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

Steiner, B; Rosendahl, J; Witt, H; Teich, N; Keim, V; Schulz, HU; Pfützer, R; Löhr, M; Lühr, M; Gress, TM; Nickel, R; Landt, O; Koudova, M; Macek, M; Farre, A; Casals, T; Desax, MC; Gallati, S; Gomez-Lira, M; Audrezet, MP; Férec, C; des Georges, M; Claustres, M; Truninger, K

doi:10.1002/humu.21511

2011

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Title:: Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens.
Document type:: Journal Article; Research Support, Non-U.S. Gov't; Article
Author(s):: Steiner, B; Rosendahl, J; Witt, H; Teich, N; Keim, V; Schulz, HU; Pfützer, R; Löhr, M; Lühr, M; Gress, TM; Nickel, R; Landt, O; Koudova, M; Macek, M; Farre, A; Casals, T; Desax, MC; Gallati, S; Gomez-Lira, M; Audrezet, MP; Férec, C; des Georges, M; Claustres, M; Truninger, K
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.
Journal title abbreviation:: Hum Mutat
Year:: 2011
Journal volume:: 32
Journal issue:: 8
Pages contribution:: 912-20
Language:: eng
Fulltext / DOI:: doi:10.1002/humu.21511
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/21520337
Print-ISSN:: 1059-7794
TUM Institution:: Klinik und Poliklinik für Kinderheilkunde und Jugendmedizin
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Klinik und Poliklinik für Kinder- und Jugendmedizin (Prof. Hauer)2011