Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis
Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis
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DOI：
10.1093/hmg/ddn123
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发表时间：
2008-07-15
影响因子：
3.5
通讯作者：
Cutting, Garry R.
中科院分区：
文献类型：
--
作者：
Bremer, Lindsay A.;Blackman, Scott M.;Cutting, Garry R.
囊性纤维化（CF）是白种人中最常见的致命单基因疾病，是由于CFTR基因突变引起的。双胞胎和兄弟姐妹分析表明，修饰基因，而不是CFTR的等位基因变异，是导致CF患者死亡的主要原因肺部疾病严重程度的大部分变异的原因。我们使用基于家族的方法来检测肺功能与转化生长因子- β 1 (TGFB1) 5‘区两个功能性snp （rs1800469, ’-509‘和rs1982073， ’密码子10'）之间的关系，TGFB1是一种假定的CF修饰基因。对472例CF患者-父母-父母三人组的定量传播不平衡测试显示，当患者按CFTR基因型分层时，两个TGFB1 snp都出现了显著的传播扭曲。尽管CF患者的肺功能和营养状况相关，但没有证据表明TGFB1 snp与营养状况变化之间存在关联。捕获TGFB1中大部分多样性的其他标记snp （rs8179181、rs2278422、rs8110090、rs4803455和rs1982072）也被分型，但没有一个显示与肺功能变异相关。然而，在CFTR基因型分组的患者中，由-509 C和密码子10t等位基因以及3' SNP rs8179181的C等位基因组成的单倍型与肺功能的增加高度相关。这些结果表明TGFB1是CF肺病的修饰因子，并揭示了TGFB1变异对肺表型的先前未被认识的有益作用。
Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, '-509' and rs1982073, 'codon 10') in the 5' region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient-parent-parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the -509 C and codon 10 T alleles along with the C allele of the 3' SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.