Common genetic variants associated with breast cancer and mammographic density measures that predict disease

Odefrey F, Stone J, Gurrin LC, Byrnes GB, Apicella C, Dite GS, Cawson JN, Giles GG, Treloar SA, English DR, Hopper JL, Southey MC (2010) Common genetic variants associated with breast cancer and mammographic density measures that predict disease. Cancer Res 70:1449-1458

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="">