A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

Abstract

Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10(-6) for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10(-7)) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.

Fig. 1

Flow chart outlining studies, number of individuals, and number of SNPs involved in each analysis stage. *MARIE Mammary Carcinoma Risk Factor Investigation, **SASBAC Case–Control Study Sample of the Singapore and Sweden Breast Cancer Study, ***BCAC Breast Cancer Association Consortium, NHS Nurses Health Study, BBCS British Breast Cancer Study, CECILE CECILE Breast Cancer Study, GENICA Gene Environment Interaction and Breast Cancer in Germany, KBCP Kuopio Breast Cancer Project, MCBCS Mayo Clinic Breast Cancer Study, SASBAC Case–Control Study Sample of the Singapore and Sweden Breast Cancer Study, TWBCS Taiwanese Breast Cancer Study, UCIBCS UCI Breast Cancer Study. Remark: MARIE cases included in stage II are distinct from those comprised in stage I. SASBAC cases and controls included in the replication are distinct from those comprised in stage II. MARIE cases and controls included in the fine mapping comprise all cases and controls also included in stages I and II

Fig. 2

Linkage disequilibrium (LD) blocks on chromosome 2, position 230,230,000–230,600,000. LD in terms of D’ between SNPs rs6707272, rs11886634, rs2909969, and rs1942574 with the genes DNER, TRIP12, and FBXO36 on chromosome 2. LD blocks were generated using data from the HapMap project. The intensity of the colour is proportional to the strength of the LD for the SNP pair. Dark red indicates D′=1