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The role of the CYP1A1 gene in long-term glucocorticoid-related adverse effects
Helena Florez1, Eva Gonzalez2, Katherine Cajiao3
1Metabolic Bone Diseases Unit, Department of Rheumatology, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain. hflorez@clinic.cat.
Abstract:
CYP1A1 gene variants may influence the development of AE of chronic GC treatment. The rs1799814 polymorphism was associated with increased BMI and lower levels of bone turnover markers, independent of GC dose, suggesting reduced GC metabolism. No association was found with OP and/or Fx, BMD or TBS values.
Introduction:
Long-term glucocorticoid (GC) use can produce adverse effects (AE) including obesity, diabetes, osteoporosis and fractures. The variability in AE severity suggests a genetic influence. CYP1A1, a cytochrome P450 family enzyme involved in GC metabolism, may play a role. This study aimed to genotype CYP1A1 variants in patients on chronic GC treatment and analyse their relationship with long-term AE.
Methods:
Seventy patients (56 ± 16.6 years; 71.4% female; 47.1% postmenopausal) receiving chronic GC treatment ( ≥5 mg/ day for >3 months) were included. Clinical data were collected at baseline and at 5 years of follow-up, including OP risk factors, previous and incidental fractures, GC dose and duration, disease activity, anthropometric data, bone metabolism parameters, bone mineral density (BMD) and trabecular bone score (TBS) (by DXA), and vertebral fractures (X-ray). CYP1A1 gene sequencing was performed by NGS using Amplicon Deep Sequencing on an Ion Torrent platform.
Results:
Four CYP1A1 polymorphisms were identified: rs41279188, rs1048943, rs1799814 and rs4646422. Nine patients had rs1048943, nine rs1799814, one rs4646422 and one rs41279188 polymorphisms, respectively. Patients with the rs1799814 polymorphism (13%) had higher BMI (29.3 vs. 25.5; p = 0.019) and greater BMI change over 5 years (ΔBMI: 1.7 vs. -0.32; p = 0.02; adjusted for cumulative GC dose). Additionally, they presented lower bone turnover markers (NTx: 21 vs. 40 nMol/mMol, p = 0.003, CTx: 0.16 vs. 0.29 ng/mL, p = 0.068, OC: 16.6 vs. 19.3 ng/mL, p = 0.059). No associations were found between CYP1A1 polymorphisms and the presence of osteoporosis and/or fractures, BMD or TBS values.
Conclusion:
The CYP1A1 rs1799814 polymorphism is associated with more severe GC-related AE, suggesting reduced GC metabolism.
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