with controls. In conclusion, we have identified a novel genetic association between the autophagy-related LRRK2 gene and susceptibility to SLE. By integrating layers of functional data, we derived the beneficial effect of autophagy on the pathogenesis of SLE.
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Yue-Miao
authors.initials: YM
authors.lastname: Zhang
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Xu-Jie
authors.initials: XJ
authors.lastname: Zhou
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Fa-Juan
authors.initials: FJ
authors.lastname: Cheng
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Qi
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Ming-Hui
authors.initials: MH
authors.lastname: Zhao
authors.affiliation: Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
mesh_terms: D044466:Asian People; D001343:Autophagy / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male
chemical_list: C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
keywords: LRRK2; autophagy; functional annotation; shared genetics; systemic lupus erythematosus