Genome wide variation in cystic fibrosis

Includes bibliographical references (p. 32-34)Cystic fibrosis (CF) is the most common monogenic disorder observed in the Caucasian population. The disease is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene. The defective CFTR produces sticky mucus that results in serious lung infections, as well as failure in the pancreas, intestine, liver, male reproductive tract, and sweat glands. The most common CFTR genotype in the patients is known as F508del, and extensive mutational heterogeneities are spread across the patient population. A wide variety of phenotypes have been observed in F508del individuals, suggesting the influence of environment and modifier genes in clinical manifestation of the disease. Since genotype-phenotype associations in CF have not been fully interpreted for decades, a genome wide survey is required. The recent development of high throughput genotyping technologies, such as array comparative genomic hybridization (array CGH) and single-nucleotide polymorphisms array (SNP array), enable us to conduct genome wide studies more efficiently and identify potential modifier genes in CF patients. Using these technologies, high density genome wide information has been accumulated from F508del patients. This research surveyed a high density single-nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in 24 CF patients using SNP arrays. A high density of minor SNPs was found in the region 7q31, where CFTR gene is located. Other SNPs were also found to be widely spread across the genome. Most of the SNPs are located in non-coding regions, but some of them are potentially in transcription factor binding sites. The CNV analysis reveals that known and unknown CNVs are prevalent in a patient's genome. The genomic variations found in this study were classified as strong markers for genetic modifiers in CF