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Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts

¹ Division of Diabetes, Department of Medicine, University of Helsinki, FIN-00029 Helsinki, Finland² Minerva Medical Research Institute, Helsinki, Finland³ Atherosclerosis Research Unit, Department of Medicine (Solna), Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital (L8:03), SE-171 76 Stockholm, Sweden⁴ The Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland⁵ Obesity Research Unit, Helsinki University Central Hospital, FIN-00029 Helsinki, Finland⁶ British Heart Foundation Laboratories, Department of Medicine, Centre for Cardiovascular Genetics, Royal Free and University College Medical School, London WC1E 6JF, UK⁷ Folkhälsan Research Center, Helsinki, Finland⁸ Malmska Municipal Health Care Center and Hospital, FIN68601 Jakobstad, Finland⁹ Department of Clinical Sciences, Diabetes and Endocrinology, University Hospital Malmö, Lund University, SE-205 02 Malmö, Sweden

(Correspondence should be addressed to R M Fisher; Email: rachel.fisher{at}ki.se)

^* R M Fisher and E Ehrenborg are joint senior authors for this manuscript.

Aims: We investigated whether polymorphisms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver fat content.

Methods: Liver fat content was measured using proton magnetic resonance spectroscopy (¹H-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4), adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were studied in two independent cohorts and related to surrogate markers of liver fat content.

Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with ¹H-MRS after adjusting for age, gender, and BMI. Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum glutamyltransferase concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of 3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations.

Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.