Human Molecular Genetics Advance Access originally published online on September 3, 2009
Human Molecular Genetics 2009 18(23):4669-4676; doi:10.1093/hmg/ddp424
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins
1 Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology and 2 Department of Neurology, Innsbruck Medical University, Innsbruck, Austria, 3 Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland, 4 Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany, 5 Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany 6 Institute for Community Medicine, University of Greifswald, Greifswald, Germany, 7 Helmholtz Zentrum München, Institute of Epidemiology, Neuherberg, Germany, 8 Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands, 9 Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, UT, USA, 10 First Department of Internal Medicine, Paracelsus Private Medical University, Salzburg, Austria, 11 Institute of Clinical Chemistry and Laboratory Medicine, University of Greifswald, Greifswald, Germany and 12 Genetics Division, R&D GlaxoSmithKline, King of Prussia, PA, USA
* To whom correspondence should be addressed at: Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Innsbruck Medical University, Schöpfstr. 41, A-6020 Innsbruck, Austria, Tel: +43 512900370560; Fax: +43 512900373560 or 73561; Email: florian.kronenberg{at}i-med.ac.at
Received July 23, 2009; Accepted September 1, 2009
Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m2) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 x 10–7), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 x 10–6) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 x 10–4). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoproteins.