Human growth hormone (GH1) gene polymorphism map in a normal-statured adult population

Abstract

Objective: GH1 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 measurements: A 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.

Results: Twenty-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).

Conclusions: This 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.

Fig. 1

Alignment of GH gene cluster paralogues (GH1, GH2, CS5, CS1 and CS2) from Genebank accession sequence GI 183148. The SNPs (P1 to P25) identified in the population, as well as 28 additional sequence changes, are signalled with their corresponding number. Segment of the GH1 sequence translocated by CS1/CS2 (box); segments where GH1 and paralogues differ (in red); the STOP codon is marked.

Fig. 2

(a), (b), (c) Box plot distribution of height SDS in normal adult height population bearing the most frequent SNPs in the GH1 gene (n = 278) according to genotypes in 5286 (P16), 5290 (P17) and 6358 (P25). SNPs P16 and P17 are in LD (r² = 0·83). SNP P25 is carried in heterozygosis by six subjects homozygous at P16 and P17. Carriers of any of these polymorphisms in heterozygosis have significantly taller stature (P = 0·016 for P16, P = 0·015 for P17 and P = 0·023 for P25; Bonferroni–Dunn test). (d) Box plot distribution of height SDS in normal adult height population bearing the most frequent SNPs in the GH1 gene (n = 278) according to their combined genotypes at SNPs 5089 (P6) and 6358 (P25). Subjects heterozygous T/G at P25 are taller than subjects with the same corresponding genotype at P6. Height SDS differed significantly between genotypes GG/TT and GG/TG (P = 0·0021; Bonferroni–Dunn test). (e) Box plot distribution of height SDS in normal adult height population bearing additional SNPs in the GH1 gene with frequencies < 1% (n = 29) according to their genotypes at SNPs 5089 (P6), 5178 (P12) and 5187 (P13). Subjects carriers of heterozygous AG at P6 and/or P12 and P13 are significantly shorter than homozygous AA (P = 0·014; Bonferroni–Dunn test).