Hierarchical fine mapping of the cystic fibrosis modifier locus on 19q13 identifies an association with two elements near the genes CEACAM3 and CEACAM6 |
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Authors: | Frauke Stanke Tim Becker Silke Hedtfeld Stephanie Tamm Thomas F Wienker Burkhard Tümmler |
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Institution: | (1) Department of Pediatrics OE6710, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany;(2) Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany |
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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. |
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Keywords: | |
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