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Title: Novel variants at KCTD10 and MVK/MMAB genes interact with dietary carbohydrates to modulate HDL-C concentrations in the genetics of lipid lowering drugs and diet network study

Author
item JUNYENT, MIREIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ARNETT, D - University Of Alabama
item TSAI, M - University Of Minnesota
item KABAGAMBE, E - University Of Alabama
item STRAKA, R - University Of Minnesota
item PROVINCE, M - Washington University
item AN, P - Washington University
item SMITH, C - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item BORECKI, I - Washington University
item Parnell, Laurence
item Lai, Chao Qiang
item LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item Ordovas, Jose

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2009
Publication Date: 7/15/2009
Citation: Junyent, M., Arnett, D.A., Tsai, M.Y., Kabagambe, E.K., Straka, R.J., Province, M., An, P., Smith, C., Borecki, I., Parnell, L.D., Lai, C., Lee, Y., Ordovas, J.M. 2009. Novel variants at KCTD10 and MVK/MMAB genes interact with dietary carbohydrates to modulate HDL-C concentrations in the genetics of lipid lowering drugs and diet network study. American Journal of Clinical Nutrition. 90(3):686-694.

Interpretive Summary: Several recent genetic studies have identified a region of three genes, KCTD10, MVK and MMAB, whose variants are associated with HDL-cholesterol (HDL-C) concentrations. Among environmental factors influencing HDL-C levels, diets high in carbohydrate have been associated with low HDL-C concentrations. In order to better distinguish which gene in this region has the strongest influence on HDL-C, we assayed eight different genetic variants across this region in 920 White persons. Biochemical measurements were determined by standard procedures. Dietary intake was estimated using a validated questionnaire. The common versions of one particular variant each from genes KCTD10 and MVK showed lower HDL-C concentrations. At the same time, a third variant, in gene MMAB, was linked to elevated LDL-cholesterol levels. Furthermore, only when the diet was high in carbohydrates did the KCTD10 and MMAB common variants showed lower, less healthy levels of HDL-C. These findings suggest that genetic variants of both genes KCTD10 and MMAB contribute to variation in HDL-C levels, particularly in persons with elevated intakes of carbohydrates.

Technical Abstract: Background - Several recent genome wide association studies have identified novel loci (KCTD10, MVK and MMAB) associated with HDL-C concentrations. Among environmental factors that influence HDL-C concentrations, high-carbohydrate diets have been associated with low concentrations. Objective - To evaluate the associations of eight single nucleotide polymorphisms (SNPs) located within the KCTD10, MVK and MMAB loci with lipid concentrations, and their potential interactions with dietary carbohydrates. Design - KCTD10, MVK and MMAB 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 determined by standard procedures. Dietary intake was estimated using a validated questionnaire. Results - For SNPs KCTD10_i5642G>C and MVK_S52NG>A, homozygotes for the major alleles (G) displayed lower HDL-C concentrations than did those carriers of the minor alleles (P=0.005 and P=0.019, respectively). Minor allele (G) homozygotes of SNP 12inter_108466061A>G exhibited higher total cholesterol and LDL-C concentrations than AG subjects (P=0.030 and P=0.034, respectively). Conversely, homozygotes for the major allele (G) at MMAB_3U3527G>C SNP, had higher LDL-C concentrations than did those carriers of the minor allele (P=0.034). Significant gene-diet interactions for HDL-C were found (P values ranging from <0.001 to 0.038), in which GG subjects at SNPs KCTD10_i5642G>C and MMAB_3U3527G>C and C allele carriers at SNP KCTD10_V206VT>C displayed lower concentrations, only if they consumed diets with high carbohydrates (P values ranging from <0.001 to 0.011). Conclusions - These findings suggest that KCTD10 (V206VT>C and i5642G>C) and MMAB_3U3527G>C genetic variants may contribute to HDL-C variation, particularly in subjects with high carbohydrate intakes.