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

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.

Figure 1.

The association of PLA2G7 V279F with vascular and non-vascular diseases. Adjusted for sex, study region, age and relatedness. Squares represent the odds ratio (OR) per Lp-PLA²-lowering minor (F) allele, with area inversely proportional to the variance of the log OR. Horizontal lines represent the corresponding 95% confidence intervals (CI). *P-values are not adjusted for multiple testing. Bonferroni correction based on one test (primary endpoint) or seven tests (secondary or tertiary endpoints) would result in thresholds of 0.05 (P = 0.05/1) or 0.007 (P = 0.05/7), respectively.

Figure 2.

The association of PLA2G7 V279F with major vascular events, among subgroups. Adjusted for sex (apart from sex subgroups), study region (apart from region subgroups), age (apart from age subgroups) and relatedness. Squares represent the odds ratio (OR) per Lp-PLA² lowering minor (F) allele, with area inversely proportional to the variance of the log OR. Horizontal lines represent the corresponding 95% confidence intervals (CI). The diamond represents the overall OR and its 95% CI.

Figure 3.

The association of PLA2G7 V279F with ICD-10 coded disease outcomes. Conventions as in Figure 1. Missing 95% CIs indicate non-convergence of the logistic regression model due to the adjustment for relatedness, and these point estimates are not plotted. *P-values are not adjusted for multiple testing. Bonferroni correction based on 41 tests would result in a threshold of 0.001 (P = 0.05/41).