HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.08-107086v1 22/9/3135    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Franks, P. W. Articles by Timmons, J. A. Search for Related Content PubMed PubMed Citation Articles by Franks, P. W. Articles by Timmons, J. A.

Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites

P. W. Franks^*,,1,2, C. Scheele^,,¶,1, R. J. F. Loos, A. R. Nielsen^¶, F. M. Finucane, C. Wahlestedt^||, B. K. Pedersen^¶, N. J. Wareham and J. A. Timmons^,

^* Genetic Epidemiology and Clinical Research Group, Department of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå, Sweden;

MRC Epidemiology Unit, Institute of Metabolic Sciences, Cambridge, UK;

The Wenner-Gren Institute, Arrhenius Laboratories, Stockholm University, Stockholm, Sweden;

School of Life Sciences, Heriot-Watt University, Edinburgh, UK;

^¶ Center of Inflammation and Metabolism, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; and

^|| Department of Biochemistry, Scripps Research Institute, Jupiter, Florida, USA

²Correspondence: Genetic Epidemiology and Clinical Research Group, Dept. of Public Health and Clinical Medicine, Division of Medicine, Umeå University Hospital, Umeå 90 187, Sweden. E-mail: paul.franks{at}medicin.umu.se

The purpose of this study was to characterize associations between PINK1 genotypes, PINK1 transcript levels, and metabolic phenotypes in healthy adults and those with type 2 diabetes (T2D). We measured PINK1 skeletal muscle transcript levels and 8 independent PINK1 single nucleotide polymorphisms (SNPs) in a cohort of 208 Danish whites and in a cohort of 1701 British whites (SNPs and metabolic phenotypes only). Furthermore, we assessed the effects of PINK1 transcript ablation in primary adipocytes using RNA interference (RNAi). Six PINK1 SNPs were associated with PINK1 transcript levels (P<0.04 to P<0.0001). Obesity modified the association between PINK1 transcript levels and T2D risk (interaction P=0.005); transcript levels were inversely related with T2D in obese (n=105) [odds ratio (OR) per SD increase in expression levels=0.44; 95% confidence interval (CI): 0.23, 0.84; P=0.013] but not in nonobese (n=103) (OR=1.20; 95% CI: 0.82, 1.76; P=0.34) individuals. In the British cohort, several PINK1 SNPs were associated with plasma nonesterified fatty acid concentrations. Nominal genotype associations were also observed for fasting glucose, 2-h glucose, and maximal oxygen consumption, although these were not statistically significant after correcting for multiple testing. In primary adipocytes, Pink1 knockdown affected fatty acid binding protein 4 (Fabp4) expression, indicating that PINK1 may influence substrate metabolism. We demonstrate that PINK1 polymorphisms are associated with PINK1 transcript levels and measures of fatty acid metabolism in a concordant manner, whereas our RNAi data imply that PINK1 may indirectly influence lipid metabolism.—Franks, P. W., Scheele, C., Loos, R. J. F., Nielsen, A. R., Finucane, F. M., Wahlestedt, C., Pedersen, B. K., Wareham, N. J., Timmons, J. A. Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites.

Key Words: oxidative metabolism • mitochondria • diabetes • single nucleotide polymorphism • gene-environment interaction