rs700518 — CYP19A1 Val80

CYP19A1 Val80 — Aromatase Activity and Estrogen Balance

The CYP19A1 gene encodes aromatase, the enzyme responsible for converting androgens into estrogens in the final step of estrogen biosynthesis. Located on chromosome 15q21.1¹¹ Located on chromosome 15q21.1
The gene spans approximately 123 kb with complex tissue-specific regulation, aromatase is expressed in gonads, adipose tissue, bone, breast, and brain. The rs700518 variant is a synonymous G>A substitution at codon 80 (Val80Val) in exon 3. While it doesn't change the amino acid sequence, this variant affects post-transcriptional gene regulation, leading to differences in aromatase expression and activity²² this variant affects post-transcriptional gene regulation, leading to differences in aromatase expression and activity.

The Mechanism

Though synonymous, rs700518 influences aromatase enzyme levels through effects on mRNA stability, translation efficiency, or linkage with regulatory variants. The GG genotype has been associated with higher aromatase expression in some tissues³³ The GG genotype has been associated with higher aromatase expression in some tissues, while the AA genotype appears to result in lower enzyme activity. This translates to differences in the conversion of testosterone to estradiol and androstenedione to estrone. Studies in women with hyperandrogenism found the GG genotype associated with lower estradiol levels and higher SHBG concentrations⁴⁴ Studies in women with hyperandrogenism found the GG genotype associated with lower estradiol levels and higher SHBG concentrations, suggesting tissue- and context-specific effects.

The variant is closely linked (high linkage disequilibrium) with rs10046 in the 3'-UTR region⁵⁵ rs10046 in the 3'-UTR region, and together these SNPs form haplotypes that influence aromatase activity across multiple tissues. This explains why effects can be complex and sometimes appear contradictory — the functional impact depends on which other variants are present and the tissue context.

The Evidence

The strongest evidence for rs700518 comes from studies of aromatase inhibitor therapy in breast cancer. A prospective study of 97 postmenopausal women found that those with the AA genotype developed significant bone loss at the lumbar spine and hip after 12 months of AI therapy⁶⁶ A prospective study of 97 postmenopausal women found that those with the AA genotype developed significant bone loss at the lumbar spine and hip after 12 months of AI therapy
Napoli N et al. Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with aromatase inhibitor associated bone loss in women with ER (+) breast cancer. Bone. 2013 (both p=0.03), while those carrying a G allele maintained bone density. In the same cohort, women with the GG genotype showed opposite body composition changes — significant increases in truncal fat and decreases in lean mass⁷⁷ women with the GG genotype showed opposite body composition changes — significant increases in truncal fat and decreases in lean mass.

A meta-analysis of 8 studies involving 2,632 subjects confirmed that the AG genotype is associated with significantly lower bone mineral density at both lumbar spine and femoral neck⁸⁸ A meta-analysis of 8 studies involving 2,632 subjects confirmed that the AG genotype is associated with significantly lower bone mineral density at both lumbar spine and femoral neck (p=0.001 and p=0.01, respectively). The relationship with osteoporosis risk was less clear, but the consistent BMD findings suggest bone health implications.

Beyond breast cancer treatment, a study of Chinese women found the AA genotype conferred a 3.66-fold increased risk of endometriosis-related infertility⁹⁹ a study of Chinese women found the AA genotype conferred a 3.66-fold increased risk of endometriosis-related infertility (OR 3.66, 95% CI 2.06-6.50, p<0.001) compared to controls. This was specific to infertility, not endometriosis alone. Research in women with hyperandrogenism showed the GG genotype associated with lower estradiol levels and altered fat distribution patterns¹⁰¹⁰ Research in women with hyperandrogenism showed the GG genotype associated with lower estradiol levels and altered fat distribution patterns, demonstrating effects beyond cancer treatment contexts.

Practical Implications

For women taking aromatase inhibitors for breast cancer, this variant predicts side effect risk. The AA genotype indicates higher risk of accelerated bone loss, while the GG genotype predicts unfavorable body composition changes. Both warrant closer monitoring, though the interventions differ. For general population health, the variant influences baseline estrogen levels, which affect bone density, body composition, cardiovascular risk, and reproductive health across the lifespan.

The evidence supports bone density monitoring and proactive bone health interventions for A allele carriers, particularly women approaching or past menopause. The GG genotype's association with altered body composition suggests attention to lean mass preservation through resistance exercise and adequate protein intake may be especially important.

Interactions

Rs700518 is part of a haplotype block with rs10046 and rs4646, both in the 3'-untranslated region of CYP19A1. These variants show high linkage disequilibrium and their combined effects may be stronger than any single SNP. Other CYP19A1 variants including rs749292, rs1062033, and rs4775936 also influence aromatase activity and may interact to determine overall enzyme function.

Interactions with estrogen receptor variants (ESR1, ESR2) likely modulate the clinical impact of altered estrogen production. In women taking aromatase inhibitors, the degree of estrogen suppression achieved depends on both baseline aromatase activity (influenced by this variant) and how well the drug inhibits the enzyme, creating pharmacogenetic interactions that affect both efficacy and toxicity.