title: Combined effect of low-penetrant SNPs on breast cancer risk.
abstract: BACKGROUND
  Although many low-penetrant genetic risk factors for breast cancer have been discovered, knowledge about the effect of multiple risk alleles is limited, especially in women <50 years. We therefore investigated the association between multiple risk alleles and breast cancer risk as well as individual effects according to age-approximated pre- and post-menopausal status.
  
  
  METHODS
  Ten previously described breast cancer-associated single-nucleotide polymorphisms (SNPs) were analysed in a joint European biobank-based study comprising 3584 breast cancer cases and 5063 cancer-free controls. Genotyping was performed using MALDI-TOF mass spectrometry, and odds ratios were estimated using logistic regression.
  
  
  RESULTS
  Significant associations with breast cancer were confirmed for 7 of the 10 SNPs. Analysis of the joint effect of the original 10 as well as the statistically significant 7 SNPs (rs2981582, rs3803662, rs889312, rs13387042, rs13281615, rs3817198 and rs981782) found a highly significant trend for increasing breast cancer risk with increasing number of risk alleles (P-trend 5.6 × 10(-20) and 1.5 × 10(-25), respectively). Odds ratio for breast cancer of 1.84 (95% confidence interval (CI): 1.59-2.14; 10 SNPs) and 2.12 (95% CI: 1.80-2.50; 7 SNPs) was seen for the maximum vs the minimum number of risk alleles. Additionally, one of the examined SNPs (rs981782 in HCN1) had a protective effect that was significantly stronger in premenopausal women (P-value: 7.9 × 10(-4)).
  
  
  CONCLUSIONS
  The strongly increasing risk seen when combining many low-penetrant risk alleles supports the polygenic inheritance model of breast cancer.
authors: Departments of Medical Microbiology and Clinical Chemistry, Lund University, SUS entrance 78, Malmö S-205 02, Sweden. sophia.harlid@med.lu.se
authors: S
authors: S
authors: Harlid
authors: M I L
authors: MI
authors: Ivarsson
authors: S
authors: S
authors: Butt
authors: E
authors: E
authors: Grzybowska
authors: J E
authors: JE
authors: Eyfjörd
authors: P
authors: P
authors: Lenner
authors: A
authors: A
authors: Försti
authors: K
authors: K
authors: Hemminki
authors: J
authors: J
authors: Manjer
authors: J
authors: J
authors: Dillner
authors: J
authors: J
authors: Carlson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D013548:Sweden
chemical_list: D017931:DNA Primers