Protein and fat intake interacts with the haplotype of PTPN11_rs11066325, RPH3A_rs886477, and OAS3_rs2072134 to modulate serum HDL concentrations in middle-aged people.

Background & Aims: Low serum HDL cholesterol (HDL-C) concentration is a risk factor for cardiovascular diseases and it is influenced by genetic and environmental factors. We hypothesized that genetic variants that decrease serum HDL-C concentrations may interact with nutrient intakes in ways that increase or decrease the risk of cardiovascular disease.

Methods: Candidate genetic variants that can lower serum HDL-C concentrations were explored by genome-wide association studies (GWAS), after adjusting for covariates, in the Ansan/Ansung cohort (n = 8842) from KoGES. The best genetic variants were selected and used to form a haplotype. According to the haplotype frequencies of SNPs, they were divided into major allele, heterozygote allele, and minor allele. The association of haplotype with serum HDL-C levels was determined using logistic regression after adjusting for confounding factors. Interaction of the haplotype with nutrient intake was also determined.

Results: PTPN11_rs11066325, RPH3A_rs886477 and OAS3_rs2072134 were selected to modulate serum HDL-C levels from GWAS(P = 1.09E-09, 7.04E-10, and 1.27E-09, respectively). The adjusted odds ratios (ORs) for a decrease in serum HDL-C concentration in the minor-allele group of the haplotype were elevated by 1.534 fold, compared to the major-allele group of the haplotype. Furthermore, the adjusted ORs for serum LDL cholesterol and levels increased by 1.645 in the minor-alleles compared to the major-alleles of the haplotype without a significant change of serum cholesterol levels. Interestingly, the adjusted ORs for serum triglyceride were lower in the minor-alleles than in the major-alleles. The haplotype had a significant interaction with the intake of protein, fat, saturated fatty acids (SAF) and polyunsaturated fatty acids (PUFA; P < 0.05). In particular, the minor alleles of the haplotype decreased serum HDL-C levels compared to the major-alleles in the high intake of protein, fat, SFA, and PUFA, not in the low intake.

Conclusions: People carrying the minor-allele of haplotypes should avoid diets that are high in protein and fat, especially rich in SFA and PUFA.