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Multiple LRRK2 variants modulate risk of Parkinson disease: a chinese multicenter study
Author(s) -
Tan EngKing,
Peng Rong,
Teo YikYing,
C. Tan Louis,
Angeles Dario,
Ho Patrick,
Chen MengLing,
Lin ChinHsien,
Mao XueYe,
Chang XueLi,
Prakash Kumar M,
Liu JianJun,
Au WingLok,
Le WeiDong,
Jankovic Joseph,
Burgunder JeanMarc,
Zhao Yi,
Wu RueyMeei
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21225
Subject(s) - biology , lrrk2 , disease , parkinson's disease , genetics , bioinformatics , medicine , gene , mutation
We and others found two polymorphic LRRK2 (leucine‐rich repeat kinase 2) variants (rs34778348:G>A; p.G2385R and rs33949390:G>C; p.R1628P) associated with Parkinson disease (PD) among Chinese patients, but the common worldwide rs34637584:G>A; p.G2019S mutation, was absent. Focusing exclusively on Han Chinese, we first sequenced the coding regions in young onset and familial PD patients and identified 59 variants. We then examined these variants in 250 patients and 250 control subjects. Among the 17 polymorphic variants, five demonstrated different frequency in cases versus controls and were considered in a larger sample of 1,363 patients and 1,251 control subjects. The relative risk of an individual with both p.G2385R and p.R1628P is about 1.9, and this is reduced to 1.5–1.6 if the individual also carries rs7133914:G>C; p.R1398H or rs7308720:C>A: p.N551K. The risk of a carrier with p.R1628P is largely negated if the individual also carries p.R1398H or p.N551K. In dopaminergic neuronal lines, p.R1398H had significantly lower kinase activity, whereas p.G2385R and p.R1628P showed higher kinase activity than wild type. We provided the first evidence that multiple LRRK2 variants exert an individual effect and together modulate the risk of PD among Chinese. Hum Mutat 31:561–568, 2010. © 2010 Wiley‐Liss, Inc.