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

P. W. Franks, C. Scheele, R. J.F. Loos, A. R. Nielsen, F. M. Finucane, C. Wahlestedt, B. K. Pedersen, N. J. Wareham, J. A. Timmons

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12 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3135-3145
Number of pages11
JournalFASEB Journal
Volume22
Issue number9
DOIs
StatePublished - Sep 2008
Externally publishedYes

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Keywords

  • Diabetes
  • Gene-environment interaction
  • Mitochondria
  • Oxidative metabolism
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

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. (2008). Genomic variants at the PINK1 locus are associated with transcript abundance and plasma nonesterified fatty acid concentrations in European whites. FASEB Journal, 22(9), 3135-3145. https://doi.org/10.1096/fj.08-107086