Quantile-Dependent Expressivity and Gene-Lifestyle Interactions Involving High-Density Lipoprotein Cholesterol

Abstract

<b><i>Background:</i></b> The phenotypic expression of a high-density lipoprotein (HDL) genetic risk score has been shown to depend upon whether the phenotype (HDL-cholesterol) is high or low relative to its distribution in the population (quantile-dependent expressivity). This may be due to the effects of genetic mutations on HDL-metabolism being concentration dependent. <b><i>Method:</i></b> The purpose of this article is to assess whether some previously reported HDL gene-lifestyle interactions could potentially be attributable to quantile-dependent expressivity. <b><i>Summary:</i></b><i></i>Seventy-three published examples of HDL gene-lifestyle interactions were interpreted from the perspective of quantile-dependent expressivity. These included interactive effects of diet, alcohol, physical activity, adiposity, and smoking with genetic variants associated with the <i>ABCA1</i>, <i>ADH3</i>,<i> ANGPTL4</i>, <i>APOA1</i>,<i> APOA4</i>,<i> APOA5</i>, <i>APOC3</i>,<i> APOE</i>,<i> CETP</i>,<i> CLASP1</i>,<i> CYP7A1</i>, <i>GALNT2</i>, <i>LDLR</i>,<i> LHX1</i>,<i> LIPC</i>,<i> LIPG</i>,<i> LPL</i>,<i> MVK-MMAB</i>,<i> PLTP</i>,<i> PON1</i>, <i>PPARα</i>,<i> SIRT1</i>,<i> SNTA1</i>,<i></i>and<i> UCP1</i>genes. The selected examples showed larger genetic effect sizes for lifestyle conditions associated with higher vis-à-vis lower average HDL-cholesterol concentrations. This suggests these reported interactions could be the result of selecting subjects for conditions that differentiate high from low HDL-cholesterol (e.g., lean vs. overweight, active vs. sedentary, high-fat vs. high-carbohydrate diets, alcohol drinkers vs. abstainers, nonsmokers vs. smokers) producing larger versus smaller genetic effect sizes. <b><i>Key Message:</i></b> Quantile-dependent expressivity provides a potential explanation for some reported gene-lifestyle interactions for HDL-cholesterol. Although overall genetic heritability appears to be quantile specific, this may vary by genetic variant and environmental exposure.