Dataset Information

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome.

ABSTRACT:

Objective

To study the role of genetic variation in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) gene in polycystic ovary syndrome (PCOS).

Design

Women with and without PCOS were genotyped for seven single-nucleotide polymorphisms (SNPs) in HMGCR. The SNPs and haplotypes were determined and tested for association with PCOS and its component traits.

Setting

Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham; control subjects were recruited from the surrounding community. Genotyping took place at Cedars-Sinai Medical Center in Los Angeles.

Patient(s)

A total of 287 white PCOS women and 187 control subjects were studied.

Intervention(s)

Phenotypic and genotypic assessment.

Main outcome measure(s)

HMGCR genotype, PCOS diagnosis, androgen levels, metabolic traits.

Result(s)

No association with PCOS was observed. SNP rs4629571 was associated with increased insulin resistance. Haplotype 3 was associated with increased insulin resistance. Haplotype 5 was associated with higher SHBG and lower free T.

Conclusion(s)

Variation in the HMGCR gene may influence component features of PCOS, including insulin resistance, SHBG, and free T. HMGCR may thus act as a modifier gene in PCOS.

SUBMITTER: Xu N

PROVIDER: S-EPMC3032056 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome.

Xu Ning N Taylor Kent D KD Azziz Ricardo R Goodarzi Mark O MO

Fertility and sterility 20090326 1

<h4>Objective</h4>To study the role of genetic variation in the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) gene in polycystic ovary syndrome (PCOS).<h4>Design</h4>Women with and without PCOS were genotyped for seven single-nucleotide polymorphisms (SNPs) in HMGCR. The SNPs and haplotypes were determined and tested for association with PCOS and its component traits.<h4>Setting</h4>Subjects were recruited from the reproductive endocrinology clinic at the University of Alabam ...[more]

PMID: 19327767

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Project description:HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme. The maturation of the mechanistic proposals for HMGR have paralleled advances in a diverse set of research areas, such as molecular biology and computational chemistry. Thus, the development of the HMGR mechanism provides a useful case study for following the advances in state-of-the-art methods in enzyme mechanism research. Similarly, the questions raised by these mechanism proposals reflect the limitations of the methods used to develop them. The mechanism of HMGR, a four-electron oxidoreductase, is unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large-scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled researchers to use site-directed mutagenesis experiments and protein sequencing to identify catalytically important glutamate, aspartate, and histidine residues. These studies, in turn, have generated new and more complicated mechanistic proposals. With the development of protein crystallography, researchers solved HMGR crystal structures to reveal an unexpected lysine residue at the center of the active site. The many crystal structures of HMGR led to increasingly complex mechanistic proposals, but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the protonation state of the glutamate residue within the active site cannot be clearly determined from the crystal structure. The differing protonation state of this residue leads to different proposed mechanisms for the enzyme. As computational analysis of large biomolecules has become more feasible, the application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, they prove to be very powerful for the study of enzyme mechanisms in conjunction with protein crystallography. Nevertheless, even the most current mechanistic proposal for HMGR remains incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms.

Dataset Information

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome.

Objective

Design

Setting

Patient(s)

Intervention(s)

Main outcome measure(s)

Result(s)

Conclusion(s)

Publications

Variants in the HMG-CoA reductase (HMGCR) gene influence component phenotypes in polycystic ovary syndrome.

Similar Datasets

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