The influence of Nos3 polymorphisms on age at menarche and natural menopause.
ABSTRACT Deficiency of the gene encoding endothelial nitric oxide synthase, i.e. Nos3, has been reported to be associated with late menarche, reduced ovulation rates, fewer deliveries, and earlier onset of menopause in a mouse model.
We assessed the Glu298Asp and the T-786C polymorphisms of Nos3 in 87 consecutive healthy postmenopausal women by pyro- and capillary-sequencing, respectively. Results were correlated with age at menarche and natural menopause, number of miscarriages and live births, as well as body mass index (BMI) and smoking habits.
Allelic frequencies of the Glu298Asp polymorphism of Nos3 were 121 (69.5%) and 53 (30.5%) for the wild-type G allele and the mutant T allele, respectively. Forty-one women (47.1%) were homozygote wild-type (G/G), 39 (44.9%) were heterozygote (G/T), and 7 (8.0%) were homozygote mutant (T/T). Allelic frequencies of the T-786C polymorphism of Nos3 were 105 (60.6%) and 69 (39.4%) for the wild-type T allele and the mutant C allele, respectively. Thirty-three women (38.0%) were homozygote wild-type (T/T), 39 (45.1%) were heterozygote (T/C), and 15 (16.9%) were homozygote mutant (C/C). Presence of at least one mutant allele of the Glu298Asp or the T-786C polymorphisms of Nos3 were not associated with age at menarche, natural menopause, and number of miscarriages and deliveries. BMI above 27 kg/m2 and smoking were associated with earlier onset of natural menopause (47.8 years versus 50.2 years (P = 0.01) and 46.8 years versus 49.8 years (p = 0.02)).
Our data show that smoking and increased BMI, but not Glu298Asp or the T-786C polymorphisms of Nos3, are associated with an early onset of natural menopause.
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ABSTRACT: BACKGROUND Timing of natural menopause has great implications for fertility and women's health. Age at natural menopause (ANM) is largely influenced by genetic factors. In the past decade, several genetic studies have been conducted to identify genes in ANM, which can help us unravel the biological pathways underlying this trait and the associated infertility and health risks. After providing an overview of the results of the genetic studies performed so far, we give recommendations for future studies in identifying genetic factors involved in determining the variation in timing of natural menopause. METHODS The electronic databases of Pubmed and Embase were systematically searched until September 2009 for genetic studies on ANM, using relevant keywords on the subject. Additional papers identified through hand search were also included. RESULTS Twenty-eight papers emerged from our literature search. A number of genetic regions and variants involved in several possible pathways underlying timing of ANM were identified, including two possible interesting regions (9q21.3 and chromosome 8 at 26 cM) in linkage analyses. Recent genome-wide association studies have identified two genomic regions (19q13.42 and 20p12.3), containing two promising candidate genes (BRKS1 and MCM). In the candidate gene association studies on ANM, very few consistent associations were found. CONCLUSION A number of genetic variants have been discovered in association with ANM, although the overall results have been rather disappointing. We have described possible new strategies for future genetic studies to identify more genetic loci involved in the variation in menopausal age.Human Reproduction Update 01/2010; 16(4):364-77. · 9.23 Impact Factor
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ABSTRACT: Recent genome-wide association (GWA) studies have identified several novel genetic loci associated with age at menarche and age at natural menopause. However, the stringent significance threshold used in GWA studies potentially led to false negatives and true associations may have been overlooked. Incorporating biologically relevant information, we examined whether common genetic polymorphisms in candidate genes of nine groups of biologically plausible pathways and related phenotypes are associated with age at menarche and age at natural menopause. A total of 18,862 genotyped and imputed single nucleotide polymorphisms (SNPs) in 278 genes were assessed for their associations with these two traits among a total of 24,341 women from the Nurses' Health Study (NHS, N = 2,287) and the Women's Genome Health Study (WGHS, N = 22,054). Linear regression was used to assess the marginal association of each SNP with each phenotype. We adjusted for multiple testing within each gene to identify statistically significant SNP associations at the gene level. To evaluate the overall evidence for an excess of statistically significant gene associations over the proportion expected by chance, we applied a one-sample test of proportion to each group of candidate genes. The steroid-hormone metabolism and biosynthesis pathway was found significantly associated with both age at menarche and age at natural menopause (P = 0.040 and 0.011, respectively). In addition, the group of genes associated with precocious or delayed puberty was found significantly associated with age at menarche (P = 0.013), and the group of genes involved in premature ovarian failure with age at menopause (P = 0.025).Human Genetics 11/2010; 128(5):515-27. · 4.63 Impact Factor
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ABSTRACT: Genome-wide association studies (GWAS) have been successful in uncovering genetic determinants of age at menarche and age at natural menopause. To date, more than 30 novel genetic loci have been identified in GWAS for age at menarche and 17 for age at natural menopause. These findings have stimulated a plethora of follow-up studies particularly with respect to the functional characterization of these novel loci and how these results can be translated into risk prediction. However, the genetic loci identified so far account for only a small fraction of the overall heritability. This review provides an overview of the current state of our knowledge of the genetic basis of menarche and menopause timing. It emphasizes recent GWAS results and outlines strategies for discovering the missing heritability and strategies to further our understanding of the underlying molecular mechanisms of the observed genetic associations.Molecular and Cellular Endocrinology 05/2012; · 4.04 Impact Factor