Molecular Biophysics & Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California, USA,
Lifestyle Genom. 2021;14(1):1-19. doi: 10.1159/000511421. Epub 2020 Dec 9.
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.
The purpose of this article is to assess whether some previously reported HDL gene-lifestyle interactions could potentially be attributable to quantile-dependent expressivity.
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.
高密度脂蛋白（HDL）遗传风险评分的表型表达取决于表型（HDL-胆固醇）相对于其在人群中的分布（分位数依赖表达）是高还是低。这可能是由于遗传突变对 HDL 代谢的影响是浓度依赖性的。
本文旨在评估先前报道的一些 HDL 基因-生活方式相互作用是否可能归因于分位数依赖表达。
从分位数依赖表达的角度解释了 73 个已发表的 HDL 基因-生活方式相互作用的例子。这些包括饮食、酒精、体力活动、肥胖和吸烟与 ABCA1、ADH3、ANGPTL4、APOA1、APOA4、APOA5、APOC3、APOE、CETP、CLASP1、CYP7A1、GALNT2、LDLR、LHX1、LIPC、LIPG、LPL、MVK-MMAB、PLTP、PON1、PPARα、SIRT1、SNTA1 和 UCP1 基因相关的遗传变异之间的交互作用。所选实例显示，与较高平均 HDL-胆固醇浓度相关的生活方式条件的遗传效应大小较大。这表明，这些报告的相互作用可能是由于选择具有区分高低 HDL-胆固醇的条件的个体（例如，瘦与超重、活跃与久坐、高脂肪与高碳水化合物饮食、饮酒者与不饮酒者、不吸烟者与吸烟者）产生较大与较小的遗传效应大小。
分位数依赖表达为一些报告的 HDL-胆固醇基因-生活方式相互作用提供了潜在的解释。尽管总体遗传可遗传性似乎是分位数特异性的，但这可能因遗传变异和环境暴露而异。
