title: Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease.
abstract: OBJECTIVE
  Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides, and often remains undiagnosed. It is a complex genetic disorder, although 95% of the patients carry the risk heterodimer human leukocyte antigen (HLA)-DQ2. Genome-wide association studies on CD have identified 9 non-HLA loci that also contribute to CD risk, most of which are shared with other immune-related diseases. Our aim is to predict the genetic risk for CD using HLA and non-HLA risk alleles.
  
  
  METHODS
  We selected 10 independent polymorphisms in 2,308 cases and 4,585 controls from Dutch, UK, and Irish populations and categorized the individuals into 3 risk groups, based on their HLA-DQ2 genotype. We used the summed number of non-HLA risk alleles per individual to analyze their cumulative effect on CD risk, adjusting for gender and population group in logistic regression analysis. We validated our findings in 436 Italian cases and 532 controls.
  
  
  RESULTS
  CD cases carried more non-HLA risk alleles than controls: individuals carrying > or = 13 risk alleles had a higher CD risk (odds ratio, 6.2; 95% confidence interval, 4.1-9.3) compared with those carrying 0-5 risk alleles. Combining HLA and non-HLA risk genotypes in one model increases sensitivity by 6.2% compared with using only HLA for identification of high-risk individuals with slight decrease in specificity.
  
  
  CONCLUSIONS
  We can use non-HLA risk factors for CD to improve identification of high-risk individuals. Our risk model is a first step toward better diagnosis and prognosis in high-risk families and population-based screening.
authors.affiliation: Department of Genetics, University Medical Centre of Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Jihane
authors.initials: J
authors.lastname: Romanos
authors.forename: Cleo C
authors.initials: CC
authors.lastname: van Diemen
authors.forename: Ilja M
authors.initials: IM
authors.lastname: Nolte
authors.forename: Gosia
authors.initials: G
authors.lastname: Trynka
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fu
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bardella
authors.forename: Donatella
authors.initials: D
authors.lastname: Barisani
authors.forename: Ross
authors.initials: R
authors.lastname: McManus
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002446:Celiac Disease / Q000175:diagnosis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005060:Europe; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D006683:HLA-DQ Antigens