High incidence of rare TGFB1 haplotypes in children with biliary atresia

Abstract

Objective: to evaluate the occurrence of single nucleotide polymorphisms (SNPs) in transforming growth factor beta 1 (TGFB1) – rs1800469, rs1800470, rs1800471 – and their haplotypes in children with biliary atresia (BA).Materials and methods. We studied 106 pediatric liver recipients aged 4 to 150 (median 8) months, of whom 44 were boys, and 199 healthy individuals aged 32.7 ± 9.6 years, of whom 79 were boys. The indication for pediatric liver transplantation was BA. Genomic DNA was isolated from peripheral blood using a commercial QIAamp DNA Blood Mini Kit on a QIAcube automated analyzer. SNPs rs1800469, rs1800470, and rs1800471 in the TGFB1 gene were determined by real-time polymerase chain reaction using TaqMan probes on a CFX96 amplifier.Results. In children with BA, the occurrence of the investigated SNPs in TGFB1 was as follows: rs1800469 – 38% GG homozygotes, 50% AG heterozygotes and 12% AA homozygotes; rs1800470 – 39% AA, 44% AG, 17% GG; rs1800471 – 88% CC, 12% GC, 0% GG. The distributions of all the three SNPs followed the Hardy–Weinberg principle. For rs1800469 and rs1800470, the genotype and allele frequencies in children with BA did not differ from those in healthy individuals, whereas for rs1800471, the heterozygous GC genotype was three-fold more frequent in children with BA than in healthy individuals. Haplotype analysis showed the presence of 6 major combinations: 2 most frequent were present in a total of about 66% of patients and 91% of healthy individuals, each of the frequencies practically did not differ between the comparison groups. Significant differences were found in the frequency of 3 rarer haplotypes, A-A-C, G-G-C and G-A-G at position rs1800469, rs1800470, rs1800471, which were observed more frequently in patients with BA by 3.10 (CI 1.59 to 6.04) (p = 0.001), 3.10 (CI 1.55 to 6.17) (p = 0.0015), and 17.02 (CI 1.94 to 149.30) (p = 0.011) times, respectively, than in healthy individuals.Conclusion. In children with BA, the occurrence of CG heterozygotes in rs1800471 and the distribution of three rare haplotypes A-A-C, G-G-C and G-A-G of the rs1800469, rs1800470 and rs1800471 SNPs in the TGFB1 gene significantly differs from that in healthy individuals. It is possible that carriage of rare genotypes and haplotypes of TGFB1 may predispose to BA in children.

Keywords

• congenital and hereditary liver diseases
• biliary atresia
• pediatric liver recipients
• liver transplantation
• rs1800469
• rs1800470
• rs1800471
• polymorphism