title: Evaluating 17 breast cancer susceptibility loci in the Nashville breast health study.
abstract: BACKGROUND
  Genome-wide association studies have discovered multiple genetic loci associated with breast cancer risk. Investigating these loci would be helpful to evaluate previous findings and identify causal variants for breast cancer. We evaluated index SNPs in 17 of these loci in a study of 1,511 cases and 1,454 controls of European descent.
  
  
  METHODS
  We investigated the overall association with breast cancer and among subtypes defined as ER+ (estrogen receptor positive), ER- (estrogen receptor negative) and triple-negative breast cancer (TNBC). Combined effects of SNPs on breast cancer risk were assessed via a genetic risk score. We evaluated the contribution of both genetic variants and traditional risk factors to a breast cancer risk assessment model.
  
  
  RESULTS
  Five of the 17 SNPs were significantly associated (P ≤ 0.05) with overall breast cancer in the same direction as previously reported: rs13387042 (2q35/TNP1), rs4973768 (3p24/SLC4A7), rs2046210 (6q25/ESR1), rs1219648 (10q26/FGFR2), and rs4784227 (16q12/TOX3). When stratified by breast cancer subtype, all five SNPs were associated (P < 0.05) with ER+ cancer, three with ER- cancer (rs13387042, rs1219648, and rs4784227), and one with TNBC (rs1219648). A GRS, based on those five significant SNPs, showed strong association with overall breast cancer with ORs (95 % CI) of 1.48 (1.22-1.79), 1.85 (1.52-2.25) and 2.26 (1.82-2.80), respectively, for each quartile, (P = 2.0 × 10(-15)). Traditional risk factors, including previous benign breast disease, breast cancer family history and parity, were significantly associated with breast cancer risk in the present study. These factors, together with the GRS, were used to build a breast cancer risk assessment model with a c statistic of 0.6321 from receiver operating characteristic analysis. The contribution of the GRS to the model was greater than prior benign breast disease, family history and parity with the c statistic change of 0.0374, 0.0324, 0.0103, 0.0012, respectively.
  
  
  CONCLUSIONS
  Our study demonstrates that five SNPs were associated with overall breast cancer, with stronger association for ER+ than ER- cancer as previously reported, and suggests that a risk assessment model incorporating the GRS from five loci is useful in identifying women at high risk of breast cancer.
authors: Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, 2525 West End Avenue, 8th Floor, Nashville, TN, 37203-1738, USA.
authors: Mi-Ryung
authors: MR
authors: Han
authors: Sandra
authors: S
authors: Deming-Halverson
authors: Qiuyin
authors: Q
authors: Cai
authors: Wanqing
authors: W
authors: Wen
authors: Martha J
authors: MJ
authors: Shrubsole
authors: Xiao-Ou
authors: XO
authors: Shu
authors: Wei
authors: W
authors: Zheng
authors: Jirong
authors: J
authors: Long
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D012307:Risk Factors; D013714:Tennessee; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D011960:Receptors, Estrogen