Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women

Authors: JUNYENT, MIREIA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ARNETT, D - University Of Alabama; TSAI, M - University Of Minnesota; KABAGAMBE, E - University Of Alabama; STRAKA, R - University Of Minnesota; PROVINCE, M - Washington University; AN, P - Washington University; SHEN, J - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BORECKI, I - Washington University; Parnell, Laurence; Lai, Chao Qiang; LEE, YU-CHI - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/16/2009
Publication Date: 6/1/2009
Citation: Junyent, M., Arnett, D.A., Tsai, M.Y., Kabagambe, E.K., Straka, R.J., Province, M., An, P., Shen, J., Borecki, I., Parnell, L.D., Lai, C., Lee, Y., Ordovas, J.M. 2009. Genetic Variants at the PDZ-Interacting Domain of the Scavenger Receptor Class B Type I Interact with Diet to Influence the Risk of Metabolic Syndrome in Obese Men and Women. Journal of Nutrition. 139(6):842-848.

Interpretive Summary: The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the activity of a critical receptor of HDL-cholesterol (HDL-C). The effect of PDZK1 genetic variants, however, on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of three of genetic variants of PDZK1 with blood lipids and risk of MetS, as well as influence by the diet. PDZK1 variants were assayed in 1000 White American persons and blood lipid sub-fractions were measured and dietary intake was estimated with a validated questionnaire. One particular genetic variant of PDZK1 (i33968C>T) was correlated with incidence of MetS, mainly via higher plasma levels of triglycerides and very low density lipoprotein (VLDL) levels, in persons carrying the less common T variant. The deleterious association of this T variant with MetS was noted in obese persons who had high dietary intakes of poly-unsaturated fat (PUFA) and carbohydrate. Conversely, there was a protective effect in non-obese persons with high PUFA intake. These findings suggest that the PDZK1 variant i33968C>T may be associated with higher risk of exhibiting MetS. The interaction and impact of a person’s obesity status (body mass index or BMI) offer the potential to identify dietary and other lifestyle changes that may obviate the onset of MetS in persons with a specific genetic background.

Technical Abstract: The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymorphisms (SNP) (i33968C > T, i15371G > A, and i19738C > T) with lipids and risk of MetS and their potential interactions with diet. PDZK1 SNP were genotyped in 1000 participants (481 men, 519 women) included in the Genetics of Lipid Lowering Drugs and Diet Network study. Lipoprotein subfractions were measured by proton NMR spectroscopy and dietary intake was estimated using a validated questionnaire. The PDZK1_i33968C > T polymorphism was associated with MetS (P = 0.034), mainly driven by the association of the minor T allele with higher plasma triglycerides (P = 0.004) and VLDL (P = 0.021), and lower adiponectin concentrations (P = 0.022) than in participants homozygous for the major allele (C). We found a significant gene x BMI x diet interaction, in which the deleterious association of the i33968T allele with MetS was observed in obese participants with high PUFA and carbohydrate (P-values ranging from 0.004 to 0.020) intakes. Conversely, a there was a protective effect in nonobese participants with high PUFA intake (P < 0.05). These findings suggest that PDZK1_i33968C > T genetic variants may be associated with a higher risk of exhibiting MetS. This gene x BMI x diet interaction offers the potential to identify dietary and other lifestyle changes that may obviate the onset of MetS in individuals with a specific genetic background.