Prevalence and clinical characteristics of celiac disease in Downs syndrome in a U.S. study

Celiac disease is an autoimmune gastrointestinal disorder characterized by mucosal atrophy of the jejunum on exposure to gluten, a protein found in grains. The purpose of our study was to determine the prevalence of celiac disease in children with Downs syndrome in a U.S.‐based Caucasian population. The 97 Downs syndrome children were screened for celiac disease using serum IgA‐anti‐endomysial antibody testing, which is highly specific and sensitive for the disorder. Children with titers greater than 1:5 (using the IgA endomysial antibody [EMA] test; EMA+) were considered affected. Ten children (10.3%) were EMA+. We examined their HLA DQA1 DQB1 genotype, karyotype, clinical characteristics, and the prevalence of celiac disease in their first‐degree relatives. The nine available karyotypes were trisomy 21. Downs syndrome‐specific mean height percentile was 64% ± 26% (range <5–99%) and weight percentile was 43% ± 28% (range 5–95%). Presence of diarrhea, constipation, vomiting, and abdominal pain was similar for children with and without celiac disease. Only bloating symptoms were significantly more frequent in those with celiac disease (EMA+). Seven of eight (88%) genotyped EMA+ children had the celiac disease‐associated high‐risk HLA DQA1*0501 DQB1*0201 genotype as compared with 13/80 (16%) of EMA− children. Five of 48 (10%) first‐degree relatives of the celiac disease (EMA+) children were EMA+. In conclusion, celiac disease, as diagnosed by positive endomysial antibody tests, has an increased prevalence in children with Downs syndrome in the U.S. as compared with the general population (1/250). Clinical and growth characteristics do not distinguish between children with and without celiac disease. Based on these observations, it is recommended that children with Downs syndrome be screened for celiac disease. © 2001 Wiley‐Liss, Inc.     

HLA DQA1*0501 and DQB1*02 in Cuban celiac patients

Celiac disease (CD) susceptibility has been strongly associated with HLA-DQ2 and HLA-DQ8. The main objective of this study was to assess the distribution of HLA DQA1*0501 and DQB1*02 alleles (DQ2) for the first time in a group of Cuban celiac patients. We evaluated 22 patients, 54 first-degree relatives, and 60 controls for detection of antitissue transglutaminase (tTG)-specific antibodies in serum. We found that 100% of the probands and 19% of the first-degree relatives were positive for the antibodies in serum. We did not detect any specific response for the healthy control individuals. We observed a significant over-representation of DQ2 heterodimer, both in patients and relatives. In the group of patients, 86.3% were positive for DQA1*0501, 90.2% were positive for DQB1*02, and 86.3% were positive for both alleles. The frequencies in relatives and controls were as follows: 70%, 90%, and 70%; and 56.6%, 45%, and 20%, respectively. In conclusion, we found that the proportion of our celiac patients carrying DQ2 was similar to the proportion of CD patients reported in populations with different genetic backgrounds. These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease.     

HLA DQ AND DP IN FINNISH FAMILIES WITH CELIAC DISEASE

We studied DQA1, DQB1, and DPB1 alleles in 31 Finnish families with celiac disease (CD). All healthy first-degree relatives underwent clinical investigation, including in most cases biopsy, to establish whether clinically silent CD was present. Our results indicate that all patients, having either full clinical CD or its silent form, had the susceptibility alleles DQA1*0501 and DQB1*0201. The different clinical outcomes of CD were therefore not directly determined by the DQ alleles. The frequency of DPB1*0101 was also higher in CD patients, but the association appeared secondary to those of DQA1*0501 and DQB1*0201 (DQ2). The primary association of CD with the DQA1*0501 and DQB1*0201 alleles, rather than with HLA haplotypes, was confirmed in multiplex families.     

Frequency distribution of HLA DQ2 and DQ8 in celiac patients and first-degree relatives in Recife, northeastern Brazil

AIMS:

The aim of this study was to evaluate the frequencies of the HLA genotypes DQ2 and DQ8 and the alleles A1*05, A1*0201, B1*0201 and B1*0302 in individuals with celiac disease in Recife, northeastern Brazil.

