Dataset Information

The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women.

ABSTRACT:

Background

Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations.

Design

We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations.

Results

We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ?0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ?0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D'?97%, r(2)?56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ?0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ?0.02).

Conclusion

Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size.

SUBMITTER: Lin JH

PROVIDER: S-EPMC3405042 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Publications

The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women.

Lin Jennifer H JH Gunter Marc J MJ Manson JoAnn E JE Rexrode Kathryn M KM Cook Nancy R NR Kraft Peter P Cochrane Barbara B BB Chlebowski Rowan T RT Ho Gloria Y F GY Zhang Shumin M SM

PloS one 20120725 7

<h4>Background</h4>Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations.<h4>Design</h4>We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who la ...[more]

PMID: 22848710

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Project description:BACKGROUND: Aromatase deficiency is a rare, autosomal recessive disorder of which there are approximately twenty four case reports. The aromatase enzyme is crucial in the biosynthesis of oestrogens from androgens. The phenotype of aromatase deficiency therefore is the result of androgen excess and oestrogen deficiency in the absence of normal aromatase activity. We report the first case of aromatase deficiency diagnosed in a female adult, at the age of 32 years, due to a novel duplication in the aromatase gene. CASE PRESENTATION: A 32 year old Indian woman presented with a history of gender assignment difficulties at birth, lack of pubertal development, osteopaenia with fracture and tall stature. She had central obesity, impaired fasting glucose and borderline hypertension. Past examinations had revealed partial fusion of urethra and vagina, hypoplastic uterus and streak ovaries. The ovaries had been excised due to malignant risk after an initial clinical diagnosis of Turner's syndrome with Y mosaicism. Oestrogen replacement commenced shortly after her fracture, in adulthood. After reassessment, aromatase deficiency was diagnosed. Sequencing of the coding exons of the aromatase (CYP19A1; OMIM 109710) gene revealed a novel 27-base duplication in exon 8 (p.Ala306_Ser314dup). This duplication, occurring within the aromatase ?-helix, would be likely to disrupt substrate (androgen) and cofactor (protoporphyrin IX) binding, resulting in a lack of oestrogen synthesis. CONCLUSIONS: We report a female with a phenotype compatible with aromatase deficiency which was unrecognised until adulthood and found she had a novel duplication in CYP19A1. Previous case reports have described polycystic ovarian morphology, especially in childhood and adolescence, but never streak ovaries. This may reflect the few adult cases reported, that aromatase deficiency in females is generally diagnosed at birth and oestrogen treatment commences decades earlier than occurred in our patient. Streak ovaries are consistent with the phenotype of the aromatase knockout mouse followed through adulthood. The observed clinical features of obesity, dysglycaemia and hypertension, are compatible with the observation that lack of a counterbalancing effect of oestrogen on tissue androgens until adulthood may lead to a metabolic syndrome phenotype. This report broadens the spectra of phenotype and genetic mutations underlying this rare disorder.

Dataset Information

The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women.

Background

Design

Results

Conclusion

Publications

The aromatase gene (CYP19A1) variants and circulating hepatocyte growth factor in postmenopausal women.

Similar Datasets

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