Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease

Jihane Romanos, Cleo C. van Diemen, Ilja M. Nolte, Gosia Trynka, Alexandra Zhernakova, Jingyuan Fu, Maria Teresa Bardella, Donatella Barisani, Ross McManus, David A. van Heel, Cisca Wijmenga

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Abstract

Background & Aims: 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 ≥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.

Original languageEnglish
JournalGastroenterology
Volume137
Issue number3
DOIs
Publication statusPublished - Sep 2009

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Celiac Disease
HLA Antigens
Alleles
Odds Ratio
Genotype
Inborn Genetic Diseases
Glutens
Genome-Wide Association Study
Immune System Diseases
Population Groups
Population
Small Intestine

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Romanos, J., van Diemen, C. C., Nolte, I. M., Trynka, G., Zhernakova, A., Fu, J., ... Wijmenga, C. (2009). Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease. Gastroenterology, 137(3). https://doi.org/10.1053/j.gastro.2009.05.040

Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease. / Romanos, Jihane; van Diemen, Cleo C.; Nolte, Ilja M.; Trynka, Gosia; Zhernakova, Alexandra; Fu, Jingyuan; Bardella, Maria Teresa; Barisani, Donatella; McManus, Ross; van Heel, David A.; Wijmenga, Cisca.

In: Gastroenterology, Vol. 137, No. 3, 09.2009.

Research output: Contribution to journalArticle

Romanos, J, van Diemen, CC, Nolte, IM, Trynka, G, Zhernakova, A, Fu, J, Bardella, MT, Barisani, D, McManus, R, van Heel, DA & Wijmenga, C 2009, 'Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease', Gastroenterology, vol. 137, no. 3. https://doi.org/10.1053/j.gastro.2009.05.040
Romanos, Jihane ; van Diemen, Cleo C. ; Nolte, Ilja M. ; Trynka, Gosia ; Zhernakova, Alexandra ; Fu, Jingyuan ; Bardella, Maria Teresa ; Barisani, Donatella ; McManus, Ross ; van Heel, David A. ; Wijmenga, Cisca. / Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease. In: Gastroenterology. 2009 ; Vol. 137, No. 3.
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abstract = "Background & Aims: 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 ≥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.",
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AU - Romanos, Jihane

AU - van Diemen, Cleo C.

AU - Nolte, Ilja M.

AU - Trynka, Gosia

AU - Zhernakova, Alexandra

AU - Fu, Jingyuan

AU - Bardella, Maria Teresa

AU - Barisani, Donatella

AU - McManus, Ross

AU - van Heel, David A.

AU - Wijmenga, Cisca

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N2 - Background & Aims: 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 ≥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.

AB - Background & Aims: 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 ≥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.

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