Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants
نویسندگان
چکیده
BACKGROUND The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. OBJECTIVE We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. DESIGN We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case-control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. RESULTS Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. CONCLUSIONS Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD.
منابع مشابه
Combination Testing Using a Single MSH5 Variant alongside HLA Haplotypes Improves the Sensitivity of Predicting Coeliac Disease Risk in the Polish Population
Assessment of non-HLA variants alongside standard HLA testing was previously shown to improve the identification of potential coeliac disease (CD) patients. We intended to identify new genetic variants associated with CD in the Polish population that would improve CD risk prediction when used alongside HLA haplotype analysis. DNA samples of 336 CD and 264 unrelated healthy controls were used to...
متن کاملHuman Leukocyte Antigen Class I and II Variants in Yemeni Patients with Chronic Renal Failure
Background: Human leukocyte antigens (HLAs) are found to be significant genetic factors concerning the susceptibility of an individual to certain diseases. Objective: To determine the association between variants of class I (A and B) and class II (DRB1) HLA alleles and chronic renal failure (CRF), compared with healthy controls, in Yemen. Methods: A case-control study in the Urology and Nephrol...
متن کاملCoeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling.
OBJECTIVE Our previous coeliac disease genome-wide association study (GWAS) implicated risk variants in the human leucocyte antigen (HLA) region and eight novel risk regions. To identify more coeliac disease loci, we selected 458 single nucleotide polymorphisms (SNPs) that showed more modest association in the GWAS for genotyping and analysis in four independent cohorts. DESIGN 458 SNPs were ...
متن کاملHLA testing for coeliac disease in Ireland?
Recent studies have shown a worldwide prevalence of coeliac disease (CD) of around 1% and one of the highest prevalence rates (1 in 300) has been found in the West of Ireland. 1,2 The incidence of coeliac disease appears to be increasing. For example, a greater than 6-fold increase over a 20 year period was evident in a recent retrospective Scottish study. 3 Children with selective IgA deficien...
متن کاملRelative power of linkage and transmission disequilibrium test strategies to detect non-HLA linked coeliac disease susceptibility genes.
BACKGROUND Susceptibility to coeliac disease is genetically determined by possession of specific HLA DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of familial risk is most parsimonious with a multiplicative model for the interaction between these two classes of genes. Haplotype sharing probabilities across the HLA region in affected sibling pairs suggest that ...
متن کامل