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Biochemical, Molecular, and Genetic Mechanisms

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^1–3,

⁴ Nutrition and Genomics Laboratory, Jean Mayer-USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111; ⁵ Department of Epidemiology, School of Public Health, and Clinical Nutrition Research Center, University of Alabama, Birmingham, AL 35294-0022; ⁶ Laboratory of Medicine and Pathology, and ⁷ Department of Experimental and Clinical Pharmacology Department, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455-0353; and ⁸ Division of Biostatistics, and ⁹ Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO 63108

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.

^* To whom correspondence should be addressed. E-mail: jose.ordovas{at}tufts.edu.

Manuscript received 21 October 2008. Initial review completed 13 December 2008. Revision accepted 24 February 2009.

Published online 25 March 2009.

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