title: Common polymorphisms in the GH/IGF-1 axis contribute to growth in extremely tall subjects.
abstract: OBJECTIVE
  The growth hormone (GH)/insulin-like growth factor-1(IGF-1) axis is the key regulator of somatic growth in humans and its genes are plausible candidates to study the genetics of height variation. Here, we studied polymorphic variation in the GH/IGF-1 axis in the extremely tall Dutch.
  
  
  METHODS
  Case-control study of 166 tall cases with height >2 SDS and 206 controls with normally distributed height <2 SDS. Excluded were subjects with endocrine disorders or growth syndromes. We analyzed genomic DNA at 7 common polymorphisms in the GH-1, GH receptor (GHR), IGF-1 and IGFBP-3 genes.
  
  
  RESULTS
  The association of the GH-1 1663 SNP with tall stature approached statistical significance, with the T-allele more present in the tall (allele frequency (AF): 0.44 vs. 0.36; p=0.084). Moreover, haplotype frequencies at this locus were significantly different between cases and controls, with the GGT haplotype most commonly seen in cases (p=0.01). Allele frequencies of GHR polymorphisms were not different. For the IGF-1 CA-repeat we observed a higher frequency of homozygous 192-bp carriers among tall males compared to control males (AF: 0.62 vs. 0.55; p=0.02). The IGFBP-3 -202 C-allele occurred more frequently in cases than in controls (AF: 0.58 vs. 0.50; p=0.002). Within cases, those carrying one or two copies of the -202 C-allele were significantly taller than AA genotype carriers (AC, p=0.028 and CC, p=0.009). Serum IGFBP-3 levels were highest in AA genotype carriers, the -202 SNP explained 5.8% of the variation.
  
  
  CONCLUSIONS
  Polymorphic variation in the GH-1, IGF-1 and IGFBP-3 genes is associated with extremely tall stature. In particular, the IGFBP-3 -202 SNP is associated not only with being very tall but also with height variation within the tall.
authors.affiliation: Pediatric Endocrinology, Erasmus Medical Center-Sophia, The Netherlands. a.e.j.hendriks@erasmusmc.nl
authors.forename: A E J
authors.initials: AE
authors.lastname: Hendriks
authors.forename: M R
authors.initials: MR
authors.lastname: Brown
authors.forename: A M
authors.initials: AM
authors.lastname: Boot
authors.forename: B A
authors.initials: BA
authors.lastname: Oostra
authors.forename: F H
authors.initials: FH
authors.lastname: de Jong
authors.forename: S L S
authors.initials: SL
authors.lastname: Drop
authors.forename: J S
authors.initials: JS
authors.lastname: Parks
mesh_terms: D001827:Body Height / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000097:blood / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D019382:Human Growth Hormone / Q000097:blood / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics*; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D008297:Male; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis
chemical_list: D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D004247:DNA