Abstract Body: Introduction: Despite identifying hundreds of susceptibility loci for coronary artery disease (CAD), the genetic factors that contribute to risk more strongly or specifically in one sex remain poorly understood. Based on sexually dimorphic patterns observed in prior metabolomics studies, we tested the hypothesis that genetically decreased activity of carbamoyl-phosphate synthetase 1 (CPS1), the rate-limiting enzyme of the urea cycle, was associated with atherosclerosis differentially in male and female humans and mice.
Methods: Logistic regression was used to test a functional genetic variant (rs715) in CPS1 for association with risk of CAD separately in men and women from multiple multi-ancestry large cohorts (n=1,803,558), followed by fixed-effects meta-analyses across all subjects, ancestries, and datasets. A genetic mouse model of Cps1 deficiency was characterized for sex-specific differences in metabolite levels, cardiometabolic traits, and atherosclerotic lesion formation. Sex differences in hepatic CPS1 expression were evaluated in subjects from the STARNET cohort and a panel of inbred mouse strains.
Results: The CPS1 activity-decreasing allele of rs715 exhibited a significant sexually dimorphic association with decreased risk of CAD (P-heterogeneity=1.3x10^-4) in women (OR=0.95, 95% CI 0.94-0.96; P=9.5x10^-13; n=1,016,646) compared to men (OR=0.99, 95% CI 0.98-1.00; P=5.3x10^-3; n=786,912). Heterozygous Cps1 deficiency decreased aortic lesion formation in male mice compared to wildtype male littermates (452,855±23,550 vs. 343,481±29,752µm²/section; P=8.7x10^-3) but not in female mice. However, Cps1 deficiency in mice did not lead to sexually dimorphic differences in levels of plasma amino acids or atherogenic metabolites. Regardless of rs715 genotype, hepatic CPS1 expression was ~19% lower in women compared to men (11.5±1.3 vs. 11.8±1.1 log₂ CPM; P=1.1x10^-5) while the opposite profile was observed among a panel of inbred mouse strains with male mice having ~28% lower expression than female mice (12.2±0.13 vs. 12.5±0.09 log₂ units; P=2.7x10^-51). Gonadectomy experiments did not provide evidence that sex hormones played a role in regulating Cps1 expression in the liver.
Conclusions: These results provide evidence for the atheroprotective properties of genetically decreased CPS1 activity in humans and mice through sexually dimorphic pattens. Additional studies will be needed to elucidate the underlying biological mechanisms for these differential effects.