Paradoxical Lower Serum Triglyceride Levels and Higher Type 2 Diabetes Mellitus Susceptibility in Obese Individuals with the PNPLA3 148M Variant
Journal article, 2012

Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity. Methods and Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O. R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction = 0.002). This provides evidence for the obesity interaction with 148M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study. Conclusions: Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.




fatty liver-disease


metabolic syndrome



domain-containing 3

association analysis



C. N. A. Palmer

Cristina Maglio

University of Gothenburg

Carlo Pirazzi

University of Gothenburg

Maria A Burza

University of Gothenburg

Martin Adiels

University of Gothenburg

L. Burch

L. A. Donnelly

H. Colhoun

A. S. Doney

J. F. Dillon

E. R. Pearson

M. McCarthy

A. T. Hattersley

T. Frayling

A. D. Morris

Markku Peltonen

Per-Arne Svensson

University of Gothenburg

Peter Jacobson

University of Gothenburg

Jan Borén

University of Gothenburg

Lars Sjöström

University of Gothenburg

Lena M S Carlsson

University of Gothenburg

Stefano Romeo

University of Gothenburg


1932-6203 (ISSN)

Vol. 7 6

Subject Categories

Endocrinology and Diabetes



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