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New England Journal of Medicine

Clinical Articles, Lead Article

Shorter height is directly associated with increased risk of coronary heart disease

There is a primary association between a genetically determined shorter height and an increased risk of coronary artery disease (CAD), a link that is partly explained by the association between shorter height and an adverse lipid profile, according to a study published recently in the New England Journal of Medicine.1

The authors used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. They tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls.

Using individual-level genotype data from 18,249 persons, they also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, they analysed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes

Professor Sir Nilesh Samani (University of Leicester)

Professor Sir Nilesh Samani (University of Leicester)

The authors observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors studied, they observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). The authors also identified several overlapping pathways involving genes associated with both development and atherosclerosis.

Lead author Professor Sir Nilesh Samani (University of Leicester) said: “For more than 60 years it has been known that there is an inverse relationship between height and risk of coronary heart disease…It was not clear whether this relationship is due to confounding factors such as poor socioeconomic environment, or nutrition, during childhood that on the one hand determine achieved height and on the other the risk of coronary heart disease, or whether it represents a primary relationship between shorter height and more coronary heart disease.”

“Now, using a genetic approach, researchers at the University of Leicester undertaking the study on behalf of an international consortium of scientists (the CADIoGRAM+C4D consortium) 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…Height has a strong genetic determination and in the last few years a large number of genetic variants have been identified in our DNA that determines one’s height,” Professor Samani added.

He continued: “While we know about many lifestyle factors such as smoking that affect risk of coronary heart disease, our findings underscore the fact that the causes of this common disease are very complex and other things that we understand much more poorly have a significant impact.”

“While our findings do not have any immediate clinical implications, better and fuller understanding of the biological mechanisms that underlie the relationship between shorter height and higher risk of coronary heart disease may open up new ways for its prevention and treatment,” Professor Samani concluded.

References

1. Nelson CP, Hamby SE, Saleheen D, et al. Genetically determined height and coronary artery disease. N Engl J Med 2015;372:1608–18. http://dx.doi.org/10.1056/NEJMoa1404881

Published on: April 29, 2015

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