Pooling-based genome-wide association study implicates gamma-glutamyltransferase 1 (GGT1) gene in pancreatic carcinogenesis.
OBJECTIVE
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 gamma-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 r(2): 0.69) and tagSNP rs2017869 is in strong LD (pairwise r(2): 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.


CONCLUSIONS
Our results suggest that common variation in the GGT1 gene may affect the risk of pancreatic cancer. .
Diergaarde
Brenda
B
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Brand
Randall
R
Lamb
Janette
J
Cheong
Soo Yeon
SY
Stello
Kim
K
Barmada
M Michael
MM
Feingold
Eleanor
E
Whitcomb
David C
DC
D055106:Genome-Wide Association Study; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D005723:gamma-Glutamyltransferase / Q000235:genetics*
D005723:gamma-Glutamyltransferase