Coronary artery disease (CAD) perennially tops the league for killer diseases. It’s estimated that over 600,000 Americans die from a heart attack every year and CAD is the leading cause of death for both men and women. Furthermore, arterial plaque formation can be detected as early as adolescence and progressively afflicts us throughout our reproductive years into old age. If CAD is not simply a disease of post-reproductive age, you might therefore expect that selection would have operated to ameliorate these fitness-reducing effects of CAD but it appears that it has not. Now an international collaboration of scientists, including Stephen Stearns from Yale University and lead researcher on the famous Framingham Heart Study, claims to have part of the answer. CAD is maintained in human populations, they say, by the classic evolutionary trade-off of antagonistic pleiotropy. Gene variants shown to confer risk of CAD are also involved in fertility. Evolution may have traded lifetime reproductive success for susceptibility to heart disease in later age.

In a paper this week in PLoS Genetics titled “Genetic loci associated with coronary artery disease harbor evidence of selection and antagonistic pleiotropy” Byars et al point out that there are two popular misconceptions about CAD. Firstly, that it only occurs in older people and, secondly, that it is a disease that has mainly afflicted modern humans. If either were true, they say, selection might not have had either the opportunity or sufficient time to affect the genetic variation that is associated with CAD. However, CAD takes root as early as adolescence where disease origins can be detected through atherosclerosis and myocardial infarction, and manifests during reproductive age. CAD is also a product of many heritable risk factors (cholesterol, weight, blood pressure) whose variation is expressed during the reproductive period, when CAD could drive selection directly or indirectly. Furthermore, CAD is no modern self-inflicted disease of the Western lifestyle. It has impacted human populations for thousands of years at least – as evidence of arterial plaque from Egyptian mummies and mummified remains from Peru and elsewhere has shown. Plenty of time for evolutionary responses to CAD to have occurred which have left their signatures in the genomes of modern humans.

Their study has identified many adaptive signals among CAD loci and for highly-ranked CAD genes there was a consistent overlap between selection and genetic risk of CAD. Thus many of these genes must have been modified by CAD-linked selection pressures. This confirms not only that CAD has indeed been present for an evolutionarily-relevant period of thousands of years but that selection has occurred in young adults partly through direct pathology of CAD, like a heart attack, or via selection on CAD risk factors. But, by dipping into data from the Framingham Heart Study, they also found that CAD-disposing genes were disproportionately linked to female lifetime reproductive success relative to genes in the rest of the genome. Out of 76 CAD genes, 51 genes contained point mutations that were significantly nominally associated with lifetime reproductive success. Some, they say, directly affected fitness by influencing offspring number or age at menarche and menopause, while others correlated with traits involving ability to fertilise eggs or successfully conceive babies, or factors influencing fetal growth, development or survival.

Specifically, out of the 40 top-ranked CAD genes they found that PPAP2B was associated with reproductive capacity, SMAD3 with twinning, and KIAA1462 and SLC22A5 on numbers of offspring produced. While PHACTR1, LPL, SMAD3, ABO and SLC22A5 seem to contribute to the timing of reproductive lifespan through influencing menarche and menopause and expression of PHACTR1, KCNK5, MRAS and ADAMST7 appear to regulate lactation capacity. Some of these genes are highly expressed during embryogenesis and may also influence female receptiveness to implantation.

So much for female fertility. What about men, who are slightly more susceptible than women for CAD? They found many genes that affected male fertility and 13 that affected fertility in both men and women. For instance, the gene SLC22A5 causes both cardiomyopathy and male infertility due to an altered ability to break down lipids.

They conclude: “Our study provides new evidence that genes underlying CAD have recently been modified by natural selection and that these same genes uniquely and extensively contribute to human reproduction, which suggests that natural selection may have maintained genetic variation contributing to CAD because of its beneficial effects on fitness. This study provides novel evidence that CAD has been maintained in modern humans as a by-product of the fitness advantages those genes provide early in human life-cycles.”

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