Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
Mucin Variable Number Tandem Repeat Polymorphisms and Severity of Cystic Fibrosis Lung Disease: Significant Association with MUC5AC
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DOI：
10.1371/journal.pone.0025452
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发表时间：
2011-10-06
期刊：
影响因子：
3.7
通讯作者：
Knowles, Michael R.
中科院分区：
文献类型：
--
作者：
Guo, XueLiang;Pace, Rhonda G.;Knowles, Michael R.
囊性纤维化（CF）肺部疾病的变异性部分是由于非cftr基因修饰因子。黏液蛋白基因具有高度多态性，黏液蛋白在CF肺病的发病机制中起关键作用；因此，粘蛋白基因是强有力的候选基因修饰。通过Southern blot或PCR分析CF患者的DNA，确定MUC1、MUC2、MUC5AC和MUC7的可变数串联重复（VNTR）长度多态性。检测了VNTR长度多态性与肺部疾病严重程度的关系，以及与侧链单核苷酸多态性（SNPs）的连锁不平衡（LD）。MUC1、MUC2或MUC7未发现强相关性。MUC5AC VNTR长度的总体分布与CF肺部疾病严重程度之间存在显著相关性（p = 0.025; n = 468例患者）；此外，特异性6.4 kb的hfivntr片段与肺部疾病的严重程度有很强的相关性（经Bonferroni校正后p = 6.2 x 10(-4)）。MUC5AC VNTR长度模式与侧链snp之间存在较强的LD。MUC5AC严重相关的6.4 kb VNTR等位基因被证实在遗传上不同于6.3 kb等位基因，因为它与附近的snp具有显著更强的相关性。这些数据提供了CF患者呼吸黏液蛋白基因VNTR等位基因的详细分布。我们的数据还显示MUC5AC 6.4 kb VNTR等位基因与CF肺部疾病严重程度之间存在新的联系。LD模式与周围snp表明，6.4 kb等位基因包含或与重要的功能性遗传变异有关。
Variability in cystic fibrosis (CF) lung disease is partially due to non-CFTR genetic modifiers. Mucin genes are very polymorphic, and mucins play a key role in the pathogenesis of CF lung disease; therefore, mucin genes are strong candidates as genetic modifiers. DNA from CF patients recruited for extremes of lung phenotype was analyzed by Southern blot or PCR to define variable number tandem repeat (VNTR) length polymorphisms for MUC1, MUC2, MUC5AC, and MUC7. VNTR length polymorphisms were tested for association with lung disease severity and for linkage disequilibrium (LD) with flanking single nucleotide polymorphisms (SNPs). No strong associations were found for MUC1, MUC2, or MUC7. A significant association was found between the overall distribution of MUC5AC VNTR length and CF lung disease severity (p = 0.025; n = 468 patients); plus, there was robust association of the specific 6.4 kb HinfI VNTR fragment with severity of lung disease (p = 6.2 x 10(-4) after Bonferroni correction). There was strong LD between MUC5AC VNTR length modes and flanking SNPs. The severity-associated 6.4 kb VNTR allele of MUC5AC was confirmed to be genetically distinct from the 6.3 kb allele, as it showed significantly stronger association with nearby SNPs. These data provide detailed respiratory mucin gene VNTR allele distributions in CF patients. Our data also show a novel link between the MUC5AC 6.4 kb VNTR allele and severity of CF lung disease. The LD pattern with surrounding SNPs suggests that the 6.4 kb allele contains, or is linked to, important functional genetic variation.