ABSTRACT
Type 1 diabetes (T1D) and celiac disease (CeD) cluster in families and can occur in the same individual. Genetic loci have been associated with susceptibility to both diseases. Our aim was to explore the genetic differences between individuals developing both these diseases (double autoimmunity) versus those with only one. We hypothesized that double autoimmunity individuals carry more of the genetic risk markers that are shared between the two diseases independently. SNPs were genotyped in loci associated with T1D (n=42) and CeD (n=28) in 543 subjects who developed double autoimmunity, 2,472 subjects with T1D only, and 2,223 CeD-only subjects. For identification of loci that were specifically associated with individuals developing double autoimmunity, two association analyses were conducted: double autoimmunity versus T1D and double autoimmunity versus CeD. HLA risk haplotypes were compared between the two groups. The CTLA4 and IL2RA loci were more strongly associated with double autoimmunity than with either T1D or CeD alone. HLA analyses indicated that the T1D high-risk genotype, DQ2.5/DQ8, provided the highest risk for developing double autoimmunity (odds ratio 5.22, P=2.25×10(-29)). We identified a strong HLA risk genotype (DQ2.5/DQ8) predisposing to double autoimmunity, suggesting a dominant role for HLA. Non-HLA loci, CTLA4 and IL2RA, may also confer risk to double autoimmunity. Thus, CeD patients who carry the DQ2.5/DQ8 genotype may benefit from periodic screening of autoantibodies related to T1D.
Subject(s)
Celiac Disease/genetics , Diabetes Mellitus, Type 1/genetics , Autoimmunity/genetics , CTLA-4 Antigen/genetics , Case-Control Studies , Celiac Disease/immunology , Diabetes Mellitus, Type 1/immunology , Female , Gene Frequency , Genetic Association Studies , Genetic Background , Genetic Loci , Genetic Predisposition to Disease , HLA Antigens/genetics , Haplotypes , Humans , Interleukin-2 Receptor alpha Subunit/genetics , Linkage Disequilibrium , Male , Odds Ratio , Polymorphism, Single Nucleotide , RiskABSTRACT
Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and observed five new associations that account for 18% of the genetic risk. Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.
Subject(s)
Celiac Disease/genetics , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Case-Control Studies , Chromosome Mapping , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Risk , Risk FactorsABSTRACT
A main underlying pathology of coronary artery disease is the deposition of cholesterol in the arteries supplying blood to the heart that leads to stenosis and myocardial infarction. We tested if dyslipidemia is a risk factor for coronary artery disease in the Lebanese population, and studied the role of the total cholesterol/HDL cholesterol (TC/HDL-C) ratio as a biological marker of coronary artery disease. We recruited 6,180 Lebanese patients undergoing cardiac catheterization. We conducted a cross-sectional association study between TC/HDL-C ratio and the number and type of vessels occluded in catheterized patients by controlling for confounding effects. The TC/HDL-C ratio ≥4 significantly predicts ≥50 % stenosis in all vessels individually with the odds ratio (OR) ranging from 1.22 to 1.92. The OR increased with increasing number of ≥50 % stenotic vessels (1.39 for 2 vessels and 1.64 for 3-4 vessels), as did risk due to diabetes, CAD family history, gender, and age. The younger than average age of onset subgroup shows a pronounced increase in risk for occlusion of the left main coronary artery due to TC/HDL-C ≥4 (OR 3.26). In conclusion, low levels of HDL-cholesterol and high levels TC/HDL-C ratio are strong biological markers of disease occurrence and severity in the Lebanese population.
