Dataset Information

Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study.

ABSTRACT: p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can induce cell cycle arrest and serve as tumor suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to pancreatic cancer.To test this hypothesis, we evaluated the associations of the Ser31Arg polymorphism in p21 and the Gly109Val polymorphism in p27, and their combinations, with pancreatic cancer risk in a case-control study of 509 pathologically confirmed pancreatic adenocarcinoma patients and 462 age- and sex-matched cancer-free controls in non-Hispanic whites.We found that the heterozygous and homozygous variant genotypes combined in a dominant model of the p21 polymorphism were associated with increased risk of pancreatic cancer compared with the homozygous wild type (adjusted odds ratio [ORadjusted], 1.70; 95% confidence interval [CI], 1.13-2.55). This increased risk was more pronounced in carriers with the p27 homozygous wild type (ORadjusted, 2.20; 95% CI, 1.32-3.68) and in nonsmokers (ORadjusted, 2.16; 95% CI, 1.14-4.10), although the p27 polymorphism alone was not associated with pancreatic cancer risk.These results indicate that the p21 polymorphism may contribute to susceptibility to pancreatic cancer, particularly among p27 homozygous wild-type carriers and nonsmokers.

SUBMITTER: Chen J

PROVIDER: S-EPMC2796289 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study.

Chen Jinyun J Amos Christopher I CI Merriman Kelly W KW Wei Qingyi Q Sen Subrata S Killary Ann M AM Frazier Marsha L ML

Pancreas 20100101 1

<h4>Objectives</h4>p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can induce cell cycle arrest and serve as tumor suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to pancreatic cancer.<h4>Methods</h4>To test this hypothesis, we evaluated the associations of the Ser31Arg polymorphism in p21 and the Gly109Val polymorphism in p27, and their combinations, with pancreatic ...[more]

PMID: 19910837

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Project description:BackgroundAtherosclerotic peripheral arterial disease (PAD) affects 8-10 million people in the United States and is associated with a marked impairment in quality of life and an increased risk of cardiovascular events. Noninvasive assessment of PAD is performed by measuring the ankle-brachial index (ABI). Complex traits, such as ABI, are influenced by a large array of genetic and environmental factors and their interactions. We attempted to characterize the genetic architecture of ABI by examining the main and interactive effects of individual single nucleotide polymorphisms (SNPs) and conventional risk factors.MethodsWe applied linear regression analysis to investigate the association of 435 SNPs in 112 positional and biological candidate genes with ABI and related physiological and biochemical traits in 1046 non-Hispanic white, hypertensive participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. The main effects of each SNP, as well as SNP-covariate and SNP-SNP interactions, were assessed to investigate how they contribute to the inter-individual variation in ABI. Multivariable linear regression models were then used to assess the joint contributions of the top SNP associations and interactions to ABI after adjustment for covariates. We reduced the chance of false positives by 1) correcting for multiple testing using the false discovery rate, 2) internal replication, and 3) four-fold cross-validation.ResultsWhen the results from these three procedures were combined, only two SNP main effects in NOS3, three SNP-covariate interactions (ADRB2 Gly 16 - lipoprotein(a) and SLC4A5 - diabetes interactions), and 25 SNP-SNP interactions (involving SNPs from 29 different genes) were significant, replicated, and cross-validated. Combining the top SNPs, risk factors, and their interactions into a model explained nearly 18% of variation in ABI in the sample. SNPs in six genes (ADD2, ATP6V1B1, PRKAR2B, SLC17A2, SLC22A3, and TGFB3) were also influencing triglycerides, C-reactive protein, homocysteine, and lipoprotein(a) levels.ConclusionWe found that candidate gene SNP main effects, SNP-covariate and SNP-SNP interactions contribute to the inter-individual variation in ABI, a marker of PAD. Our findings underscore the importance of conducting systematic investigations that consider context-dependent frameworks for developing a deeper understanding of the multidimensional genetic and environmental factors that contribute to complex diseases.

Dataset Information

Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study.

Publications

Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study.

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