Genetically Determined Height and Coronary Artery Disease
abstract
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Access this abstract nowBackground
The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.
Methods
We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We 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, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.
Results
We 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 quar-tile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.
Conclusions
There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association.
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Additional Info
Disclosure statements are available on the authors' profiles:
Short stature has been observed to be associated with an increased risk of coronary artery disease (CAD) in several epidemiological studies. The GIANT, or Genetic Investigation of ANthropometric Traits, consortium reexamined this relationship in 65,066 patients with CAD and 128,383 CAD-free controls, the majority of whom were men (74% and 50% of the groups, respectively).1 CAD risk increased 13.5% for every 6.5 cm decrease in stature. The relationship between height and CAD risk was not observed in women, possibly because fewer women were included. The authors also examined the effect of 180 genetic variants previously shown to be related to height on this relationship. Risk of CAD increased with the frequency of these height-related variants, suggesting that the relationship of height and CAD is due to genetic, and not environmental, factors. The authors searched for factors contributing to the reduction in CAD with increasing height by examining how 12 known CAD risk factors related to height. LDL cholesterol and triglycerides were greater in shorter individuals and explained 30% of the height–CAD relationship. Finally, the authors performed pathway analyses to identify biological mechanisms that could contribute to the effect of height on CAD risk. Signaling pathways for bone morphogenetic protein (BMP), transforming growth factor beta (TGFβ), insulin-like growth factor one (IGF-1), and signal transducer and activator of transcription 3 (STAT3) have all been shown to affect atherosclerosis in experimental models and were identified in the pathway analyses.
All of this suggests that genetic factors affect both height and CAD risk, but the explanation may be less genetics and more physics. Factors that change the vascular architecture, such as limb amputation, have long been known to be associated with an increased prevalence of aortic aneurysms,2 possibly because differences in distal flow affect the proximal aorta more. Similarly, changes in blood flow related to longer arteries in taller individuals could conceivably affect the atherosclerotic process in the coronaries. I guess not all good things come in small packages.
References