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

Pubmed ID: 33296900

Pubmed Central ID: PMC8116986

Journal: Lifestyle genomics

Publication Date: Jan. 1, 2021

MeSH Terms: Humans, Polymorphism, Single Nucleotide, Life Style, Diet, Alcohol Drinking, Cholesterol, HDL, Genetic Association Studies, Metabolic Networks and Pathways, Gene-Environment Interaction, Cholesterol 7-alpha-Hydroxylase, Cholesterol Ester Transfer Proteins, Lipase

Grants: R21 ES020700

Authors: Williams PT

Cite As: Williams PT. Quantile-Dependent Expressivity and Gene-Lifestyle Interactions Involving High-Density Lipoprotein Cholesterol. Lifestyle Genom 2021;14(1):1-19. Epub 2020 Dec 9.

Studies:

Abstract

BACKGROUND: 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. METHOD: The purpose of this article is to assess whether some previously reported HDL gene-lifestyle interactions could potentially be attributable to quantile-dependent expressivity. SUMMARY: 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 ABCA1, ADH3, ANGPTL4, APOA1, APOA4, APOA5, APOC3, APOE, CETP, CLASP1, CYP7A1, GALNT2, LDLR, LHX1, LIPC, LIPG, LPL, MVK-MMAB, PLTP, PON1, PPARα, SIRT1, SNTA1,and UCP1genes. 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. Key Message: 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.