An association study on contrasting cystic fibrosis endophenotypes recognizes KRT8 but not KRT18 as a modifier of cystic fibrosis disease severity and CFTR mediated residual chloride secretion

<p>Abstract</p> <p>Background</p> <p>F508del-CFTR, the most frequent disease-causing mutation among Caucasian cystic fibrosis (CF) patients, has been characterised as a mutant defective in protein folding, processing and trafficking. We have investigated the two neighbouring cytokeratin genes <it>KRT8 </it>and <it>KRT18 </it>in a candidate gene approach to ask whether variants in <it>KRT8 </it>and/or <it>KRT18 </it>modify the impaired ion conductance known as the CF basic defect, and whether they are associated with correct trafficking of mutant CFTR and disease severity of CF.</p> <p>Methods</p> <p>We have selected contrasting F508del-<it>CFTR </it>homozygous patient subpopulations stratified for disease severity, comparing 13 concordant mildly affected sib pairs vs. 12 concordant severely affected sib pairs, or manifestation of the CF basic defect in intestinal epithelium, comparing 22 individuals who exhibit CFTR-mediated residual chloride secretion vs. 14 individuals who do not express any chloride secretion, for an association. The <it>KRT8</it>/<it>KRT18 </it>locus was initially interrogated with one informative microsatellite marker. Subsequently, a low density SNP map with four SNPs in KRT8 and two SNPs in KRT18, each selected for high polymorphism content, was used to localize the association signal.</p> <p>Results</p> <p><it>KRT8</it>, but not <it>KRT18</it>, showed an association with CF disease severity (P_best= 0.00131; P_corr= 0.0185) and CFTR mediated residual chloride secretion (P_best= 0.0004; P_corr= 0.0069). Two major four-marker-haplotypes spanning 13 kb including the entire <it>KRT8 </it>gene accounted for 90% of chromosomes, demonstrating strong linkage disequilibrium at that locus. Absence of chloride secretion was associated with the recessive haplotype 1122 at rs1907671, rs4300473, rs2035878 and rs2035875. The contrasting haplotype 2211 was dominant for the presence of CFTR mediated residual chloride secretion. In consistency, the <it>KRT8 </it>haplotype 2211 was associated with mild CF disease while 1122 was observed as risk haplotype. Analysis of microsatellite allele distributions on the SNP background suggests that the mild <it>KRT8 </it>haplotype 2211 is phylogenetically older than its severe counterpart.</p> <p>Conclusions</p> <p>The two opposing <it>KRT8 </it>alleles which have been identified as a benign and as a risk allele in this work are likely effective in the context of epithelial cell differentiation. As the mild <it>KRT8 </it>allele is associated with CFTR mediated residual chloride secretion among F508del-<it>CFTR </it>homozygotes, the KRT8/KRT18 heterodimeric intermediary filaments of the cytoskeleton apparently are an essential component for the proper targeting of CFTR to the apical membrane in epithelial cells.</p

Estimated breeding values and association mapping for persistency and total milk yield using natural cubic smoothing splines

BackgroundFor dairy producers, a reliable description of lactation curves is a valuable tool for management and selection. From a breeding and production viewpoint, milk yield persistency and total milk yield are important traits. Understanding the genetic drivers for the phenotypic variation of both these traits could provide a means for improving these traits in commercial production.MethodsIt has been shown that Natural Cubic Smoothing Splines (NCSS) can model the features of lactation curves with greater flexibility than the traditional parametric methods. NCSS were used to model the sire effect on the lactation curves of cows. The sire solutions for persistency and total milk yield were derived using NCSS and a whole-genome approach based on a hierarchical model was developed for a large association study using single nucleotide polymorphisms (SNP).ResultsEstimated sire breeding values (EBV) for persistency and milk yield were calculated using NCSS. Persistency EBV were correlated with peak yield but not with total milk yield. Several SNP were found to be associated with both traits and these were used to identify candidate genes for further investigation.ConclusionNCSS can be used to estimate EBV for lactation persistency and total milk yield, which in turn can be used in whole-genome association studies.Klara L. Verbyla and Arunas P. Verbyl

Clinical presentation of exclusive cystic fibrosis lung disease

The diagnosis of cystic fibrosis (CF) is based on the occurrence of two mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and on assays that measure the basic defect of abnormal chloride transport in the affected organs. However, in cases of atypical CF not all diagnostic tests may be positive. We present a patient with an atypical CF phenotype in whom the only presenting symptom was severe CF-like lung disease substantiated by an abnormal nasal potential difference. Genetic analysis showed that the patient was a symptomatic heterozygote, which suggests that one lesion in the CFTR gene may be sufficient to cause CF-like lung disease.