Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Feb;269:42-49.
doi: 10.1016/j.atherosclerosis.2017.12.013. Epub 2017 Dec 8.

Genetic Variants in PPARGC1B and CNTN4 Are Associated With Thromboxane A 2 Formation and With Cardiovascular Event Free Survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Affiliations
Free PMC article

Genetic Variants in PPARGC1B and CNTN4 Are Associated With Thromboxane A 2 Formation and With Cardiovascular Event Free Survival in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

Nina S McCarthy et al. Atherosclerosis. .
Free PMC article

Abstract

Background and aims: Elevated urinary 11-dehydro thromboxane B2 (TxB2), a measure of thromboxane A2 formation in vivo, predicts future atherothrombotic events. To further understand this relationship, the genetic determinants of 11-dehydro TxB2 and their associations with cardiovascular morbidity were investigated in this study.

Methods: Genome-wide and targeted genetic association studies of urinary 11-dehydro TxB2 were conducted in 806 Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) participants.

Results: The strongest associations were in PPARGC1B (rs4235745, rs32582, rs10515638) and CNTN4 (rs10510230, rs4684343), these 5 single nucleotide polymorphisms (SNPs) were independently associated with 11-dehydro TxB2 formation. Haplotypes of 11-dehydro TxB2 increasing alleles for both PPARGC1B and CNTN4 were significantly associated with 11-dehydro TxB2, explaining 5.2% and 4.5% of the variation in the whole cohort, and 8.8% and 7.9% in participants not taking aspirin, respectively. In a second ASCOT population (n = 6199), addition of these 5 SNPs significantly improved the covariate-only Cox proportional hazards model for cardiovascular events (chisq = 14.7, p=0.01). Two of the risk alleles associated with increased urinary 11-dehydro TxB2 were individually associated with greater incidences of cardiovascular events - rs10515638 (HR = 1.31, p=0.01) and rs10510230 (HR = 1.25, p=0.007); effect sizes were larger in those not taking aspirin.

Conclusions: PPARGC1B and CNTN4 genotypes are associated with elevated thromboxane A2 formation and with an excess of cardiovascular events. Aspirin appears to blunt these associations. If specific protection of PPARGC1B and CNTN4 variant carriers by aspirin is confirmed by additional studies, PPARGC1B and CNTN4 genotyping could potentially assist in clinical decision making regarding the use of aspirin in primary prevention.

Keywords: Genome wide association study; Thrombosis; Thromboxane.

Figures

Figure 1
Figure 1. Association with 11-dehydro TxB2 for the 31,570 SNPs (MAF≥0.05) on the CVD50K chip (A) and 2,031,499 SNPs (MAF≥0.05) on the CNV370 chip (B).
X-axis: chromosomal location. All SNP associations were adjusted for age, sex, smoking habit, diabetes, systolic blood pressure, BMI, HDL, LDL, aspirin and anti-hypertensive regimen. The lower dashed lines are the threshold for ‘suggestive’ association (P<1E-03), and the upper dashed lines are the Bonferroni threshold for significance (P<2.4E-06 for the CNV50K chip and P=1.8E-07 for the CNV370K chip). The most strongly associated locus in all subjects on the CVD50K chip, PPARGC1B, is coloured in red and on the CNV370 chip, CNTN4, is coloured in blue.
Figure 2
Figure 2. Kaplan Meier plot of survival by genotype for the two SNPs independently associated with cardiovascular event-free survival, rs10515638 (PPARGC1B) and rs10510230 (CNTN4).
‘Carriers’: carriers of one or more minor allele. ‘Non carriers’: major allele homozygotes. HR: Hazard ratio for the SNP in the multivariate Cox proportional hazards analysis, and corresponding P value (Table 3).

Similar articles

See all similar articles

Publication types

MeSH terms

Feedback