Genetically determined height and coronary artery disease

Abstract

Background: 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 quartile 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. (Funded by the British Heart Foundation and others.).

Figure 1. Forest Plot Showing the Effect Size of Height on the Risk of Coronary Artery Disease (CAD) for Each Height-Associated Genetic Variant

Shown are odds ratios for each height-associated single-nucleotide polymorphism (SNP) for β₃ values (i.e., the putative association between height and CAD mediated through that variant). The number of cases and controls that were analyzed for each variant are shown. The β₃ odds ratios are organized in ascending values across two panels for ease of visualization. The overall β₃ estimate (shown in red) is from a random-effects meta-analysis of all SNPs.

Figure 1. Forest Plot Showing the Effect Size of Height on the Risk of Coronary Artery Disease (CAD) for Each Height-Associated Genetic Variant

Shown are odds ratios for each height-associated single-nucleotide polymorphism (SNP) for β₃ values (i.e., the putative association between height and CAD mediated through that variant). The number of cases and controls that were analyzed for each variant are shown. The β₃ odds ratios are organized in ascending values across two panels for ease of visualization. The overall β₃ estimate (shown in red) is from a random-effects meta-analysis of all SNPs.

Figure 2. Analysis of the Association between the Presence of an Increasing Number of Height-Related Alleles and the Risk of CAD, According to Quartile of Genetic Risk Score (GRS)

The analysis was performed in 18,249 samples (including 8240 obtained from patients with CAD) with the use of individual-level genotype data. Shown are odds ratios and 95% confidence intervals. Participants were divided into quartiles on the basis of the number of height-increasing alleles that were present, with quartile 1 (reference quartile) carrying the fewest.

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).