Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens

Steiner, Bernhard; Rosendahl, Jonas; Witt, Heiko; Teich, Niels; Keim, Volker; Schulz, Hans-Ulrich; Pfützer, Roland; Löhr, Matthias; Lühr, Matthias; Gress, Thomas M; Nickel, Renate; Landt, Olfert; Koudova, Monika; Macek, Milan; Farre, Antoni; Casals, Teresa; Desax, Marie-Claire; Gallati, Sabina; Gomez-Lira, Macarena; Audrezet, Marie Pierre; ... (2011). Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Human mutation, 32(8), pp. 912-20. Hoboken, N.J.: Wiley-Blackwell 10.1002/humu.21511

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine

UniBE Contributor:

Gallati, Sabina

ISSN:

1059-7794

Publisher:

Wiley-Blackwell

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:24

Last Modified:

17 Mar 2015 21:04

Publisher DOI:

10.1002/humu.21511

PubMed ID:

21520337

Web of Science ID:

000293961000008

URI:

https://boris.unibe.ch/id/eprint/8344 (FactScience: 213870)

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