Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study.

Samantha A Streicher ,Steven Buchthal,Iona Cheng,Xin Sheng,Unhee Lim,Thomas Ernst,Lucy Xia,Victor Hom,Maarit Tiirikainen,David Bogumil,Yuqing Li,Veronica Wendy Setiawan,Loreall Pooler,Lenora W M Loo ,Heather M Highland ,Daniel O Stram ,Adrian A Franke ,Christopher A Haiman ,S Lani Park ,Burcu F Darst ,John Shepherd,Linda M Polfus ,Lynne R Wilkens ,Loı̈c Le Marchand

doi:10.1371/journal.pone.0249615

Abstract

Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10-8) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10-8) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89–1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO, and rs79967607 is in intron 1 of EPM2A. PLUTO, a lncRNA, regulates transcription of an adjacent gene, PDX1, that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes.

Highlights

Pancreatic fat accumulation was first described in the 1920s
Research has shown that the process of pancreatic fat infiltration and associated adverse health outcomes may be partially reversible through diet, exercise, and/or bariatric surgery [11,12,13], including a study that revealed reduction in pancreatic triglyceride levels only in type 2 diabetes (T2D) patients and not in normal glucose tolerance patients after bariatric surgery [13]
Rs73449607 was associated with decreased pancreatic fat content and decreased risk of T2D, and rs79967607 was associated with decreased pancreatic fat content, but not T2D

Summary

Introduction

Pancreatic fat accumulation ( referred to as pancreatic steatosis or pancreatic lipomatosis) was first described in the 1920s. Research has shown that the process of pancreatic fat infiltration and associated adverse health outcomes may be partially reversible through diet, exercise, and/or bariatric surgery [11,12,13], including a study that revealed reduction in pancreatic triglyceride levels only in type 2 diabetes (T2D) patients and not in normal glucose tolerance patients after bariatric surgery [13]. This finding, along with the research showing varying amounts of pancreatic fat by race/ ethnicity, further raise the possibility of a genetic component for pancreatic fat accumulation that has yet to be explored. In this study, we conducted a GWAS of pancreatic fat evaluated by MRI in the Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS) and examined two identified genome-wide significant variants for association with obesity-related biomarkers in MEC-APS, and with T2D in independent populations

Results

Discussion

Materials and methods