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.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Feigelson
Heather Spencer
HS
Department of Epidemiology and Surveillance Research, American Cancer Society, Williams Street, NW, Atlanta, Georgia 30303-1002, USA. heather.feigelson@cancer.org
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
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D001943:Breast Neoplasms / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D015331:Cohort Studies; D014644:Genetic Variation; D005838:Genotype; D054439:Ghrelin / Q000235:genetics*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D009765:Obesity / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics*; D012306:Risk
C515349:GHRL protein, human; D054439:Ghrelin; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human