A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults.
Lipoprotein-associated phospholipase A2(Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2METHODS: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories.



PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing.



Lifelong lower Lp-PLA2activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Iona Y
IY
Millwood
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Derrick A
DA
Bennett
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Robin G
RG
Walters
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Robert
R
Clarke
GlaxoSmithKline (GSK) Medicines Research Centre, GSK, Stevenage, UK, Research Triangle Park, NC, USA and King of Prussia, PA, USA.
Dawn
D
Waterworth
GlaxoSmithKline (GSK) Medicines Research Centre, GSK, Stevenage, UK, Research Triangle Park, NC, USA and King of Prussia, PA, USA.
Toby
T
Johnson
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Yiping
Y
Chen
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Ling
L
Yang
Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, China and.
Yu
Y
Guo
Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, China and.
Zheng
Z
Bian
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Alex
A
Hacker
GlaxoSmithKline (GSK) Medicines Research Centre, GSK, Stevenage, UK, Research Triangle Park, NC, USA and King of Prussia, PA, USA.
Astrid
A
Yeo
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Sarah
S
Parish
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Michael R
MR
Hill
GlaxoSmithKline (GSK) Medicines Research Centre, GSK, Stevenage, UK, Research Triangle Park, NC, USA and King of Prussia, PA, USA.
Stephanie
S
Chissoe
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Richard
R
Peto
GlaxoSmithKline (GSK) Medicines Research Centre, GSK, Stevenage, UK, Research Triangle Park, NC, USA and King of Prussia, PA, USA.
Lon
L
Cardon
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK.
Rory
R
Collins
Chinese Academy of Medical Sciences, Dong Cheng District, Beijing, China and.|Department of Epidemiology & Biostatistics, Peking University Health Science Centre, Beijing, China.
Liming
L
Li
Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, UK zhengming.chen@ndph.ox.ac.uk.
Zhengming
Z
Chen
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D002681:China; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D038801:International Classification of Diseases; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D014652:Vascular Diseases / Q000235:genetics*
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C526684:PLA2G7 protein, human
China; Lp-PLA2; genetic association; phenome-wide; vascular disease