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Haplotype structure and association to Crohn's disease of CARD15 mutations in two ethnically divergent populations

Authors
 Peter J P Croucher  ;  Silvia Mascheretti  ;  Won Ho Kim and Stefan Schreiber  ;  Michael Krawczak  ;  Suk-Kyun Yang  ;  Susanna Nikolaus  ;  Tim Lu  ;  Monika Stoll  ;  Henning Frenzel  ;  Klaus Huse  ;  Jochen Hampe 
Citation
 EUROPEAN JOURNAL OF HUMAN GENETICS, Vol.11(1) : 6-16, 2003 
Journal Title
 EUROPEAN JOURNAL OF HUMAN GENETICS 
ISSN
 1018-4813 
Issue Date
2003
MeSH
Asian Continental Ancestry Group/genetics ; Carrier Proteins/genetics* ; Cohort Studies ; Crohn Disease/epidemiology ; Crohn Disease/genetics* ; European Continental Ancestry Group/genetics ; Genetic Predisposition to Disease ; Genetic Variation ; Genetics, Population ; Germany/epidemiology ; Haplotypes/genetics* ; Humans ; Intracellular Signaling Peptides and Proteins* ; Korea/epidemiology ; Linkage Disequilibrium ; Mutation* ; Nod2 Signaling Adaptor Protein ; Polymorphism, Single Nucleotide ; United Kingdom/epidemiology
Keywords
Crohn’s disease ; CARD15 ; haplotype analysis ; SNP
Abstract
Current debate focuses on the relevance of linkage disequilibrium (LD), ethnicity and underlying haplotype structure to the search for genes involved in complex disorders. The recently described association between single nucleotide polymorphisms (SNPs) of the CARD15 (NOD2) gene and Crohn's disease (CD) in populations of north-European descent provides a test case that we have subjected to detailed SNP haplotype based analyses. We examined 23 SNPs spanning 290 kb, including CARD15, in large North-European and Korean samples of patients with Crohn's disease and normal controls. In Europeans we confirmed that the three disease-associated SNPs occur independently but share a common background haplotype. This suggests a common origin and the possibility of an undiscovered more strongly predisposing mutation. Korean CD patients present a phenotype identical to the European patients and have not previously been screened for CARD15. The three disease-associated SNPs were absent and there was no evidence of association between CARD15 and CD. Consequently, the disease-associated mutations in the Europeans, which are rare, have arisen recently (after the Asian–European split). Our results highlight important issues relevant to mapping the genes that predispose to complex disorders. First, although ethnically divergent populations may present identical phenotypes they do not necessarily share the same set of predisposing genes. Second, although single-locus tests of association showed consistent association with markers throughout the gene, pair-wise LD between markers (r2 and D') yielded very little information about actual disease-association. Third, a population comparative approach allowed refining of the marker set through the examination of shared polymorphisms and common LD-groups. This approach, in conjunction with the examination of the mutational steps in a haplotype network, allows unambiguous identification of the potentially causative mutations.
Files in This Item:
T200305978.pdf Download
DOI
10.1038/sj.ejhg.5200897
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Ho(김원호) ORCID logo https://orcid.org/0000-0002-5682-9972
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/114256
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