Paradoxical lower serum triglyceride levels and higher type 2 diabetes mellitus susceptibility in obese individuals with the PNPLA3 148M variant

Colin N A Palmer, Cristina Maglio, Carlo Pirazzi, Maria Antonella Burza, Martin Adiels, Lindsay Burch, Louise A Donnelly, Helen Colhoun, Alexander S Doney, John F Dillon, Ewan R Pearson, Mark McCarthy, Andrew T Hattersley, Tim Frayling, Andrew D Morris, Markku Peltonen, Per-Arne Svensson, Peter Jacobson, Jan Borén, Lars Sjöström, Lena M S Carlsson, Stefano Romeo, Colin N A Palmer, Cristina Maglio, Carlo Pirazzi, Maria Antonella Burza, Martin Adiels, Lindsay Burch, Louise A Donnelly, Helen Colhoun, Alexander S Doney, John F Dillon, Ewan R Pearson, Mark McCarthy, Andrew T Hattersley, Tim Frayling, Andrew D Morris, Markku Peltonen, Per-Arne Svensson, Peter Jacobson, Jan Borén, Lars Sjöström, Lena M S Carlsson, Stefano Romeo

Abstract

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 I48M 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.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Study design.
Figure 1. Study design.
PNPLA3 I148M was genotyped in the Swedish Obese Subjects (SOS) study (A) and Genetics of Diabetes Audit and Research Tayside Scotland (Go-DARTS) study (B) participants (n = 3,473 and 15,448 respectively).
Figure 2. Serum triglycerides and homeostasis model…
Figure 2. Serum triglycerides and homeostasis model assessment for insulin resistance (HOMA-IR) at 2- and 10-year follow-up.
Serum triglycerides (panel A and B) levels and HOMA-IR (panel C and D) at 2- and 10- year follow up (FU) in the control (A, C) and the surgery (B, D) group across the PNPLA3 genotypes. Values are means and standard deviations. * HOMA-IR values are shown only in non-diabetic individuals.

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