The influence of Nos3 polymorphisms on age at menarche and natural menopause

Department of Obstetrics & Gynecology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Maturitas (Impact Factor: 2.94). 11/2004; 49(2):157-62. DOI: 10.1016/j.maturitas.2004.01.004
Source: PubMed


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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    • "Previous candidate gene association studies have focused on the genes involved in steroid-hormone metabolism and biosynthesis pathway, such as estrogen receptor genes (ESR1 and ESR2) (Boot et al. 2004; Dvornyk et al. 2006; Gorai et al. 2003; He et al. 2007; Kok et al. 2005; Long et al. 2005; Stavrou et al. 2006; Stavrou et al. 2002; Weel et al. 1999), sex hormone binding globulin gene (SHBG) (Xita et al. 2005), and genes involved in estrogen biosynthesis (CYP17, CYP19, and HSD17), hydroxylation (CYP1A1, CYP1B1, and CYP3A4), and inactivation of the reactive metabolites (COMT) (Gorai et al. 2003; Guo et al. 2006b; He et al. 2007; Hefler et al. 2005; Lai et al. 2001; Long et al. 2006; Mitchell et al. 2008). Association studies of candidate genes in other biologically plausible pathways are sparse, including IGF1 (Zhao et al. 2007), AMHR2 (Kevenaar et al. 2007), and genes associated with thrombophilia and vascular homeostasis such as F5 (Tempfer et al. 2005; van Asselt et al. 2003), APOE (Koochmeshgi et al. 2004; Tempfer et al. 2005), NOS3 (Hefler et al. 2002; Tempfer et al. 2005; Worda et al. 2004), F2, and SERPINE1 (Tempfer et al. 2005). Recently, a few studies focused on genes associated with the extremes of these two phenotypes, for example, ten hypogonadotropic hypogonadism genes (FGFR1, GNRH, GNRHR, GPR54/KISS1R, KAL1, KISS1, LEP, LEPR, PROK2, and PROKR2) (Gajdos et al. 2008), and the FMR1 gene (Ennis et al. 2006; Mallolas et al. 2001) have been examined in relation to age at menarche and age at menopause, respectively. "
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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. DOI:10.1007/s00439-010-0878-4 · 4.82 Impact Factor
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    • "were also performed to assess the association between candidate gene polymorphisms and AANM (Cramer et al. 1989; Weel et al. 1999; van Asselt et al. 2003; Worda et al. 2004; Hefler et al. 2005; Kok et al. 2005b; Long et al. 2006). As oestrogens plays an important role in the regulation of female reproductive systems, estrogen-receptor-α gene (ESR1) and estrogen-metabolizing genes were regarded as important candidate genes for AANM (Weel et al. 1999; Hefler et al. 2005; Kok et al. 2005b; Long et al. 2006). "
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    ABSTRACT: Genetic factors play a significant role in influencing the variation of age at natural menopause (AANM). Estrogen receptor beta (ESR2), is an important factor in the mechanism of action of estrogen, while the aromatase gene (CYP19) and the 17-alpha-hydroxylase gene (CYP17) are involved in the biosynthesis of estrogen. We tested whether polymorphisms of ESR2, CYP19 and CYP17 genes are associated with AANM in Caucasian females. A total of 52 SNPs (17 for ESR2, 28 for CYP19, and 7 for CYP17) were successfully genotyped for 229 Caucasian women having experienced natural menopause. Comprehensive statistical analyses focusing on the association of these genes with AANM were conducted. The effects of age, height and age at menarche on AANM were adjusted when conducting association analyses. We found that six SNPs (2, 6-7, 9, 13 and 16) within ESR2 were not significantly associated with AANM after Bonferroni correction. However, two blocks of ESR2 were associated with AANM. For CYP19, two SNPs (24 and 27) were nominally associated with AANM. No significant association was observed between CYP17 and AANM. Our results suggest that genetic variation in the ESR2 and CYP19 genes may influence the variation in AANM in Caucasian women.
    Journal of Genetics 12/2008; 86(3):269-76. DOI:10.1007/s12041-007-0034-7 · 1.09 Impact Factor
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    • "Thus, it is valuable and necessary to explore the potential factors influencing the variation of age at menarche (AAM). AAM is determined by different environmental and genetic factors(van Noord et al., 1997; Worda et al., 2004). It was reported that 53 – 74% of the variation in AAM could be due to genetic effects (Kaprio et al., 1995; Sharma, 2002). "
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    ABSTRACT: The insulin-like growth factor 1 (IGF1) gene, which plays a crucial role in hypothalamic-pituitary-ovarian hormone-controlled metabolic processes, may influence the onset of menarche. Our study aimed to test association between IGF1 polymorphisms with the variation of age at menarche (AAM) in Caucasian females. We recruited a sample of 1048 females from 354 Caucasian nuclear families and genotyped 19 single-nucleotide polymorphisms (SNPs) spanning the entire IGF1 gene. Pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both single SNP markers and haplotypes were tested for association with AAM using the quantitative transmission disequilibrium test. Significant association (P = 0.0153) between AAM and SNP3 (rs6214) in block1 was detected. Our results suggested a potential effect of SNP3 in the IGF1 gene on AAM variation in Caucasian women for the first time. However, further independent studies are needed to confirm our findings.
    Human Reproduction 07/2007; 22(6):1789-94. DOI:10.1093/humrep/dem052 · 4.57 Impact Factor
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