Abstract
ObjectiveGH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height.Design, subjects and measurementsA systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: −2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height.ResultsTwenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5′UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6·2% of the variation in adult height (P = 0·0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (−0·063 ± 0·031, −0·693 ± 0·350 and −0·489 ± 0·265, Mean ± SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1·094 ± 0·456 and +1·184 ± 0·432).ConclusionsThis study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.
Highlights
Human skeletal growth and final height attainment are a result of a multifactorial regulation involving systemic and local hormones, growth and nutritional factors, lifestyle and genetic factors
Systematic GH1 gene analysis in patients with growth delay and suspected growth hormone (GH) deficiency/ insufficiency will clarify whether different single nucleotide polymorphic points (SNPs) frequencies and/ or the presence of different sequence changes may be associated with phenotypes in them. (Received 6 March 2006; returned for revision 16 June 2006; revised 5 September 2006; accepted 10 September 2006)
GH1 gene sequence comparison with the GI-183148 sequence published by Chen et al.[6] yielded a total of 54 single or multiple nucleotide changes
Summary
Human skeletal growth and final height attainment are a result of a multifactorial regulation involving systemic and local hormones, growth and nutritional factors, lifestyle and genetic factors. Heritability estimates[1] and genome-wide linkage analysis[2] have shown that genetic factors play a major role in determining stature. Among these factors, the GH-IGF-I axis plays an important role during postnatal life, and associations between structural variations in its genes and height are currently under study.[3] growth hormone (GH) deficiency is a well-known cause of growth retardation, which responds to GH replacement therapy, the diagnosis and physiopathological mechanisms for the so-called ‘idiopathic isolated GH deficiency’ (IIGHD) require further clarification. Large deletions within the GH1 gene cluster were described first followed by point mutations, the majority of which affect introns 3 or 4, provoke skipping of exon 3 product and exert a dominant effect.[3,7,8] More recently, the presence of single nucleotide polymorphic points (SNPs) in the promoter region or in
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