A phenome-wide association study of a lipoprotein-associated phospholipase A2 loss-of-function variant in 90 000 Chinese adults

Int J Epidemiol. 2016 Oct;45(5):1588-1599. doi: 10.1093/ije/dyw087. Epub 2016 Jun 14.

Abstract

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition 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-PLA2 METHODS: 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.

Results: 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.

Conclusions: Lifelong lower Lp-PLA2 activity 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.

Keywords: China; Lp-PLA2; genetic association; phenome-wide; vascular disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics*
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism*
  • Adult
  • Aged
  • Asian Continental Ancestry Group / genetics*
  • China
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • International Classification of Diseases
  • Linear Models
  • Logistic Models
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Risk Factors
  • Vascular Diseases / genetics*

Substances

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PLA2G7 protein, human