Subject(s)
Cholesterol, HDL/blood , Coronary Angiography , Coronary Artery Disease/blood , Coronary Artery Disease/diagnostic imaging , Aged , Cross-Sectional Studies , Female , Humans , Male , Middle AgedABSTRACT
Studies in European populations have contributed to a better understanding of the genetics of complex diseases, for example, in coeliac disease (CeD), studies of over 23 000 European samples have reported association to the HLA locus and another 39 loci. However, these associations have not been evaluated in detail in other ethnicities. We sought to better understand how disease-associated loci that have been mapped in Europeans translate to a disease risk for a population with a different ethnic background. We therefore performed a validation of European risk loci for CeD in 497 cases and 736 controls of north Indian origin. Using a dense-genotyping platform (Immunochip), we confirmed the strong association to the HLA region (rs2854275, P=8.2 × 10(-49)). Three loci showed suggestive association (rs4948256, P=9.3 × 10(-7), rs4758538, P=8.6 × 10(-5) and rs17080877, P=2.7 × 10(-5)). We directly replicated five previously reported European variants (P<0.05; mapping to loci harbouring FASLG/TNFSF18, SCHIP1/IL12A, PFKFB3/PRKCQ, ZMIZ1 and ICOSLG). Using a transferability test, we further confirmed association at PFKFB3/PRKCQ (rs2387397, P=2.8 × 10(-4)) and PTPRK/THEMIS (rs55743914, P=3.4 × 10(-4)). The north Indian population has a higher degree of consanguinity than Europeans and we therefore explored the role of recessively acting variants, which replicated the HLA locus (rs9271850, P=3.7 × 10(-23)) and suggested a role of additional four loci. To our knowledge, this is the first replication study of CeD variants in a non-European population.
Subject(s)
Celiac Disease/genetics , White People/genetics , Alleles , Carrier Proteins/genetics , Chromosome Mapping , Fas Ligand Protein/genetics , Genetic Loci , Genetic Predisposition to Disease , Genotyping Techniques , Humans , India , Inducible T-Cell Co-Stimulator Ligand/genetics , Interleukin-12 Subunit p35/genetics , Isoenzymes/genetics , Phosphofructokinase-2/genetics , Polymorphism, Single Nucleotide , Protein Kinase C/genetics , Protein Kinase C-theta , Reproducibility of Results , Risk Factors , Transcription Factors/genetics , Tumor Necrosis Factors/geneticsABSTRACT
Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are crucial to the understanding of Type 2 Diabetes Mellitus (T2DM) pathophysiology. We report a GWAS on the genetic basis of T2DM in a 3,286 Lebanese participants. More than 5,000,000â SNPs were directly genotyped or imputed using the 1000 Genomes Project reference panels. We identify genome-wide significant variants in two loci CDKAL1 and TCF7L2, independent of sex, age and BMI, with leading variants rs7766070 (OR = 1.39, P = 4.77 × 10(-9)) and rs34872471 (OR = 1.35, P = 1.01 × 10(-8)) respectively. The current study is the first GWAS to find genomic regions implicated in T2DM in the Lebanese population. The results support a central role of CDKAL1 and TCF7L2 in T2DM susceptibility in Southwest Asian populations and provide a plausible component for understanding molecular mechanisms involved in the disease.
Subject(s)
Cyclin-Dependent Kinase 5/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Genome-Wide Association Study , Transcription Factor 7-Like 2 Protein/genetics , Aged , Comorbidity , Diabetes Mellitus, Type 2/epidemiology , Female , Humans , Lebanon/epidemiology , Male , Middle Aged , Odds Ratio , Polymorphism, Single Nucleotide , Risk Factors , tRNA MethyltransferasesABSTRACT
BACKGROUND: A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled dietary-intervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age. RESULTS: Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention. CONCLUSIONS: As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.).
