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Novel variants at KCTD10, MVK, and MMAB genes interact with dietary carbohydrates to modulate HDL-cholesterol concentrations in the Genetics of Lipid Lowering Drugs and Diet Network Study^1,2,3,4

¹ From the Nutrition and Genomics Laboratory, JM-USDA-HNRCA at Tufts University, Boston, MA (MJ, LDP, C-QL, Y-CL, CES, and JMO); the Department of Epidemiology, School of Public Health, and Clinical Nutrition Research Center, University of Alabama at Birmingham, Birmingham, AL (DKA and EKK); the Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, MN (MYT); the Department of Experimental and Clinical Pharmacology Department, College of Pharmacy, University of Minnesota, MN (RJS); the Division of Biostatistics, Washington University School of Medicine, St Louis, MO (MP and IB); and the Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO (PA).

² Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study—ID no. R01 HL091357 (https://dsgweb.wustl.edu/goldn).

³ Supported by grant U01 HL72524 from the National Institutes of Health, Heart, Lung, and Blood Institute; grants HL-54776 and DK075030 from the Genetic and Environmental Determinants of Triglycerides, and contracts 53-K06-5-10 and 58-1950-9-001 from the US Department of Agriculture Research Service. MJ was supported by a grant from the Fulbright-Spanish Ministry of Education and Science (reference 2007-1086). CES was supported by grant T32 DK007651-19.

⁴ Address correspondence to M Junyent, Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: mireia.junyent{at}tufts.edu.

Background: Several genome-wide association studies have identified novel loci (KCTD10, MVK, and MMAB) that are associated with HDL-cholesterol concentrations. Of the environmental factors that determine HDL cholesterol, high-carbohydrate diets have been shown to be associated with low concentrations.

Objective: The objective was to evaluate the associations of 8 single nucleotide polymorphisms (SNPs) located within the KCTD10, MVK, and MMAB loci with lipids and their potential interactions with dietary carbohydrates.

Design: KCTD10, MVK, and MMAB SNPs were genotyped in 920 subjects (441 men and 479 women) who participated in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. Biochemical measurements were made by using standard procedures. Dietary intakes were estimated by using a validated questionnaire.

Results: For the SNPs KCTD10_i5642GC and MVK_S52NGA, homozygotes for the major alleles (G) had lower HDL-cholesterol concentrations than did carriers of the minor alleles (P = 0.005 and P = 0.019, respectively). For the SNP 12inter_108466061AG, homozygotes for the minor allele (G) had higher total cholesterol and LDL-cholesterol concentrations than did AG subjects (P = 0.030 and P = 0.034, respectively). Conversely, homozygotes for the major allele (G) at MMAB_3U3527GC had higher LDL-cholesterol concentrations than did carriers of the minor allele (P = 0.034). Significant gene-diet interactions for HDL cholesterol were found (P < 0.001–0.038), in which GG subjects at SNPs KCTD10_i5642GC and MMAB_3U3527GC and C allele carriers at SNP KCTD10_V206VTC had lower concentrations only if they consumed diets with a high carbohydrate content (P < 0.001–0.011).

Conclusion: These findings suggest that the KCTD10 (V206VTC and i5642GC) and MMAB_3U3527GC variants may contribute to the variation in HDL-cholesterol concentrations, particularly in subjects with high carbohydrate intakes.