Genetic analysis of steroid pathway enzymes associated with adverse musculoskeletal effects of aromatase inhibitors

Objetives: Identify putative functional variants in the CYP11A1 and CYP17A1 genes associated with musculoskeletal effects (accelerated bone mass loss and arthralgia) derived from treatment with aromatase inhibitors (AI). Material and methods: The B-ABLE cohort is a prospective study of postmenopausal women with breast cancer undergoing AI treatment. Bone mineral density in the lumbar spine and femoral neck was measured by densitometry and joint pain using visual analogue scale. From single-nucleotide polymorphisms (SNPs) in genes CYP11A1 (rs4077581, rs11632698 and rs900798) and CYP17A1 (rs4919686, rs4919683, rs4919687, rs3781287, rs10786712, rs6163, rs743572), previously associated with musculoskeletal events, haplotypes were constructed for each pacient from the cohort, and those haplotypes that showed greatest phenotypic differences were chosen (p<0.05). Within each haplotype, patients with extreme phenotypes were chosen for the sequencing of respective genes and identifying functional genetic variants. Finally, a multiple linear regression analysis was carried out considering the models of dominant, recessive and additive genetic inheritance. Results: No mutation was found in coding regions. A genetic variant (D15S520), in the basal promoter region of gene CYP11A1, was found associated with femoral neck bone loss at 24 month of AI treatment. Conclusions: Variants in regulatory regions of the CYP11A1 gene could modulate the expression of this gene, thus explaining part of the phenotypic variability found in bone loss of patients undergoing AI treatment.