Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females

The Key Laboratory of Biomedical Information Engineering, Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, People's Republic of China.
Human Reproduction (Impact Factor: 4.57). 07/2007; 22(6):1789-94. DOI: 10.1093/humrep/dem052
Source: PubMed


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.

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Available from: Yan Guo, Nov 26, 2014
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    • "However, previous studies also suggested no relationship between IGF-1 and BMD,14 and reported that the low levels of circulating IGF-1 had no actually relation with osteoporosis.15 Several SNPs of IGF-1 have been recognized to be involved in cancer, myopia, muscle function, BMD regulation and affects age at menarche.16,17 However, study investigated the links between polymorphisms of IGF-I and BMD or osteoporosis is lacking. "
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    ABSTRACT: Objective: It has been shown that Insulin-like growth factor-1 (IGF-1) may be related with bone mineral density (BMD) or osteoporosis. But there are few evidences on the role of genetic variation of IGF-1 on the BMD or osteoporosis. We observed the relationship between polymorphisms of IGF-1(rs35767, rs2288377 and rs5742612) with osteoporosis and BMD in the postmenopausal female population in our study. Methods: A total of 216 postmenopausal women with a primary diagnosis of osteoporosis and 220 normal healthy women were included in the study. Genomic DNA of IGF-1 rs35767, rs2288377 and rs5742612 was extracted from the whole blood using QIAamp blood DNA mini kits (QIAGEN, Hilden, Germany) according to the methods recommended by the manufacturer. Results: We found that T allele of rs35767 had higher increased risk of osteoporosis (OR=1.34, 95%CI=1.0-1.81). Those carrying T allele of rs35767 had a significant lower BMD at L1–L4 vertebrae, femoral neck, total hip and trochanter when compared with those carrying C allele (P < 0.05). In addition, the BMD of L1–L4 vertebrae, femoral neck, total hip and trochanter decreased by 2.09%, 3.74%, 3.52% and 2.54% in women carrying T alleles compared with those carrying C alleles. Conclusion: Our study suggests that polymorphism in IGF-I rs35767 was significantly associated with BMD and osteoporosis in postmenopausal female population, and polymorphism of rs35767 could be a marker for lower BMD and risk of osteoporosis.
    Pakistan Journal of Medical Sciences Online 03/2014; 30(1):131-5. DOI:10.12669/pjms.301.4264 · 0.23 Impact Factor
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    • "Higher serum levels of IGF1 and a single nucleotide polymorphisms (SNP) in IGF1R were associated with premature pubarche in humans (Roldan et al. 2007). Furthermore, the IGF1 gene is located in a quantitative trait locus found for age at menarche (Anderson et al. 2008), and a SNP in exon 4 of IGF1 was associated with age at menarche in women (Zhao et al. 2007). In Brahman cattle, serum concentration of IGF1 was found to be negatively correlated (r = À0.7 at 18 months of age, r = À0.43 at 24 months of age) with age of puberty (Johnston et al. 2009). "
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    ABSTRACT: Insulin-like growth factor I (somatomedin C) (IGF1) influences gonadotrophin-releasing hormone (GnRH) neurons during puberty, and GnRH release guides pubertal development. Therefore, genes of the IGF1 pathway are biological candidates for the identification of single-nucleotide polymorphisms (SNPs) affecting age of puberty. In a genome-wide association study, genotyped heifers were Tropical Composite (TCOMP, n = 866) or Brahman (BRAH, n = 843), with observation of age at first corpus luteum defining puberty. We examined SNPs in or near genes of the IGF1 pathway and report seven genes associated with age at puberty in cattle: IGF1R, IGFBP2, IGFBP4, PERK (HUGO symbol EIF2AK3), PIK3R1, GSK3B and IRS1. SNPs in the IGF1 receptor (IGF1R) showed the most promising associations: two SNPs were associated with puberty in TCOMP (P < 0.05) and one in BRAH (P = 0.00009). This last SNP explained 2% of the genetic variation (R(2) = 2.04%) for age of puberty in BRAH. Hence, IGF1R was examined further. Additional SNPs were genotyped, and haplotypes were analysed. To test more SNPs in this gene, four new SNPs from dbSNP were selected and genotyped. Single SNP and haploytpe analysis revealed associations with age of puberty in both breeds. There were two haplotypes of 12 IGF1R SNPs associated with puberty in BRAH (P < 0.05) and one in TCOMP (P < 0.05). One haplotype of two SNPs was associated (P < 0.01) with puberty in BRAH, but not in TCOMP. In conclusion, the IGF1 pathway appeared more relevant for age of puberty in Brahman cattle, and IGF1R showed higher significance when compared with other genes from the pathway.
    Animal Genetics 05/2012; 44(1). DOI:10.1111/j.1365-2052.2012.02367.x · 2.21 Impact Factor
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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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