Pooling-Based Genome-Wide Association Study Implicates Gamma-Glutamyltransferase 1 (GGT1) Gene in Pancreatic Carcinogenesis

Abstract

Background/Aims: Knowledge regarding genetic factors that influence pancreatic cancer risk is currently limited. To identify novel pancreatic cancer susceptibility loci, we conducted a two-stage genome-wide association study. Methods: The Affymetrix® Genome-Wide Human SNP Array 6.0 and DNA pooling were used in the screening stage. Twenty-six single-nucleotide polymorphisms (SNPs) were selected for follow-up. These 26 lead SNPs and additionally selected tagSNPs for the regions around the lead SNPs were evaluated by individual genotyping of the pooling population and an independent validation population. Results: Of the lead SNPs, the strongest association was found with rs4820599 located in the γ-glutamyltransferase 1 (GGT1) gene. This SNP was significantly associated with pancreatic cancer risk in the validation population and the combined dataset (p_allele-based = 0.019 and p_allele-based = 0.003, respectively). Statistically significant associations were also observed with two GGT1 tagSNPs: rs2017869 and rs8135987. Lead SNP rs4820599 is in high linkage disequilibrium (LD; pairwise r²: 0.69) and tagSNP rs2017869 is in strong LD (pairwise r²: 0.96) with SNP rs5751901, which has been reported to be associated with increased GGT1 serum levels. GGT is expressed in the pancreas and plays a key role in glutathione metabolism. Conclusion: Our results suggest that common variation in the GGT1 gene may affect the risk of pancreatic cancer.

Establishment and Characterization of a Highly Tumourigenic and Cancer Stem Cell Enriched Pancreatic Cancer Cell Line as a Well Defined Model System

“…A strong association for pancreatic cancer risk was identified for rs4820599 [45]. In JoPaca-1, this location is mutated in 9 out of 32 reads (28%).…”

Current status of molecular markers for early detection of sporadic pancreatic cancer

“…One study even examined the entire mitochondrial DNA for SNPs associated with the risk of PC [60], while another examined for possible correlation with survival [61], but none were observed. A recent study employing 178 PC and 182 healthy controls identified a SNP in the gamma glutamyl transferase (GGT) gene that was significantly (p<0.05) associated with a risk of PC in a separate validation set [62]. A genomewide association analysis employing 3,851 PC and 3,934 healthy controls recently identified eight novel SNPs on chromosome loci 1q32.1 (5 SNPs), 5p15.33 (1 SNP) and 13q22.1 (2 SNPs) that were significantly associated with a risk of developing PC [63].…”

Disentangling Pooled Triad Genotypes for Association Studies

“…Accurate DNA quantification and careful pool construction are essential to reduce measurement variance and to ensure equimolar amounts of DNA in a pool (Sham et al , 2002). Estimated allele frequencies from pooled DNA have shown high reproducibility (Kirov et al , 2006, Sham et al , 2002, Meaburn et al , 2006, Ozerov et al , 2013, Uemoto et al , 2012) and approaches that estimate allele frequencies in pools have been successfully used in many genome-wide association studies (Lu et al , 2012 among others, Liu et al , 2011, Janicki et al , 2011, Krumbiegel et al , 2011, Diergaarde et al , 2010, Huang et al , 2010, Tournas et al , 2010, Craig et al , 2009, Kirov et al , 2009, Kawase et al , 2008, Zaharieva et al , 2008, Abraham et al , 2008, Melquist et al , 2007). Especially when working within tight budget constraints, pooling strategies offer effective ways to reduce genotyping costs while conserving limited specimens.…”