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Shared Pathways Likely Behind Height-Heart Disease Risk, Researchers Say

NEW YORK (GenomeWeb) – The shorter someone is, the higher the risk that person has of developing coronary artery disease, according to a genetic analysis conducted by researchers from the CARDIoGRAM+C4D Consortium.

As the consortium researchers reported in the New England Journal of Medicine, this link is likely mediated by biological processes involved in both growth and the development of atherosclerosis.

Researchers led by the University of Leicester's Nilesh Samani investigated the association between some 180 height-linked genetic variants and CAD in more than 65,000 cases and 128,000 controls, while also examining individual-level genotyping data and CAD risk from more than 18,000 people. A pathway analysis further identified genes with roles in pathways involved in both development and atherosclerosis.

As the researchers noted in their paper, there is an established link between being short and having an increased risk of CAD, as well as of high blood pressure, high low-density lipoprotein cholesterol, and diabetes, but the mechanism underlying the association wasn't clear.

"We have shown that the association between shorter height and higher risk of coronary heart disease is a primary relationship and is not due to confounding factors such as nutrition or poor socioeconomic conditions," Samani said in a statement.

For this study, Samani and his colleagues drew on the Coronary Artery Disease Genome-wide Replication and Meta-Analysis (CARDIoGRAM) Consortium and the Coronary Artery Disease (C4D) Consortium datasets to examine which height-related variants the cases and controls harbored. In particular they focused on some 180 loci that had previously been linked to height that, all together, explain some 10 percent of variation in height.

For each variant, the researchers calculated the putative association between height and CAD mediated by that variant, as well as the effect size of the association between the variant and height, and the effect size of the association between the variant and CAD.

From this, Samani and his colleagues found that for every one standard deviation decrease in height, or about 2.5 inches, there was a corresponding 13.5 percent increase in CAD risk.

While most of the height-associated variants the researchers studied didn't have an effect on CAD risk, those that did exhibited a graded relationship with CAD risk. Data from 18,249 individuals also indicated that CAD risk was linked to the number of height-associated alleles the person had.

"The more height-increasing genetic variants that you carry, the lower your risk of coronary heart disease, and conversely, if you were genetically shorter, the higher your risk," added first author Christopher Nelson, a lecturer at Leicester.

Samani and his colleagues also investigated whether there were any links between these height-associated variants and cardiovascular risk factors like BMI, blood pressure, and cholesterol and triglyceride levels.

From this, they found small, but significant associations between LDL cholesterol and triglyceride levels and height and CAD risk. They estimated that 19 percent of the observed association between height and CAD risk could be explained by the effect of shorter height on LDL cholesterol and about 12 percent by its effect on triglyceride levels.

A greater portion of the association is likely due to overlapping biological pathways, the researchers said. Through pathway analysis, they found, for instance, that height-linked SNPs could affect the BMP- and TGF-β-signaling pathways, axon-guidance pathways, and the STAT3 and IGF-I pathways — all of which are involved in the development of atherosclerosis.