Multiple LRRK2 variants modulate risk of Parkinson disease: a Chinese multicenter study.
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.
Tan
Eng-King
EK
Departments of Neurology, Singapore General Hospital, Singapore.
Peng
Rong
R
Teo
Yik-Ying
YY
Tan
Louis C
LC
Angeles
Dario
D
Ho
Patrick
P
Chen
Meng-Ling
ML
Lin
Chin-Hsien
CH
Mao
Xue-Ye
XY
Chang
Xue-Li
XL
Prakash
Kumar M
KM
Liu
Jian-Jun
JJ
Au
Wing-Lok
WL
Le
Wei-Dong
WD
Jankovic
Joseph
J
Burgunder
Jean-Marc
JM
Zhao
Yi
Y
Wu
Ruey-Meei
RM
D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D016366:Open Reading Frames; D010300:Parkinson Disease / Q000208:ethnology / Q000235:genetics*; D011110:Polymorphism, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases