Background:

The effect of genetic polymorphisms on fasting blood lipid levels have been widely studied but the effects of these within the context of a high-fat meal challenge remain less characterized. The current study aimed to investigate the association of SNPs in lipoprotein-related genes with blood lipid profiles in healthy adults in the U.S.

Methods:

Subjects (n=393) between 18-66 years of age with BMIs ranging from 18.5-45 kg/m 2 completed the cross-sectional Nutritional Phenotyping Study. Among them, 349 subjects (men: 48%; women: 52%) gave consent for genotyping. SNPs in APOA5 , APOB , APOC3 , APOE , and LDLR were assessed. The association between lipid markers and genotypes was tested separately for each SNP with analysis of variance (ANOVA), adjusted for sex, age, and BMI. We also examined two-factor interactions between SNPs and sex, age, or BMI.

Results:

Women carrying the C allele of rs3135506 in APOA5 or men carrying the C allele of rs429358 in APOE had reduced HDL-cholesterol levels during fasting and postprandially. The C allele in APOE was also correlated to increased LDL-C levels. The TT genotype of rs2854116 in APOC3 was associated with elevated total cholesterol. Additive effect of the risk alleles of APOA5 and APOE or APOC3 and APOE was detected. Nevertheless, the tested SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. We found no significant effects of SNPs in APOB (rs1042034) or LDLR (rs2228671) on triglycerides, cholesterol, or free fatty acid levels.

Conclusions:

In healthy adults, fasting and postprandial cholesterol levels are strongly correlated with the tested APOA5 , APOE , and APOC3 genotypes. Sex attributes to the genetic impact of the tested SNPs on lipid profiles. Trial registration: ClinicalTrials.gov, NCT02367287. Registered February 20, 2015, https://clinicaltrials.gov/ct2/show/NCT02367287.

Background

The common C-allele of rs13266634 (c.973C>T or p.Arg325Trp) in SLC30A8 (ZNT8) is associated with increased risk of type 2 diabetes. While previous studies have examined the correlation of the variant with insulin and glucose metabolism, the effects of this variant on insulin and lipid responses after a lipid challenge in humans remain elusive. The goal of this study was to determine whether the C-allele had an impact on an individual's risk to metabolic syndromes in U.S. adults.

Method

We studied the genotypes of rs13266634 in 349 individuals aged between 18 and 65 y with BMI ranging from 18.5 to 45 kg/m². The subjects were evaluated for insulin, glucose, HbA1c, ghrelin, and lipid profiles before and after a high-fat mixed macronutrient tolerance test (MMTT).

Results

We found that the effects of variants rs13266634 on glucose and lipid metabolism were sex-dimorphic, greater impact on males than on females. Insulin incremental area under the curve (AUC) after MMTT was significantly decreased in men with the CC genotype (p < 0.05). Men with the CC genotype also had the lowest fasting non-esterified fatty acid (NEFA) concentrations. On the other hand, the TT genotype was associated with a slower triglyceride removal from the circulation in men after MMTT. The reduced triglyceride removal was also observed in subjects with BMI ≥ 30 carrying either the heterozygous or homozygous T-allele. Nevertheless, the SNP had little effect on fasting or postprandial blood glucose and cholesterol concentrations.

Conclusion

We conclude that the CC genotype negatively affects insulin response after MMTT while the T-allele may negatively influence lipolysis during fasting and postprandial blood triglyceride removal in men and obese subjects, a novel finding in this study.