Becker Tim, Jansen Silke, Tamm Stephanie, Wienker Thomas F, Tümmler Burkhard, Stanke Frauke
Institute of Medical Biometrics, Informatics and Genetics (IMBIE), University of Bonn, Bonn, Germany.
Eur J Hum Genet. 2007 Jul;15(7):774-8. doi: 10.1038/sj.ejhg.5201825. Epub 2007 Apr 4.
Two entities localised within in a 5 Mb interval on 19q13, that is the transforming growth factor beta 1 (TGFbeta1) and the cystic fibrosis modifier 1, have been reported to modulate disease severity of cystic fibrosis (CF), albeit the designation of the risk allele for TGFbeta1 differs between studies. We have analysed genotyping data at seven microsatellite loci and four single nucleotide polymorphisms targeting the 19q13 area from 37 nuclear CF families with two affected offspring exhibiting extreme clinical phenotypes for indicators of transmission-ration distortion, maternal genetic or maternal non-genetic effects. Evidence for a transmission-ratio distortion was obtained at D19S112 (P=0.0304) near the recently characterised myotonic dystrophy locus myotonic dystrophy protein kinase (DMPK). Maternal and paternal genotype distributions were significantly different at rs1982073 (Leu10Pro at TGFbeta1) whereby all CF sibs heterozygous at rs1982073 inherited the Leu10 allele from their mother (P=0.000132) in our sibling panel. To ask whether the improved survival in CF over the last decades has any influence on TGFbeta1 allele frequencies, we analysed unrelated F508del homozygotes who were stratified by birth cohort. Sensitivity with respect to the survivor bias was reflected by significantly higher incidence of mild cystic fibrosis transmembrane conductance regulator mutation genotypes in the early born patient cohort (P=0.0169), and an allelic imbalance was also observed at TGFbeta1 (P=0.0664). In conclusion, the role of TGFbeta1 as a CF modulator, suggested from studies with a case-control setting, needs to be interpreted with caution unless family-based analysis is carried out to identify parental genetic and non-genetic effects.
据报道，位于19号染色体长臂1区3带（19q13）上5兆碱基区间内的两个基因座，即转化生长因子β1（TGFbeta1）和囊性纤维化修饰因子1，可调节囊性纤维化（CF）的疾病严重程度，尽管不同研究中TGFbeta1风险等位基因的命名有所不同。我们分析了来自37个核心CF家庭的19q13区域的7个微卫星位点和4个单核苷酸多态性的基因分型数据，这些家庭中有两个患病后代表现出极端临床表型，以检测传递不平衡、母系遗传或母系非遗传效应的指标。在最近确定的强直性肌营养不良基因座强直性肌营养不良蛋白激酶（DMPK）附近的D19S112处获得了传递不平衡的证据（P = 0.0304）。在rs1982073（TGFbeta1的Leu10Pro）处，母系和父系基因型分布存在显著差异，在我们的同胞组中，所有在rs1982073处杂合的CF同胞都从其母亲那里继承了Leu10等位基因（P = 0.000132）。为了探究过去几十年中CF患者生存率的提高是否对TGFbeta1等位基因频率有任何影响，我们分析了按出生队列分层的无关F508del纯合子。早期出生患者队列中轻度囊性纤维化跨膜传导调节因子突变基因型的发生率显著更高（P = 0.0169），这反映了对幸存者偏差的敏感性，并且在TGFbeta1处也观察到了等位基因不平衡（P = 0.0664）。总之，除非进行基于家系的分析以识别父母的遗传和非遗传效应，否则从病例对照研究中得出的TGFbeta1作为CF调节因子的作用需要谨慎解释。
