title: Genetic variants in apoptosis-related genes associated with colorectal hyperplasia.
abstract: Deregulation of apoptosis is a frequent alteration in early benign lesions of the colon mucosa and is thought to be a major contributor to tumor progression and cancer. Single nucleotide polymorphisms (SNPs) within apoptosis-related genes could affect apoptotic responses and their identification might provide a basis to assess individual risk for development of early lesions. To investigate a possible association between genetic polymorphisms and the occurrence of hyperplastic polyps (HP), we developed a custom DNA chip assay for 1,536 SNPs in the coding and flanking regions of 826 genes with known functional roles in apoptosis or apoptosis-associated (e.g., stress-related) pathways. During a first round of screening, genotypes were determined for 272 endoscopy patients harboring hyperplastic colorectal polyps and for 512 sex and aged-matched controls. A set of 14 candidate SNPs associated with HP (P < 0.01) was then evaluated in an independent cohort of patients (n = 38) and controls (n = 38). Following meta-analysis of Stages I and II, a false discovery rate approach was applied. Among the 14 candidate SNPs, eight showed significant association (combined P < 0.01) with the occurrence of HP. The SNPs rs4709583 (PARK2) and rs10476823 (HDAC3) were analyzed for potential functional effects on RNA splicing and RNA half-life. Despite its location near a splice site, alternative splicing was not detected for rs4709583 (PARK3). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3'UTR of HDAC3 mRNA and a longer mRNA half-life in a cell line heterozygous for rs10476823.
authors.affiliation: Institute for Clinical Chemistry, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, 68167, Germany.
authors.forename: Stefano
authors.initials: S
authors.lastname: Gerola
authors.forename: Stefanie
authors.initials: S
authors.lastname: Nittka
authors.forename: Georg
authors.initials: G
authors.lastname: Kähler
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Giorgio
authors.initials: G
authors.lastname: Binelli
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.forename: Michael
authors.initials: M
authors.lastname: Neumaier
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D003111:Colonic Polyps / Q000235:genetics / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D007417:Intestinal Polyps / Q000235:genetics / Q000473:pathology*; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012007:Rectum / Q000473:pathology; D000099186:Histone Deacetylase 3
chemical_list: D005819:Genetic Markers; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3