Dataset Information

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

ABSTRACT:

Background

Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.

Methods

We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m²) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics.

Results

No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10^-6) was observed in the meta-analysis (P _GxE = 1.2 ×10^-6, P _Joint = 4.2 ×10^-7).

Conclusions

This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans.

Impact

This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

SUBMITTER: Tang H

PROVIDER: S-EPMC7483330 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Tang Hongwei H Jiang Lai L Stolzenberg-Solomon Rachael Z RZ Arslan Alan A AA Beane Freeman Laura E LE Bracci Paige M PM Brennan Paul P Canzian Federico F Du Mengmeng M Gallinger Steven S Giles Graham G GG Goodman Phyllis J PJ Kooperberg Charles C Le Marchand Loïc L Neale Rachel E RE Shu Xiao-Ou XO Visvanathan Kala K White Emily E Zheng Wei W Albanes Demetrius D Andreotti Gabriella G Babic Ana A Bamlet William R WR Berndt Sonja I SI Blackford Amanda A Bueno-de-Mesquita Bas B Buring Julie E JE Campa Daniele D Chanock Stephen J SJ Childs Erica E Duell Eric J EJ Fuchs Charles C Gaziano J Michael JM Goggins Michael M Hartge Patricia P Hassam Manal H MH Holly Elizabeth A EA Hoover Robert N RN Hung Rayjean J RJ Kurtz Robert C RC Lee I-Min IM Malats Núria N Milne Roger L RL Ng Kimmie K Oberg Ann L AL Orlow Irene I Peters Ulrike U Porta Miquel M Rabe Kari G KG Rothman Nathaniel N Scelo Ghislaine G Sesso Howard D HD Silverman Debra T DT Thompson Ian M IM Tjønneland Anne A Trichopoulou Antonia A Wactawski-Wende Jean J Wentzensen Nicolas N Wilkens Lynne R LR Yu Herbert H Zeleniuch-Jacquotte Anne A Amundadottir Laufey T LT Jacobs Eric J EJ Petersen Gloria M GM Wolpin Brian M BM Risch Harvey A HA Chatterjee Nilanjan N Klein Alison P AP Li Donghui D Kraft Peter P Wei Peng P

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20200616 9

<h4>Background</h4>Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level.<h4>Methods</h4>We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancre ...[more]

PMID: 32546605

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Project description:The obesity epidemic is responsible for a substantial economic burden in developed countries and is a major risk factor for type 2 diabetes and cardiovascular disease. The disease is the result not only of several environmental risk factors, but also of genetic predisposition. To take advantage of recent advances in gene-mapping technology, we executed a genome-wide association scan to identify genetic variants associated with obesity-related quantitative traits in the genetically isolated population of Sardinia. Initial analysis suggested that several SNPs in the FTO and PFKP genes were associated with increased BMI, hip circumference, and weight. Within the FTO gene, rs9930506 showed the strongest association with BMI (p = 8.6 x10(-7)), hip circumference (p = 3.4 x 10(-8)), and weight (p = 9.1 x 10(-7)). In Sardinia, homozygotes for the rare "G" allele of this SNP (minor allele frequency = 0.46) were 1.3 BMI units heavier than homozygotes for the common "A" allele. Within the PFKP gene, rs6602024 showed very strong association with BMI (p = 4.9 x 10(-6)). Homozygotes for the rare "A" allele of this SNP (minor allele frequency = 0.12) were 1.8 BMI units heavier than homozygotes for the common "G" allele. To replicate our findings, we genotyped these two SNPs in the GenNet study. In European Americans (N = 1,496) and in Hispanic Americans (N = 839), we replicated significant association between rs9930506 in the FTO gene and BMI (p-value for meta-analysis of European American and Hispanic American follow-up samples, p = 0.001), weight (p = 0.001), and hip circumference (p = 0.0005). We did not replicate association between rs6602024 and obesity-related traits in the GenNet sample, although we found that in European Americans, Hispanic Americans, and African Americans, homozygotes for the rare "A" allele were, on average, 1.0-3.0 BMI units heavier than homozygotes for the more common "G" allele. In summary, we have completed a whole genome-association scan for three obesity-related quantitative traits and report that common genetic variants in the FTO gene are associated with substantial changes in BMI, hip circumference, and body weight. These changes could have a significant impact on the risk of obesity-related morbidity in the general population.

Dataset Information

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Background

Methods

Results

Conclusions

Impact

Publications

Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.

Similar Datasets

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