title: Hierarchical fine mapping of the cystic fibrosis modifier locus on 19q13 identifies an association with two elements near the genes CEACAM3 and CEACAM6.
abstract: On 19q13, TGFB1 and the cystic fibrosis modifier 1 locus (CFM1) have been identified as modifiers of the course of the monogenic disease cystic fibrosis (CF). Recently, we have described a transmission disequilibrium at the microsatellite D19S197, localized between TGFB1 and CFM1. To map the corresponding molecular variants, we have selected informative SNP markers within a 600-kb area and compared two-marker-haplotype-distributions between phenotypically contrasting sib pair groups, intending to type only phylogenetically old markers by aiming for close-to-maximal polymorphism information content of the SNPs. Starting with a seed set of five SNPs that cover intermarker distances of up to 50 kb, we have iteratively added more SNPs to the map, until we could identify two genomic fragments of 3,289 and 2,052 bp for which pairs with contrasting phenotypes showed different haplotype distributions on the final 17-SNP-map (P(raw) = 0.0002, P(corr17SNPs) = 0.0106 and P(raw) = 0.0008, P(corr17SNPs) = 0.0469, respectively). Resequencing of these fragments of four unrelated individuals for each element showed that the mildly and severely affected pairs differ in seven SNPs and concordant pairs differ from discordant pairs in five SNPs. Annotation of these variants indicate that CEACAM6 and a regulatory element near the 3' end of CEACAM3 are associated with CF disease severity and intrapair discordance, respectively. While our approach was only guided by the markers' position, the involvement of genes from the CEACAM family in host defense and innate immunity designates these proteins as likely modifiers of the multi-organ disease cystic fibrosis which is known for its cytokine imbalance and pro-inflammatory phenotype.
authors.affiliation: Department of Pediatrics, Hannover Medical School, Hannover, Germany. mekus.frauke@mh-hannover.de
authors.forename: Frauke
authors.initials: F
authors.lastname: Stanke
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Silke
authors.initials: S
authors.lastname: Hedtfeld
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tamm
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
mesh_terms: D015703:Antigens, CD / Q000235:genetics*; D002272:Carcinoembryonic Antigen / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics*; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004200:Diseases in Twins / Q000235:genetics; D058851:GPI-Linked Proteins / Q000235:genetics; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D050436:Regulatory Elements, Transcriptional; D017384:Sequence Deletion; D014430:Twins, Monozygotic
chemical_list: D015703:Antigens, CD; C075729:CEACAM3 protein, human; C504117:CEACAM6 protein, human; C505032:CFTR protein, human; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator