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

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.

Fig 1. Manhattan plot of SNP P-values from the pancreas fat genome-wide association study in the Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS).

The Y-axis shows the negative base ten logarithm of the P-values and the X-axis shows the chromosomes. The genome-wide significance threshold, P<5x10^-8, is shown in red.

Fig 2. Regional plots of SNP P-values in a +/-200 kb window around rs73449607 and rs79967607.

The X-axis shows the chromosome and physical location (Mb), the left Y-axis shows the negative base ten logarithm of the P-values, and the right Y-axis shows recombination activity (cM/Mb) as a blue line. Positions, recombination rates, and gene annotations are according to NCBI’s build 37 (hg 19) and the 1000 Genomes Project Phase 3 multiethnic data set.