title: Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.
abstract: CFTR mutations enhance susceptibility for idiopathic chronic pancreatitis (ICP) and congenital bilateral absence of the vas deferens (CBAVD); however, it is unknown why CFTR heterozygotes are at increased disease risk. We recently showed that common CFTR variants are associated with aberrantly spliced transcripts. Here, we genotyped for common CFTR variants and tested for associations in two ICP (ICP-A: 126 patients, 319 controls; ICP-B: 666 patients, 1,181 controls) and a CBAVD population (305 patients, 319 controls). Haplotype H10 (TG11-T7-470V) conferred protection (ICP-A: OR 0.19, P<0.0001; ICP-B: OR 0.78, P = 0.06; CBAVD OR 0.08, P<0.001), whereas haplotype H3 (TG10-T7-470M) increased disease risk (ICP-A: OR 8.34, P = 0.003; ICP-B: OR 1.88, P = 0.007; CBAVD: OR 5.67, P = 0.01). The risk of heterozygous CFTR mutations carriers for ICP (OR 2.44, P<0.001) and CBAVD (OR 14.73, P<0.001) was fully abrogated by the H10/H10 genotype. Similarly, ICP risk of heterozygous p.Asn34Ser SPINK1 mutation carriers (OR 10.34, P<0.001) was compensated by H10/H10. Thus, common CFTR haplotypes modulate ICP and CBAVD susceptibility alone and in heterozygous CFTR and p.Asn34Ser mutation carriers. Determination of these haplotypes helps to stratify carriers into high- and low-risk subjects, providing helpful information for genetic counseling.
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schwerzenbach and Children's Hospital, Cantonal Hospital Lucerne, Lucerne, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Steiner
authors.forename: Jonas
authors.initials: J
authors.lastname: Rosendahl
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.forename: Niels
authors.initials: N
authors.lastname: Teich
authors.forename: Volker
authors.initials: V
authors.lastname: Keim
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schulz
authors.forename: Roland
authors.initials: R
authors.lastname: Pfützer
authors.forename: Matthias
authors.initials: M
authors.lastname: Löhr
authors.forename: Matthias
authors.initials: M
authors.lastname: Lühr
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gress
authors.forename: Renate
authors.initials: R
authors.lastname: Nickel
authors.forename: Olfert
authors.initials: O
authors.lastname: Landt
authors.forename: Monika
authors.initials: M
authors.lastname: Koudova
authors.forename: Milan
authors.initials: M
authors.lastname: Macek
authors.forename: Antoni
authors.initials: A
authors.lastname: Farre
authors.forename: Teresa
authors.initials: T
authors.lastname: Casals
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Desax
authors.forename: Sabina
authors.initials: S
authors.lastname: Gallati
authors.forename: Macarena
authors.initials: M
authors.lastname: Gomez-Lira
authors.forename: Marie Pierre
authors.initials: MP
authors.lastname: Audrezet
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Marie
authors.initials: M
authors.lastname: des Georges
authors.forename: Mireille
authors.initials: M
authors.lastname: Claustres
authors.forename: Kaspar
authors.initials: K
authors.lastname: Truninger
mesh_terms: D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007248:Infertility, Male / Q000235:genetics; D008297:Male; D052801:Male Urogenital Diseases / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D050500:Pancreatitis, Chronic / Q000235:genetics*; D014359:Trypsin Inhibitor, Kazal Pancreatic; D014649:Vas Deferens / Q000002:abnormalities; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C486642:SPINK1 protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014359:Trypsin Inhibitor, Kazal Pancreatic