SNPs in apolipoproteins contribute to sex-dependent differences in blood lipids before and after a high-fat dietary challenge in healthy U.S. adults

Authors: WANG, YINING - University Of California, Davis; Kirschke, Catherine; Woodhouse, Leslie; Bonnel, Ellen; Stephensen, Charles; Bennett, Brian; Newman, John; Keim, Nancy; Huang, Liping

Submitted to: BMC Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/21/2022
Publication Date: 9/1/2022
Citation: Wang, Y.E., Kirschke-Schneide, C.P., Woodhouse, L.R., Bonnel, E.L., Stephensen, C.B., Bennett, B.J., Newman, J.W., Keim, N.L., Huang, L. 2022. SNPs in apolipoproteins contribute to sex-dependent differences in blood lipids before and after a high-fat dietary challenge in healthy U.S. adults. Biomed Central (BMC) Nutrition. 8. Article 95. https://doi.org/10.1186/s40795-022-00592-x.
DOI: https://doi.org/10.1186/s40795-022-00592-x

Interpretive Summary: Higher blood lipid levels are major risk factors for cardiovascular diseases. Cholesterol and fat circulate in the blood via several protein (apolipoprotein)-containing particles. The current study was aimed to investigate the association of single nucleotide polymorphisms (SNPs) in apolipoprotein-related genes with blood lipid levels in healthy adults in the U.S. A SNP is a single base pair change in the DNA genome sequence. When arising in genes, SNPs may influence the amount of the gene products produced, such as apolipoproteins, which directly impact on the levels of lipids in the circulation. Healthy men and women (n =393) between 18-66 years of age with BMIs ranging from 18.5-45 were enrolled and completed the cross-sectional Nutritional Phenotyping Study. Among them, 349 subjects (men =167, 48%; women =182, 52%) were consented for genotyping. SNPs in several apolipoprotein genes, such as APOA5, APOB, APOC3, and APOE as well as a lipoprotein binding receptor gene, LDLR, were genotyped. Our results demonstrate that cholesterol in HDL particles were lower in women carrying a risk C genotype of APOA5 rs3135506 whereas men carrying a risk C allele of the APOE SNP (rs429358) had higher LDL-C levels than the non-carriers in both fasting and postprandial states. The APOC3 rs2854116 TT genotype was associated with elevated total cholesterol in both genders. Nevertheless, these SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. In addition, the TT genotype of APOC3 rs2854116 had an adverse effect on total cholesterol levels observed in both men and women. Moreover, no significant effects of SNPs in APOB rs429358 or LDLR rs2228671 on blood lipid profiles were found during fasting or after the high-fat meal challenge. We conclude that cholesterol levels are strongly correlated with genotypes of the SNPs in APOA5 and APOE in a sex-dependent manner in healthy adults. However, the postprandial triglyceride appearance or clearance after a high-fat dietary challenge seemed unaffected by the SNPs investigated.

Technical Abstract: The effect of genetic polymorphisms on fasting blood lipid levels have been widely studied but the effects of these within the context of a meal challenge remains less characterized. The current study aimed to investigate the association of SNPs in lipoprotein-related genes with blood lipid levels in healthy adults in the U.S. Men and women (n = 393) between 18-66 years of age with BMIs ranging from 18.5-45 kg/m2 completed the cross-sectional Nutritional Phenotyping Study. Among them, 349 subjects (men = 167, 48%; women = 182, 52%) gave consent for genotyping. SNPs in APOA5, APOB, APOC3, APOE, and LDLR were assessed. We found that reduced blood HDL-cholesterol levels were associated with the C allele of the APOA5 SNP (rs3135506) in women and the C allele of the APOE SNP (rs429358) in men in both fasting and postprandial states. The C allele of the APOE SNP was also correlated with increased LDL-C levels. The APOC3 rs2854116 TT genotype was associated with elevated total cholesterol in both genders. Nevertheless, these SNPs had little impact on the postprandial triglyceride responses to the high-fat challenge meal. Additionally, no significant effects of SNPs in APOB (rs1042034) and LDLR (rs2228671) on TG, cholesterol, or NEFA levels were found. In conclusion, cholesterol levels are strongly correlated with genotypes of the SNPs in APOA5 and APOE in a sex-dependent manner in healthy adults.