Sex-specific interaction between APOE genotype and carbohydrate intake affects plasma HDL-C levels: the Strong Heart Family Study

Abstract

Low plasma levels of high-density lipoprotein cholesterol (HDL-C) are identified as a risk factor for cardiovascular disease (CVD). Sexual dimorphism, however, is widely reported in both HDL-C and CVD, with the underlying explanations of these sexual differences not fully understood. HDL-C is a complex trait influenced by both genes and dietary factors. Here we examine evidence for a sex-specific effect of APOE and the macronutrient carbohydrate on HDL-C, triglycerides (TG) and apoprotein A-1 (ApoA-1) in a sample of 326 male and 423 female participants of the Strong Heart Family Study (SHFS). Using general estimating equations in SAS to account for kinship correlations, stratifying by sex, and adjusting for age, body mass index (BMI) and SHS center, we examine the relationship between APOE genotype and carbohydrate intake on circulating levels of HDL-C, TG, and ApoA-1 through a series of carbohydrate-by-sex interactions and stratified analyses. APOE-by-carbohydrate intake shows significant sex-specific effects. All males had similar decreases in HDL-C levels associated with increased carbohydrate intake. However, only those females with APOE-4 alleles showed significantly lower HDL-C levels as their percent of carbohydrate intake increased, while no association was noted between carbohydrate intake and HDL-C in those females without an APOE-4 allele. These findings demonstrate the importance of understanding sex differences in gene-by-nutrient interaction when examining the complex architecture of HDL-C variation.

Elevated PLA2G7 Gene Promoter Methylation as a Gender-Specific Marker of Aging Increases the Risk of Coronary Heart Disease in Females

“…As shown in the Figure S1, there is an APOE -dependent correlation between PLA2G7 expression and aging in mice (F = 12.42, P = 0.0074) [52]. Moreover, a female-specific interaction was found between APOE4 genotype and the metabolism of HDL [53], which is an important protective factor in cardiovascular diseases including CHD. Another piece of evidence has shown a significant association between APOE expression and aging [54].…”

Genetic causes of high and low serum HDL-cholesterol

“…Therefore, the possibility of an interaction between gender and genetic factors has been explored in several studies ( 227,228 ). Recently, a GWA study of 18,245 women from a population-based prospective cohort identifi ed a novel locus for HDL-C at 2q24.3 near the genes COBLL1 and GRB14 ( 154 ).…”

Apolipoprotein E Genotype, Meat, Fish, and Egg Intake in Relation to Mortality Among Older Adults: A Longitudinal Analysis in China

“…APOE is a multifunctional protein which transports and delivers cholesterol and other lipids in the plasma via binding to cell surface apoE receptors (28). Carriers of the ε4 allele of the APOE gene have higher total and low-density lipoprotein cholesterol levels than non-carriers (29)(30)(31)(32)(33).…”