Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Abstract

Purpose Aromatase inhibitors (AI) can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant AIs. Experimental Design We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and AI metabolism pathways with fasting lipid profiles during the first three months of AI therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. Results A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides (TG) by 20.2 mg/dL and 39.3mg/dL (p<0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (p<0.00053). Conclusion Variants in CYP19A1 are associated with decreases in TG and variable changes in HDL-C in postmenopausal women on adjuvant AIs. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with AI therapy.

Genome-Wide Association Analysis for Blood Lipid Traits Measured in Three Pig Populations Reveals a Substantial Level of Genetic Heterogeneity

“…NCOA1 encodes a transcriptional coactivator for steroid. It controls energy balance between white and brown adipose tissues [ 30 ]. Both KLHL29 and APOB have been reported as candidate genes for blood lipids [ 31 ].…”

A phase II study evaluating the efficacy of zoledronic acid in prevention of aromatase inhibitor-associated musculoskeletal symptoms: the ZAP trial

“…As directed per protocol, the percentage of women who developed AIMSS over 12 months was compared to historical controls from the Exemestane and Letrozole Pharmacogenetics (ELPh) trial (NCT00263913) who were not taking bisphosphonates. The ELPh trial was a prospective multicenter randomized observational open-label trial in postmenopausal women with early-stage breast cancer (stage 0-III) evaluating the effects of 2 years of therapy with either letrozole or exemestane on a variety of biomarkers of estrogen activity and potential AI toxicity, including a prospective evaluation of AIMSS; these results have been previously published [8, 17]. Participants on the ELPh trial who were randomized to letrozole not taking bisphosphonates at any point during the initial 12 months were included in this analyses as historical controls; those randomized to exemestane or taking bisphosphonates were excluded.…”

Genetic Polymorphisms in Aromatase (CYP19) Gene and Cancer

“…Santa-Maria et al [84] have recently reported that several SNPs influence the plasma lipid levels in patients treated with letrozole, where rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 decreased triglyceride levels and had a variable effect on the level of HDL-C.…”