Subject(s)
Celiac Disease/prevention & control , Diet , Dietary Proteins/administration & dosage , Glutens/administration & dosage , Autoantibodies/blood , Biopsy , Breast Feeding , Celiac Disease/diagnosis , Celiac Disease/genetics , Child , Child, Preschool , Double-Blind Method , Female , GTP-Binding Proteins/immunology , Genotype , Gliadin/immunology , HLA-DQ Antigens/genetics , Humans , Infant , Intestine, Small/pathology , Male , Proportional Hazards Models , Prospective Studies , Protein Glutamine gamma Glutamyltransferase 2 , Risk , Transglutaminases/immunologyABSTRACT
OBJECTIVE: The purpose of this study was to explore whether non-human leukocyte antigen (non-HLA) genetic markers can improve type 1 diabetes(T1D) prediction in a prospective cohort with high-risk HLA-DR,DQ genotypes. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) follows prospectively for the development of T1D and islet autoimmunity (IA)children at increased genetic risk. A total of 1709 non-Hispanic White DAISY participants have been genotyped for 27 non-HLA single nucleotide polymorphisms (SNPs) and one microsatellite. RESULTS: In multivariate analyses adjusting for family history and HLA-DR3/4 genotype, PTPN22 (rs2476601) and two UBASH3A (rs11203203 and rs9976767) SNPs were associated with development of IA [hazard ratio(HR)=1.87, 1.55, and 1.54, respectively, all p ≤ 0.003], while GLIS3 and IL2RA showed borderline association with development of IA. INS,UBASH3A, and IFIH1 were significantly associated with progression from IA to diabetes (HR=1.65, 1.44, and 1.47, respectively, all p ≤ 0.04), while PTPN22 and IL27 showed borderline association with progression from IA to diabetes. In survival analysis, 45% of general population DAISY children with PTPN22 rs2476601 TT or HLA-DR3/4 and UBASH3A rs11203203 AA developed diabetes by age 15, compared with 3% of children with all other genotypes (p<0.0001). Addition of non-HLA markers to HLA-DR3/4,DQ8 did not improve diabetes prediction in first-degree relatives. CONCLUSION: Addition of PTPN22 and UBASH3A SNPs to HLA-DR,DQ genotyping can improve T1D risk prediction.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Autoimmunity/immunology , Diabetes Mellitus, Type 1/genetics , HLA Antigens/immunology , HLA-DR Antigens/immunology , Islets of Langerhans/immunology , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Adolescent , Child , Child, Preschool , Disease Progression , Genetic Predisposition to Disease , Genetic Testing , HLA-DQ Antigens/genetics , Humans , Polymorphism, Single Nucleotide , Prospective Studies , Risk FactorsABSTRACT
AIM: To assess the distribution of human leukocyte antigen (HLA)-DQ2 and -DQ8 in Iranian celiac disease (CD) patients and compare them to healthy Iranian controls. METHODS: To predict the HLA-DQA1 and -DQB1 genes, we used six previously reported HLA-tagging single nucleotide polymorphism to determine HLA genotypes in 59 Iranian patients with 'biopsy-confirmed' CD and in 151 healthy Iranian individuals. To test the transferability of the method, 50 cases and controls were also typed using a commercial kit that identifies individual carriers of DQ2, DQ7 and DQ8 alleles. RESULTS: In this pilot study 97% of CD cases (n = 57) and 58% of controls (n = 87) were carriers of HLA-DQ2 and/or HLA-DQ8 heterodimers, either in the homozygous or heterozygous state. The HLA-DQ pattern of these 57 CD patients: heterozygous DQ2.2 (n = 14) and homozygous DQ2.2 (n = 1), heterozygous DQ2.5 (n = 33) and homozygous DQ2.5 (n = 8), heterozygous DQ8 (n = 13) and homozygous DQ8 (n = 2). Two CD patients were negative for both DQ2 and DQ8 (3%). CONCLUSION: The prevalence of DQ8 in our CD population was higher than that reported in other populations (25.4%). As reported in other populations, our results underline the primary importance of HLA-DQ alleles in the Iranian population's susceptibility to CD.
Subject(s)
Celiac Disease/genetics , Gene Frequency , HLA-DQ Antigens/genetics , Haplotypes , Polymorphism, Single Nucleotide , Adolescent , Adult , Aged , Alleles , Case-Control Studies , Child , Child, Preschool , Female , Genotype , HLA-DQ alpha-Chains/genetics , HLA-DQ beta-Chains/genetics , Humans , Iran , Male , Middle Aged , Pilot Projects , Prevalence , Young AdultABSTRACT
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.
