Genetic modifiers of menopausal hormone replacement therapy and breast cancer risk: A genome-wide interaction study

Women using menopausal hormone therapy (MHT) are at increased risk of developing breast cancer (BC). To detect genetic modifiers of the association between current use of MHT and BC risk, we conducted a meta-analysis of four genome-wide case-only studies followed by replication in 11 case–control studies. We used a case-only design to assess interactions between single-nucleotide polymorphisms (SNPs) and current MHT use on risk of overall and lobular BC. The discovery stage included 2920 cases (541 lobular) from four genome-wide association studies. The top 1391 SNPs showingPvalues for interaction (Pint) −3were selected for replication using pooled case–control data from 11 studies of the Breast Cancer Association Consortium, including 7689 cases (676 lobular) and 9266 controls. Fixed-effects meta-analysis was used to derive combinedPint. No SNP reached genome-wide significance in either the discovery or combined stage. We observed effect modification of current MHT use on overall BC risk by two SNPs on chr13 nearPOMP(combinedPint≤8.9×10−6), two SNPs inSLC25A21(combinedPint≤4.8×10−5), and three SNPs inPLCG2(combinedPint≤4.5×10−5). The association between lobular BC risk was potentially modified by one SNP inTMEFF2(combinedPint≤2.7×10−5), one SNP inCD80(combinedPint≤8.2×10−6), three SNPs on chr17 nearTMEM132E(combinedPint≤2.2×10−6), and two SNPs on chr18 nearSLC25A52(combinedPint≤4.6×10−5). In conclusion, polymorphisms in genes related to solute transportation in mitochondria, transmembrane signaling, and immune cell activation are potentially modifying BC risk associated with current use of MHT. These findings warrant replication in independent studies.