Common genetic variants associated with breast cancer and mammographic density measures that predict disease.
Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (P(x)), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P(c)) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (P(u)). For dense area and percent dense area, the distributions of P(c) values were not uniform (both P(u) <0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility.
Odefrey
Fabrice
F
Department of Pathology and Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, University of Melbourne, Melbourne 3053, Australia.
Stone
Jennifer
J
Gurrin
Lyle C
LC
Byrnes
Graham B
GB
Apicella
Carmel
C
Dite
Gillian S
GS
Cawson
Jennifer N
JN
Giles
Graham G
GG
Treloar
Susan A
SA
English
Dallas R
DR
Hopper
John L
JL
Southey
Melissa C
MC
D000328:Adult; D000367:Age Factors; D000368:Aged; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D002452:Cell Count; D003430:Cross-Sectional Studies; D004198:Disease Susceptibility / Q000175:diagnosis* / Q000473:pathology; D005260:Female; D005787:Gene Frequency; D006801:Humans; D042361:Mammary Glands, Human / Q000033:anatomy & histology / Q000166:cytology* / Q000473:pathology; D008327:Mammography; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D035781:Siblings; D014427:Twins