title: IBD Genetic Risk Profile in Healthy First-Degree Relatives of Crohn's Disease Patients.
abstract: BACKGROUND
  Family history provides important information on risk of developing inflammatory bowel disease [IBD], and genetic profiling of first-degree relatives [FDR] of Crohn's disease [CD]- affected individuals might provide additional information. We aimed to delineate the genetic contribution to the increased IBD susceptibility observed in FDR.
  
  
  METHODS
  N = 976 Caucasian, healthy, non-related FDR; n = 4997 independent CD; and n = 5000 healthy controls [HC]; were studied. Genotyping for 158 IBD-associated single nucleotide polymorphisms [SNPs] was performed using the Illumina Immunochip. Risk allele frequency [RAF] differences between FDR and HC cohorts were correlated with those between CD and HC cohorts. CD and IBD genetic risk scores [GRS] were calculated and compared between HC, FDR, and CD cohorts.
  
  
  RESULTS
  IBD-associated SNP RAF differences in FDR and HC cohorts were strongly correlated with those in CD and HC cohorts, correlation coefficient 0.63 (95% confidence interval [CI] 0.53 - 0.72), p = 9.90 x 10(-19). There was a significant increase in CD-GRS [mean] comparing HC, FDR, and CD cohorts: 0.0244, 0.0250, and 0.0257 respectively [p < 1.00 x 10(-7) for each comparison]. There was no significant difference in the IBD-GRS between HC and FDR cohorts [p = 0.81]; however, IBD-GRS was significantly higher in CD compared with FDR and HC cohorts [p < 1.00 x 10(-10) for each comparison].
  
  
  CONCLUSIONS
  FDR of CD-affected individuals are enriched with IBD risk alleles compared with HC. Cumulative CD-specific genetic risk is increased in FDR compared with HC. Prospective studies are required to determine if genotyping would facilitate better risk stratification of FDR.
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Kevans
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Silverberg
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Borowski
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Anne
authors.initials: A
authors.lastname: Griffiths
authors.affiliation: Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Venus
authors.initials: V
authors.lastname: Onay
authors.affiliation: The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Paterson
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada Institute of Medical Science, University of Toronto, Toronto, ON, Canada Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Jo
authors.initials: J
authors.lastname: Knight
authors.affiliation: Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, ON, Canada KCroitoru@mtsinai.on.ca.
authors.forename: Ken
authors.initials: K
authors.lastname: Croitoru
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D003424:Crohn Disease / Q000235:genetics*; D005190:Family; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D053473:Nod2 Signaling Adaptor Protein
keywords: Crohn’s disease; first-degree relatives; genotyping