Subject(s)
Celiac Disease/diagnosis , Decision Support Techniques , Genetic Predisposition to Disease , Genetic Testing , HLA-DQ Antigens/genetics , Polymorphism, Single Nucleotide , Case-Control Studies , Celiac Disease/genetics , Female , Genetic Markers , Humans , Logistic Models , Male , Models, Genetic , Proportional Hazards Models , Prospective Studies , ROC Curve , Risk AssessmentABSTRACT
The manifestation of coronary artery disease (CAD) follows a well-choreographed series of events that includes damage of arterial endothelial cells and deposition of lipids in the sub-endothelial layers. Genome-wide association studies (GWAS) of multiple populations with distinctive genetic and lifestyle backgrounds are a crucial step in understanding global CAD pathophysiology. In this study, we report a GWAS on the genetic basis of arterial stenosis as measured by cardiac catheterization in a Lebanese population. The locus of the phosphatase and actin regulator 1 gene (PHACTR1) showed association with coronary stenosis in a discovery experiment with genome wide data in 1,949 individuals (rs9349379, ORâ=â1.37, pâ=â1.57×10(-5)). The association was replicated in an additional 2,547 individuals (ORâ=â1.31, pâ=â8.85×10(-6)), leading to genome-wide significant association in a combined analysis (ORâ=â1.34, pâ=â8.02×10(-10)). Results from this GWAS support a central role of PHACTR1 in CAD susceptibility irrespective of lifestyle and ethnic divergences. This association provides a plausible component for understanding molecular mechanisms involved in the formation of stenosis in cardiac vessels and a potential drug target against CAD.
Subject(s)
Coronary Stenosis/genetics , Genome-Wide Association Study/methods , Microfilament Proteins/genetics , Genetic Predisposition to Disease/genetics , Genotype , Humans , Lebanon , Polymorphism, Single Nucleotide/geneticsABSTRACT
We assessed the effects of non-HLA gene polymorphisms on the risk of islet autoimmunity (IA) and progression to type 1 diabetes in the Diabetes Autoimmunity Study in the Young. A total of 1,743 non-Hispanic, white children were included: 861 first-degree relatives and 882 general population children identified as having high-risk HLA-DR/DQ genotypes for type 1 diabetes. Of those, 109 developed IA and 61 progressed to diabetes. Study participants were genotyped for 20 non-HLA polymorphisms, previously confirmed as type 1 diabetes susceptibility loci. PTPN22 and UBASH3A predicted both IA and diabetes in regression models controlling for family history of type 1 diabetes and presence of HLA-DR3/4-DQB1*0302 genotype. In addition, PTPN2 predicted IA whereas INS predicted type 1 diabetes. The final multivariate regression models for both IA and type 1 diabetes included PTPN22, UBASH3A, and INS, in addition to family history of type 1 diabetes and HLA-DR3/4. In general population children, the most frequent combinations including these five significant predictors conferred hazard ratio of up to 13 for IA and >40 for type 1 diabetes. Non-HLA susceptibility alleles may help estimate risk for development of type 1 diabetes in the general population. These findings require replication in different populations.
Subject(s)
Autoimmunity , Diabetes Mellitus, Type 1/genetics , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Islets of Langerhans/immunology , Polymorphism, Single Nucleotide , Adaptor Proteins, Signal Transducing/genetics , Genotype , Humans , Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics , Risk FactorsABSTRACT
Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.
Subject(s)
Celiac Disease/genetics , Polymorphism, Single Nucleotide , Case-Control Studies , Chromosome Mapping , Gene Frequency , Genetic Loci , Genome-Wide Association Study , Haplotypes , Humans , Linkage Disequilibrium , Risk FactorsABSTRACT
BACKGROUND AND AIM: Potential celiacs have the 'celiac type' HLA, positive anti-transglutaminase antibodies but no damage at small intestinal mucosa. Only a minority of them develops mucosal lesion. More than 40 genes were associated to Celiac Disease (CD) but we still do not know how those pathways transform a genetically predisposed individual into an affected person. The aim of the study is to explore the genetic features of Potential CD individuals. METHODS: 127 'potential' CD patients entered the study because of positive anti-tissue transglutaminase and no mucosal lesions; about 30% of those followed for four years become frankly celiac. They were genotyped for 13 polymorphisms of 'candidate genes' and compared to controls and celiacs. Moreover, 60 biopsy specimens were used for expression studies. RESULTS: Potential CD bear a lighter HLA-related risk, compared to celiac (χ(2)â=â48.42; p valueâ=â1×10(-8)). They share most of the polymorphisms of the celiacs, but the frequency of c-REL* G allele was suggestive for a difference compared to celiac (χ(2)â=â5.42; p valueâ=â0.02). One marker of the KIAA1109/IL-2/IL-21 candidate region differentiated potentials from celiac (rs4374642: χ2â=â7.17, p valueâ=â0.01). The expression of IL-21 was completely suppressed in potentials compared to celiacs (p valueâ=â0.02) and to controls (p valueâ=â0.02), in contrast IL-2, KIAA1109 and c-REL expression were over-expressed. CONCLUSIONS: Potential CD show genetic features slightly different from celiacs. Genetic and expression markers help to differentiate this condition. Potential CD is a precious biological model of the pathways leading to the small intestinal mucosal damage in genetically predisposed individuals.
