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Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II.

ABSTRACT: Obesity has consistently been associated with postmenopausal breast cancer risk. Proteins that are secreted by adipose tissue or are involved in regulating body mass may play a role in breast tumor development.We conducted a nested case-control study among postmenopausal women from the American Cancer Society Cancer Prevention Study II Nutrition Cohort to determine whether genes associated with obesity increase risk for breast cancer. Tagging single nucleotide polymorphisms (SNPs) were selected to capture common variation across seven candidate genes that encode adipose-related proteins: ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1. Thirty-nine SNPs were genotyped in 648 cases and 659 controls. Logistic regression models were used to examine the association between each tagging SNP and risk for breast cancer while adjusting for matching factors and potential confounders. We also examined whether these SNPs were associated with measures of adult adiposity.Two out of five tagging SNPs in HSD11B1 were associated with breast cancer (rs11807619, P = 0.006; rs932335, P = 0.0001). rs11807619 and rs932335 were highly correlated (r2 = 0.74) and, when modeled as a haplotype, only haplotypes containing the rs932335 C allele were associated with breast cancer. The rs932335 C allele was associated with a nearly twofold increased risk for breast cancer (odds ratio = 1.83, 95% confidence interval = 1.01-3.33 for C/C versus G/G). Three of the 11 SNPs for IRS2 were associated with breast cancer (rs4773082, P = 0.007; rs2289046, P = 0.016; rs754204, P = 0.03). When these three SNPs were examined as a haplotype, only the haplotype that included the G allele of rs2289046 was associated with breast cancer (odds ratio = 0.76, 95% confidence interval = 0.63-0.92 for TGC versus CAT). IRS2 rs2289046, rs754204, and rs12584136 were also associated with adult weight gain but only among cases. None of the other SNPs in any gene investigated were associated with breast cancer or adiposity.Our findings suggest that these tagging SNPs in HSD11B1 and IRS2 mark regions of the genome that may harbor risk alleles for breast cancer, and these associations are probably independent of adiposity.

SUBMITTER: Feigelson HS

PROVIDER: S-EPMC2575528 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II.

Feigelson Heather Spencer HS Teras Lauren R LR Diver W Ryan WR Tang Weining W Patel Alpa V AV Stevens Victoria L VL Calle Eugenia E EE Thun Michael J MJ Bouzyk Mark M

Breast cancer research : BCR 20080708 4

<h4>Introduction</h4>Obesity has consistently been associated with postmenopausal breast cancer risk. Proteins that are secreted by adipose tissue or are involved in regulating body mass may play a role in breast tumor development.<h4>Methods</h4>We conducted a nested case-control study among postmenopausal women from the American Cancer Society Cancer Prevention Study II Nutrition Cohort to determine whether genes associated with obesity increase risk for breast cancer. Tagging single nucleotid ...[more]

PMID: 18611262

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Project description:Insulin receptor substrate (IRS) proteins are cytoplasmic adaptors that transmit the signal from the IR and insulin-like growth factor-1 receptor to effector proteins. Overexpression of IRS proteins has been indicated to be linked to cancer development. In addition to their expression profiles, studies have indicated that polymorphisms of IRS1 and IRS2 are also associated with the susceptibility to numerous cancer types. IRS1 Gly972Arg and IRS2 Gly1057Asp are the common variants of these genes. The present study aimed to determine the association of IRS1 Gly972Arg and IRS2 Gly1057Asp polymorphisms with gastric cancer development. The study included 100 patients with gastric cancer and 100 controls. Single-nucleotide polymorphisms were detected by real-time PCR using Taqman assays. The results suggested that in individuals with the IRS1 Gly/Arg genotype, the odds of having gastric cancer was increased by 7.891-fold (95% CI: 3.251-19.154, P<0.001) and in individuals with the IRS1 Arg/Arg genotype, it was increased by 22.716-fold (95% CI: 6.311-81.761, P<0.001) compared with those with the IRS1 Gly/Gly genotype. Although the IRS2 Gly1057Asp genotype analysis suggested that subjects with the Asp/Asp genotype had a 2,311-fold increased odds of having gastric cancer compared to those with the Gly/Gly genotype, the result was not statistically significant (95% CI: 0.800-6.678, P=0.122). The combined effects of the IRS1 and IRS2 variants on gastric cancer were also determined. The results suggested that individuals with Gly/Arg+Gly/Asp and Gly/Arg+Asp/Asp genotypes had a higher odds of having gastric cancer compared to individuals of the Gly/Gly+Gly/Gly genotype (P=0.001 and P=0.027, respectively). In conclusion, the present results suggested that the IRS1 Gly972Arg and IRS2 Gly1057Asp variations may be associated with an increased susceptibility to develop gastric cancer. Further studies with larger sample sizes are required to support the present results and to explore the use of these variations as a biomarker for gastric cancer.

Project description:Aim and objectiveThe aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians.MethodA total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing.ResultMean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45-60 years group as compared to 20-45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06-12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8-2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the 'Gly' allele were inclined to develop more severe OSA.ConclusionWe concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.

Dataset Information

Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II.

Publications

Genetic variation in candidate obesity genes ADRB2, ADRB3, GHRL, HSD11B1, IRS1, IRS2, and SHC1 and risk for breast cancer in the Cancer Prevention Study II.

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