Identification of Non-HLA Genes Associated with Celiac Disease and Country-Specific Differences in a Large, International Pediatric Cohort

• Published in: PloS one Vol. 11; no. 3; p. e0152476
• Main Authors: Sharma, Ashok, Liu, Xiang, Hadley, David, Hagopian, William, Liu, Edwin, Chen, Wei-Min, Onengut-Gumuscu, Suna, Simell, Ville, Rewers, Marian, Ziegler, Anette-G, Lernmark, Åke, Simell, Olli, Toppari, Jorma, Krischer, Jeffrey P, Akolkar, Beena, Rich, Stephen S, Agardh, Daniel, She, Jin-Xiong
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.03.2016; Public Library of Science (PLoS)
• Subjects: Adolescent; Analysis; Autoantibodies; Autoantibodies - blood; Autoimmune diseases; Basic Medicine; Bioinformatics; Biology and Life Sciences; Biopsy; CCR9 protein; Celiac disease; Celiac Disease - genetics; Celiac Disease - immunology; Child; Child, Preschool; Children; CTLA-4 protein; Data processing; Development and progression; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Disease Progression; Disease susceptibility; Epidemiology; Europe; Family Health; Female; Follow-Up Studies; Genes; Genetic analysis; Genetic aspects; Genomes; Genomics; Genotype; Genotypes; Gluten; GTP-Binding Proteins - genetics; GTP-Binding Proteins - immunology; Haplotypes; Hazards; Health risk assessment; Health risks; Heterozygote; Histocompatibility antigen HLA; HLA Antigens - genetics; Humans; Infant; Infant, Newborn; Interleukin 1; International Cooperation; Kinases; Loci; Male; Medical and Health Sciences; Medical Genetics; Medicin och hälsovetenskap; Medicine and Health Sciences; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Neonates; Pediatrics; People and Places; Polymorphism, Single Nucleotide; Population; Prevalence studies (Epidemiology); Principal components analysis; Proportional Hazards Models; Prospective Studies; Protein Glutamine gamma Glutamyltransferase 2; Public health; Rheumatoid arthritis; Single-nucleotide polymorphism; Small intestine; Survival analysis; Sweden; Transglutaminase 2; Transglutaminases - genetics; Transglutaminases - immunology; United States; United States; Sweden; Europe; Georgia; United States > US; Finland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0152476

There are significant geographical differences in the prevalence and incidence of celiac disease that cannot be explained by HLA alone. More than 40 loci outside of the HLA region have been associated with celiac disease. We investigated the roles of these non-HLA genes in the development of tissue transglutaminase autoantibodies (tTGA) and celiac disease in a large international prospective cohort study. A total of 424,788 newborns from the US and European general populations and first-degree relatives with type 1 diabetes were screened for specific HLA genotypes. Of these, 21,589 carried 1 of the 9 HLA genotypes associated with increased risk for type 1 diabetes and celiac disease; we followed 8676 of the children in a 15 y prospective follow-up study. Genotype analyses were performed on 6010 children using the Illumina ImmunoChip. Levels of tTGA were measured in serum samples using radio-ligand binding assays; diagnoses of celiac disease were made based on persistent detection of tTGA and biopsy analysis. Data were analyzed using Cox proportional hazards analyses. We found 54 single-nucleotide polymorphisms (SNPs) in 5 genes associated with celiac disease (TAGAP, IL18R1, RGS21, PLEK, and CCR9) in time to celiac disease analyses (10-4>P>5.8x10-6). The hazard ratios (HR) for the SNPs with the smallest P values in each region were 1.59, 1.45, 2.23, 2.64, and 1.40, respectively. Outside of regions previously associated with celiac disease, we identified 10 SNPs in 8 regions that could also be associated with the disease (P<10-4). A SNP near PKIA (rs117128341, P = 6.5x10-8, HR = 2.8) and a SNP near PFKFB3 (rs117139146, P<2.8x10-7, HR = 4.9) reached the genome-wide association threshold in subjects from Sweden. Analyses of time to detection of tTGA identified 29 SNPs in 2 regions previously associated with celiac disease (CTLA4, P = 1.3x10-6, HR = 0.76 and LPP, P = 2.8x10-5, HR = .80) and 6 SNPs in 5 regions not previously associated with celiac disease (P<10-4); non-HLA genes are therefore involved in development of tTGA. In conclusion, using a genetic analysis of a large international cohort of children, we associated celiac disease development with 5 non-HLA regions previously associated with the disease and 8 regions not previously associated with celiac disease. We identified 5 regions associated with development of tTGA. Two loci associated with celiac disease progression reached a genome-wide association threshold in subjects from Sweden.