Subject(s)
Celiac Disease/etiology , Celiac Disease/genetics , Models, Biological , Adolescent , Alleles , Celiac Disease/immunology , Child , Child, Preschool , Chromosomes, Human, Pair 4/genetics , Female , Genetic Association Studies , Genetic Predisposition to Disease , Genome, Human/genetics , Histocompatibility Testing , Humans , Infant , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Polymorphism, Single Nucleotide/genetics , Risk FactorsABSTRACT
Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined)â=â 1.2 × 10(-12)), rs864537 near CD247 (P(combined)â=â 2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined)â=â 2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined)â=â 1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.
Subject(s)
Arthritis, Rheumatoid/genetics , Celiac Disease/genetics , Alleles , Arthritis, Rheumatoid/immunology , Celiac Disease/immunology , Genetic Loci , Genome-Wide Association Study , Histocompatibility Antigens/genetics , Lymphocyte Activation , Polymorphism, Single Nucleotide , Selection, Genetic , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Celiac disease (CD) is an intolerance to dietary proteins of wheat, barley, and rye. CD may have substantial morbidity, yet it is quite common with a prevalence of 1%-2% in Western populations. It is not clear why the CD phenotype is so prevalent despite its negative effects on human health, especially because appropriate treatment in the form of a gluten-free diet has only been available since the 1950s, when dietary gluten was discovered to be the triggering factor. The high prevalence of CD might suggest that genes underlying this disease may have been favored by the process of natural selection. We assessed signatures of selection for ten confirmed CD-associated loci in several genome-wide data sets, comprising 8154 controls from four European populations and 195 individuals from a North African population, by studying haplotype lengths via the integrated haplotype score (iHS) method. Consistent signs of positive selection for CD-associated derived alleles were observed in three loci: IL12A, IL18RAP, and SH2B3. For the SH2B3 risk allele, we also show a difference in allele frequency distribution (Fst) between HapMap phase II populations. Functional investigation of the effect of the SH2B3 genotype in response to lipopolysaccharide and muramyl dipeptide revealed that carriers of the SH2B3 rs3184504*A risk allele showed stronger activation of the NOD2 recognition pathway. This suggests that SH2B3 plays a role in protection against bacteria infection, and it provides a possible explanation for the selective sweep on SH2B3, which occurred sometime between 1200 and 1700 years ago.
Subject(s)
Bacterial Infections/genetics , Celiac Disease/genetics , Disease Susceptibility , Nod2 Signaling Adaptor Protein/genetics , Polymorphism, Single Nucleotide , Proteins/genetics , Selection, Genetic , Adaptor Proteins, Signal Transducing , Africa, Northern , Europe , Evolution, Molecular , Genetics, Population , Humans , Intracellular Signaling Peptides and ProteinsABSTRACT
We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.
Subject(s)
Celiac Disease/genetics , Genes, MHC Class I , Polymorphism, Single Nucleotide , Case-Control Studies , Gene Expression , Gene Expression Profiling , Genome-Wide Association Study , Humans , Meta-Analysis as Topic , RiskABSTRACT
BACKGROUND: PreventCD (www.preventcd.com) is a European multicentre study, which studies the influence of infant nutrition, and that of genetic, immunologic and environmental factors, on the risk of developing coeliac disease (CD). The hypothesis is that it is possible to induce tolerance to gluten by introducing small quantities of gluten to infants, preferably while they are still being breast-fed, and that this might also reduce the risk for related autoimmune disorders. AIM: To describe the design of this ongoing European CD research project. METHODS: PreventCD encompasses two study designs and two study populations: (i) a European multicentre study: a prospective, double-blind, randomized dietary-intervention study among infants from families with high risk of CD, and (ii) a Swedish population-based CD screening study among 12-year-olds from the general population, divided into two birth cohorts that differ with respect to infant feeding practices. DISCUSSION: PreventCD is expected to elucidate some of the genetic and immunological mechanisms involved in the process of immune intolerance.
