In this study, we found an association between a genetically determined decrease in height and an increased risk of CAD. Our finding validates the epidemiologic observation of an inverse association between height and CAD.1,2

Figure 3. Figure 3. Interpreting the Association between Genetically Determined Shorter Height and Increased Risk of CAD. The main advantage of the genetic approach is that it reduces the likelihood of known and unknown demographic, lifestyle, socioeconomic, or behavioral confounders that have an independent effect on height and the risk of CAD (solid black lines) and could give rise to a false association between the two factors. It is possible that the association between the studied genetic variants and height and the association with CAD are through completely different mechanisms (dashed black lines). However, the more likely scenario on the basis of our findings is that height variants affect biologic pathways, which on the one hand determine achieved height and on the other hand influence the risk of CAD (solid red lines). It is also possible that genetically determined height itself alters lifestyle or behavior, which then affects the risk of CAD (dashed red line).

A key advantage of using a genetic approach over a traditional epidemiologic approach to investigate an association such as that between height and CAD is that genotypes (because they are randomly distributed at birth) are unlikely to be confounded by lifestyle or environmental factors. Regardless of whether such factors are known (e.g., poor nutrition or socioeconomic conditions during childhood) or unknown, they can independently affect achieved height and the risk of CAD and lead to a spurious association between them (Figure 3). It is nonetheless possible that the genetic variants themselves affect height and CAD risk through entirely different mechanisms. However, given the large number of variants that we included in the analysis, all of which were selected only because of their association with height, it is likely that at least some of the processes are shared. This hypothesis is supported by the finding from the individual-level analysis of genetic risk score showing a direct correlation between the presence of an increasing number of height-related alleles and a reduction in the risk of CAD (Figure 2).

A genetic approach also offers novel methods to explore potential mechanisms linking shorter height with an increased risk of CAD (Figure 3). In this context, we performed two analyses. First, we applied the same genetic approach to investigate the association between height-related genetic variants and several established and potential cardiovascular risk factors. Notable negative findings here include the lack of an overall effect of height-associated SNPs on body-mass index. This suggests that the association between shorter stature and an increased risk of CAD is not mediated by an effect on obesity. On the other hand, there was a significant overall association between height SNPs and LDL cholesterol and triglycerides in a direction consistent with their association with CAD. The association between shorter stature and increased plasma LDL cholesterol and triglyceride levels has also been observed in epidemiologic studies.2 The mechanisms by which height-associated SNPs have an effect on LDL cholesterol and triglyceride levels are not clear. In any case, these effects in combination potentially explain less than one third of the observed association between genetically determined shorter height and an increased risk of CAD.

Second, we performed pathway analysis, which identified a number of overlapping pathways linking height-associated SNPs that could also have an effect on the risk of CAD, including the BMP- and TGF-β–signaling pathways, axon-guidance pathways, and the STAT3 and IGF-I pathways, all of which have experimentally documented roles in the development of atherosclerosis.21-26 The limitations of pathway analysis included the need to assign a specific gene for each height-associated locus and incomplete knowledge regarding how such pathways are constructed. (A fuller discussion of the pathways is provided in the Supplementary Appendix.) Taken together, these findings suggest that several overlapping and complex biologic pathways on the one hand influence development and height and on the other hand influence the risk of atherosclerosis through an effect on vascular biology and function (Figure 3).

In contrast to epidemiologic studies in which a similar inverse association between height and CAD was present in both men and women,2 we did not see a significant association in women. Whether this represents a genuine difference in the effect of genetically determined height on the risk of CAD between men and women or simply reflects the reduced power from the much smaller sample size available for analysis in women is unclear. Notably, the effect sizes that were observed in men and women were not significantly different in an interaction analysis.

Height and other measurements of body size have a positive correlation with the diameter of coronary arteries.27 Therefore, a potential simple explanation for an increased risk of CAD in shorter persons is that they have proportionally smaller-caliber coronary arteries, so a similar plaque burden could result in greater probability of symptomatic disease. However, women also have smaller-caliber arteries than men, independent of body size and height.27 Reduced height and female sex would therefore be expected to have an additive effect if this was the mechanism linking shorter height with an increased risk of CAD. In this context, the finding of a weaker association between genetically determined shorter height and CAD in women than in men would argue against a structural explanation on the basis of coronary-vessel caliber as the main explanation for the inverse association between height and CAD.

Although the genetic approach that we used allows us to reduce the possibility of confounding of any observed association by socioeconomic, lifestyle, or environmental factors, it does not rule out the possibility that the association between genetically determined shorter height with an increased risk of CAD is due to lifestyle choices or behavior adopted by such persons as a direct consequence of being shorter (Figure 3). Indeed, in an exemplar exploration of this possibility, we examined whether the height-related variants showed an association with the quantity of cigarettes smoked among smokers but found no evidence for this hypothesis (Table 1). Other relevant behavioral changes that could have an effect on the risk of CAD that could be adopted by persons of short stature include those related to diet, physical activity, and alcohol consumption.

In conclusion, using a genetic approach, we found an association between genetically determined shorter height and an increased risk of CAD. Part of this inverse association may be driven by the association between shorter height and an adverse lipid profile, although the majority of the relationship is likely to be determined by shared biologic processes that determine achieved height and atherosclerosis development. More generally, our findings underscore the complexity underlying the inherited component of CAD.