A common polymorphism in the CYP3A7 gene is associated with a nearly 50% reduction in serum dehydroepiandrosterone sulfate levels
ABSTRACT CYP3A7, expressed in the human fetal liver and normally silenced after birth, plays a major role in the 16alpha-hydroxylation of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and estrone. Due to a replacement of part of the CYP3A7 promoter with a sequence identical with the same region in the CYP3A4 promoter (referred to as CYP3A7*1C), some individuals still express a variant of the CYP3A7 gene later in life.
The objective of this study was to examine the effect of the CYP3A7*1C polymorphism on serum steroid hormone levels.
Two population-based cohort studies were performed. Study group 1 consisted of 208 subjects randomly selected from the Rotterdam Study, and study group 2 consisted of 345 elderly independently living men.
Serum DHEA(S), androstenedione, estradiol, estrone, and testosterone levels were the main outcome measures.
In study groups 1 and 2, heterozygous CYP3A7*1C carriers had almost 50% lower DHEAS levels compared with homozygous carriers of the reference allele [study group 1, 1.74 +/- 0.25 vs. 3.33 +/- 0.15 micromol/liter (P = 0.02); study group 2, 2.09 +/- 0.08 vs. 1.08 +/- 0.12 micromol/liter (P < 0.001)]. No differences in circulating DHEA, androstenedione, estradiol, or testosterone levels were found. However, in study group 2, serum estrone levels were lower in heterozygous CYP3A7*1C carriers compared with homozygous carriers of the reference allele (0.11 +/- 0.002 vs. 0.08 +/- 0.006 nmol/liter; P < 0.001).
The CYP3A7*1C polymorphism causes the persistence of enzymatic activity of CYP3A7 during adult life, resulting in lower circulating DHEAS and estrone levels.
Article: DHEA, DHEAS and PCOS.[Show abstract] [Hide abstract]
ABSTRACT: Approximately 20-30% of PCOS women demonstrate excess adrenal precursor androgen (APA) production, primarily using DHEAS as a marker of APA in general and more specifically DHEA, synthesis. The role of APA excess in determining or causing PCOS is unclear, although observations in patients with inherited APA excess (e.g., patients with 21-hydroxylase deficient congenital classic or non-classic adrenal hyperplasia) demonstrate that APA excess can result in a PCOS-like phenotype. Inherited defects of the enzymes responsible for steroid biosynthesis, or defects in cortisol metabolism, account for only a very small fraction of women suffering from hyperandrogenism or APA excess. Rather, women with PCOS and APA excess appear to have a generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation, although they do not have an overt hypothalamic-pituitary-adrenal axis dysfunction. In general, extra-adrenal factors, including obesity, insulin and glucose levels, and ovarian secretions, play a limited role in the increased APA production observed in PCOS. Substantial heritabilities of APAs, particularly DHEAS, have been found in the general population and in women with PCOS; however, the handful of SNPs discovered to date account only for a small portion of the inheritance of these traits. Paradoxically, and as in men, elevated levels of DHEAS appear to be protective against cardiovascular risk in women, although the role of DHEAS in modulating this risk in women with PCOS remains unknown. In summary, the exact cause of APA excess in PCOS remains unclear, although it may reflect a generalized and inherited exaggeration in androgen biosynthesis of an inherited nature.The Journal of Steroid Biochemistry and Molecular Biology 07/2014; DOI:10.1016/j.jsbmb.2014.06.003 · 4.05 Impact Factor
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ABSTRACT: Context.Because of the elevated dehydroepiandrosterone sulfate (DHEAS) levels in PCOS and the heritability of DHEAS serum levels, genes encoding the enzymes that control the sulfation of dehydroepiandrosterone (DHEA) to DHEAS and vice versa are obvious candidate genes to explain part of the heritability of PCOS.Objective.To determine the role of genetic variants in sulfotransferase (SULT2A1), 3-phosphoadenosine 5-phosphosulfate synthase isoform 2 (PAPSS2) and steroid sulfatase (STS) in PCOS and in hormone levels related to the hyperandrogenic phenotype of PCOS.Design.Candidate-gene study.Patients.Discovery set consisted of 582 patients and 2017 controls.Main outcome measures.A pruned subset of 28 SNPs in SULT2A1, PAPSS2 and STS was generated based on pairwise genotypic correlation. Association with PCOS was tested and we studied whether the SNPs modulate DHEAS levels, DHEA levels and their ratio in PCOS. Significant SNPs were replicated in an independent sample of patients.Results.None of the SNPs in SULT2A1, PAPSS2 and STS constituted risk alleles for PCOS. SNP rs2910397 in SULT2A1 decreased the DHEAS to DHEA ratio in PCOS by 5% in the discovery sample. Meta-analysis of discovery and replication sample resulted in a combined effect of -0.095 (p-value = 0.027). However, carrying the minor T-allele did not contribute to differences in hyperandrogenic phenotype, including levels of testosterone and androstenedione, of PCOS patients.Conclusions.Genetic variants in SULT2A1, PAPSS2 and STS do not predispose to PCOS. Although a variant in SULT2A1 decreased the DHEAS to DHEA ratio, no changes in other androgenic hormone levels were observed.The Journal of Clinical Endocrinology and Metabolism 07/2013; 98(9). DOI:10.1210/jc.2013-1976 · 6.31 Impact Factor
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ABSTRACT: OBJECTIVE: We previously demonstrated that maternal and fetal genotypes are independently associated with neonatal respiratory distress syndrome (RDS). The objective of the current study is to determine the impact of maternal and fetal single nucleotide polymorphisms (SNPs) in key betamethasone (BMZ) pathways on respiratory outcomes that serve as markers for severity of disease. STUDY DESIGN: DNA was obtained from women given BMZ and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway SNPs. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis controlling for relevant clinical variables to determine SNP impact on bronchopulmonary dysplasia (BPD), need for respiratory support, and surfactant therapy use was performed. RESULTS: 109 women delivering 117 infants were analyzed. 14.5% of the infants developed BPD, 70.8% needed some respiratory support after birth, and 27.5% needed surfactant. In a multivariable regression analysis, gestational age at delivery was associated with most neonatal respiratory outcomes (p≤0.01) and chorioamnionitis was associated with BPD (p<0.03). Genotypes associated with respiratory severity outcomes were as follows: BPD- Fetal IPO13 (rs4448553; OR 0.01, 95% CI 0.00-0.92); Surfactant use- Maternal IPO13 (rs2428953 and 2486014; OR 13.8, 95%CI 1.80-105.5 and OR 35.5, 95% CI 1.71-736.6, respectively). CONCLUSIONS: Several discrete maternal and fetal SNPs in the Importin 13 gene (IPO13) may be associated with neonatal respiratory outcomes after maternal antenatal corticosteroid treatment for anticipated preterm birth.American journal of obstetrics and gynecology 01/2013; 208(3). DOI:10.1016/j.ajog.2012.12.031 · 3.97 Impact Factor