AUTHOR=Hur Haeng Jeon , Yang Hye Jeong , Kim Min Jung , Lee Kyunhee , Jang Dai Ja , Kim Myung-Sunny , Park Sunmin 

TITLE=Interaction of energy and sulfur microbial diet and smoking status with polygenic variants associated with lipoprotein metabolism

JOURNAL=Frontiers in Nutrition

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2023.1244185

DOI=10.3389/fnut.2023.1244185

ISSN=2296-861X

ABSTRACT=<sec id="sec1"><title>Introduction</title><p>Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES).</p></sec><sec id="sec2"><title>Methods</title><p>Participants were categorized into the Low-HDL (case; <italic>n</italic> = 16,980) and Normal-HDL (<italic>n</italic> = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (&lt;40 mg/dL for men and &lt; 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters.</p></sec><sec id="sec3"><title>Results</title><p>The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely <italic>ZPR1</italic>_rs3741297, <italic>CETP</italic>_rs708272, <italic>BUD13</italic>_rs180327, and <italic>ALDH1A2</italic>_rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with <italic>p</italic> &lt; 5×10<sup>−8</sup>. The risk alleles of <italic>CETP</italic>_rs708272 and <italic>ALDH1A2</italic>_rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status.</p></sec><sec id="sec4"><title>Discussion</title><p>Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.</p></sec>