Subject(s)
Celiac Disease/prevention & control , Glutens/administration & dosage , Immune Tolerance , Infant Nutritional Physiological Phenomena , Research Design , Bottle Feeding , Breast Feeding , Celiac Disease/etiology , Celiac Disease/genetics , Celiac Disease/immunology , Celiac Disease/physiopathology , Child , Child, Preschool , Diet , Double-Blind Method , Environment , Europe , Genetic Predisposition to Disease , Glutens/immunology , HLA Antigens/genetics , Humans , Infant , Infant, Newborn , Polymorphism, Single Nucleotide , Prospective Studies , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
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 > 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.
Subject(s)
Alleles , Celiac Disease/diagnosis , Genetic Predisposition to Disease , HLA-DQ Antigens/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Celiac Disease/genetics , Child , Child, Preschool , Europe , Female , Genetic Markers , Genotype , HLA-DQ Antigens/analysis , Humans , Infant , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk Factors , Young AdultABSTRACT
The OTOF gene encoding otoferlin is associated with auditory neuropathy (AN), a type of non-syndromic deafness. We investigated the contribution of OTOF mutations to AN and to non-syndromic recessive deafness in Brazil. A test for the Q829X mutation was carried out on a sample of 342 unrelated individuals with non-syndromic hearing loss, but none presented this mutation. We selected 48 cases suggestive of autosomal recessive inheritance, plus four familial and seven isolated cases of AN, for genotyping of five microsatellite markers linked to the OTOF gene. The haplotype analysis showed compatibility with linkage in 11 families (including the four families with AN). Samples of the 11 probands from these families and from seven isolated cases of AN were selected for an exon-by-exon screening for mutations in the OTOF gene. Ten different pathogenic variants were detected, among which six are novel. Among the 52 pedigrees with autosomal recessive inheritance (including four familial cases of AN), mutations were identified in 4 (7.7%). Among the 11 probands with AN, seven had at least one pathogenic mutation in the OTOF gene. Mutations in the OTOF gene are frequent causes of AN in Brazil and our results confirm that they are spread worldwide.
Subject(s)
Deafness/genetics , Membrane Proteins/genetics , Mutation/genetics , Brazil , Case-Control Studies , Genetic Testing , Humans , Mutation, Missense/geneticsABSTRACT
Human leukocyte antigen (HLA) genes, located on chromosome 6p21.3, have a crucial role in susceptibility to various autoimmune and inflammatory diseases, such as celiac disease and type 1 diabetes. Certain HLA heterodimers, namely DQ2 (encoded by the DQA1*05 and DQB1*02 alleles) and DQ8 (DQA1*03 and DQB1*0302), are necessary for the development of celiac disease. Traditional genotyping of HLA genes is laborious, time-consuming, and expensive. A novel HLA-genotyping method, using six HLA-tagging single-nucleotide polymorphisms (SNPs) and suitable for high-throughput approaches, was described recently. Our aim was to validate this method in the Finnish, Hungarian, and Italian populations. The six previously reported HLA-tagging SNPs were genotyped in patients with celiac disease and in healthy individuals from Finland, Hungary, and two distinct regions of Italy. The potential of this method was evaluated in analyzing how well the tag SNP results correlate with the HLA genotypes previously determined using traditional HLA-typing methods. Using the tagging SNP method, it is possible to determine the celiac disease risk haplotypes accurately in Finnish, Hungarian, and Italian populations, with specificity and sensitivity ranging from 95% to 100%. In addition, it predicts homozygosity and heterozygosity for a risk haplotype, allowing studies on genotypic risk effects. The method is transferable between populations and therefore suited for large-scale research studies and screening of celiac disease among high-risk individuals or at the population level.