title: Genetic variation in telomeric repeat binding factors 1 and 2 in aplastic anemia.
abstract: OBJECTIVE
  Abnormal telomere shortening has been observed in a subset of individuals with aplastic anemia (AA). We hypothesized that genetic variation in two genes critical in telomere biology, TERF1 and TERF2, could be a risk factor for AA.
  
  
  METHODS
  The proximal promoter and all coding regions of TERF1 and TERF2 were sequenced in 47 individuals with acquired AA. Regions with genetic variation were sequenced in an additional 95 AA patients and 289 healthy controls. Single nucleotide polymorphism (SNP) frequencies were analyzed using co-dominant and dominant models and haplotypes determined. Functional studies evaluated telomerase activity, telomere and telomeric overhang lengths, and TRF2 protein expression in select patients.
  
  
  RESULTS
  Two nonsynonymous amino acid changes were detected, one in exon 9 of TERF1 and another in exon 6 of TERF2. These sequence variants resulted in conservative amino acid changes and were not predicted to alter TRF1 or TRF2 protein expression or function. SNP and haplotype analyses in acquired AA patients suggested that one variant allele, in intron 9 of TERF1, and haplotype could be associated with increased risk for aplastic anemia (OR 1.59, 95% confidence interval 1.06-2.39, p = 0.033). TERF2 SNPs and haplotypes were not significantly associated with aplastic anemia.
  
  
  CONCLUSIONS
  It is possible that a common genetic variant in TERF1 is associated with risk for AA but additional studies are required. Highly penetrant, non-synonymous, or insertion-deletion mutations in TERF1 and TERF2 were not identified and therefore are not likely to be major genetic risk factors for the development of AA.
authors.affiliation: Section of Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4605, USA. savagesh@mail.nih.gov
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.forename: Rodrigo T
authors.initials: RT
authors.lastname: Calado
authors.forename: Zhong-Tao
authors.initials: ZT
authors.lastname: Xin
authors.forename: Hinh
authors.initials: H
authors.lastname: Ly
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics*; D015153:Blotting, Western; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D016133:Polymerase Chain Reaction; D035321:Telomeric Repeat Binding Protein 1 / Q000235:genetics*; D035341:Telomeric Repeat Binding Protein 2 / Q000235:genetics*
chemical_list: D035321:Telomeric Repeat Binding Protein 1; D035341:Telomeric Repeat Binding Protein 2