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Heart Disease Variants May Also Affect Reproductive Success

NEW YORK (GenomeWeb) – Coronary artery disease may persist in the human population because the genes that contribute to the disease also influence reproductive success.

Coronary artery disease has long plagued human populations — atherosclerosis has been found among Egyptian mummies — leading scientists to wonder why natural selection hasn't removed the responsible gene variants from the population.

Researchers led by the University of Melbourne's Michael Inouye searched for signs of positive selection affecting coronary artery disease in a number of human populations. As they reported yesterday in PLOS Genetics, they found that candidate adaptive loci that appear to modify coronary artery disease are also associated with reproductive traits, suggesting a reason why disease-linked loci have been maintained in human populations.

"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 lifecycles," Inouye and his colleagues wrote in their paper.

The researchers drew on SNP summary statistics from a previously reported case-control genome-wide association study meta-analysis of coronary artery disease that had uncovered 76 candidate disease loci. The study included 60,801 cases and 123,504 controls of mostly European ancestry, but also of South and East Asian and Hispanic- and African-American ancestry.

Using the integrated Haplotype Score, the researchers estimated positive selection for each SNP in these coronary artery disease genes within each population. In this way, they identified candidate selection signals for most of these genes within worldwide populations. Most candidate selection signals were small, but a few like BCAS3 and MKK were stronger in certain populations.

Inouye and his colleagues noted that their findings suggest that selection on coronary artery disease loci is more widespread than previously appreciated.

For a subset of the coronary artery disease loci, the researchers used a mixed effects linear model to tease out significant quantitative associations between disease risk and selection signals. The direction of this association, they noted, was typically the same across populations, especially populations that belonged to the same ancestral group.

In particular, coronary artery disease risk variants in BCAS3 were positively associated with a large candidate adaptive signal in all European populations and two of the three East Asian populations in the cohort. In Yorubans, however, there was no detectable signal near the index SNP.

To gauge whether these coronary artery disease-linked genes affect human reproductive success, Inouye and his colleagues turned to data from the Framingham Heart Study. They found that, of the 76 coronary artery disease genes, 51 contained SNPs associated with lifetime reproductive success.

Through a literature search of the top 40 genes, the researchers unearthed evidence for direct links between these genes and fitness. For instance, PPAP2B is associated with reproductive capacity, while genes like PHACTR1, LPL, and SMAD3 may contribute to timing of menarche and menopause in women. Other genes have been linked to pregnancy loss, like LDLR and COL4A2.

The researchers also noted pleiotropic connections. They reported that a number of coronary artery disease-linked genes in this study — PHACTR1, LPL, and IL6R, among others — are differentially expressed in women with polycystic ovarian syndrome. Women with this condition exhibit higher rates of infertility and cardiovascular disease risk factors.

"The pleiotropic effects that genes associated with CAD have on traits associated with reproduction that are expressed early in life strongly suggests some of the evolutionary reasons for the existence of human vulnerability to CAD," the researchers wrote.