METHODS:

HLA DQ2 and DQ8 genotyping was performed for 73 individuals with celiac disease and 126 first-degree relatives with negative transglutaminase serology. The alleles DQA1*05, DQA1*0201, DQB1*02 and DQB1*0302 were identified by sequencing using specific primers and the EU-DQ kit from the Eurospital Laboratory, Trieste, Italy and double-checked by the All Set SPP kit (Dynal).

RESULTS:

Among the 73 cases, 50 (68.5%) had the genotype DQ2, 13 (17.8%) had DQ8, 5 (6.8%) had DQ2 and DQ8, and 5 did not have any of these genotypes. Among the 5 negative individuals, four had the B1*02 allele and one did not have any of the alleles studied. B1*02 was the most frequent allele in both groups (94% in the patients and 89% in the control relatives).

CONCLUSIONS:

In this study, celiac disease was associated with the genotypes DQ2 and DQ8. DQ2 predominated, but the distribution of the frequencies was different from what has been found in European populations and was closer to what has been found in the Americas. The high frequencies of the HLA genotypes DQ2 and DQ8 that were found in first-degree relatives would make it difficult to use these HLA genotypes for routine diagnosis of celiac disease in this group.     

One third of HLA DQ2 homozygous patients with type 1 diabetes express celiac disease-associated transglutaminase autoantibodies.

Type 1 diabetes and celiac disease are both immunologic disorders where specific HLA alleles are associated with disease risk. We have developed a radioassay for autoantibodies to tissue transglutaminase (tTG) following the report that this enzyme is 'the' endomysial autoantigen (EMA) of celiac disease. The radioassay for transglutaminase autoantibodies is similar to that utilized for detecting anti-islet autoantibodies. The 'cut-off' for the IgA autoantibody assay was established as 3 x 100th percentile of 184 healthy control subjects at an index of 0.05. Ninety-eight of 847 patients with type 1 diabetes (11.6%) had tissue transglutaminase autoantibodies (tTG). All EMA-positive patients were positive (49/49) for transglutaminase autoantibodies, as were 49/540 EMA-negative patients. Twenty transglutaminase-positive patients consented to intestinal biopsy and 15 biopsies were positive for celiac disease. All patients with a transglutaminase level greater than 0.70 (13/13) had a positive biopsy, while none (0/3) with a level <0.3 had a positive biopsy. The prevalence of transglutaminase autoantibodies was higher in diabetic patients with HLA DQ2 or DQ8. One third of DQ2 homozygous patients (22/68) expressed transglutaminase autoantibodies vs. less than 2% of patients lacking DQ2 or DQ8. A simple radioassay for IgA transglutaminase autoantibodies detects all endomysial antibody positive patients and detects transglutaminase autoantibodies in 5% of endomysial autoantibody negative patients. The prevalence of transglutaminase autoantibodies is associated with DQ2 and DQ8 and in particular DQ2 homozygosity. Autoimmunity to transglutaminase is remarkably prevalent amongst patients with type 1 diabetes expressing certain class II HLA alleles.     

HLA DQA1-DQB1 genotypes in Bedouin families with celiac disease

Celiac disease (CD) has a strong genetic association with human leukocyte antigens (HLA). The primary susceptibility for CD is HLA-DQA1*05 DQB1*02 (also known as DQ2), with the remainder of cases primarily HLA-DQA1*03 DQB1*03 (also known as DQ8). In a set of nine Bedouin multiplex celiac disease families and one simplex, we genotyped DNA samples at HLA DQA1 and DQB1. Nineteen celiac disease patients had at least one DQA1*05 DQB1*02 genotype (= DQ2), 4 affecteds had the second most common genotype of DQA1*03 DQB1*0302 (= DQ8), 9 were DQ2 and DQ8, and 4 had at least one copy of DQB1*02 without the DQA1*05 genotype. Using transmission disequilibrium testing, we observed a significant over-representation in affecteds of the DQA1*05 DQB1*02 genotype (p = 0.0089), as well as over-representation of the DQA1*03 DQB1*0302 genotype (p = 0.078). The HLA DQA1 DQB1 high-risk genotypes associated with celiac disease are similar in these Bedouin families with CD to what is observed in Northern and Southern Europeans.     

HLA-DQ alleles in patients with celiac disease in Turkey

The prevalence of the HLA-DQA1 and DQB1 alleles in 55 Turkish children with celiac disease and 50 control subjects was investigated by using an allele-specific DNA-based polymerase chain reaction-sequence-specific primer (PCR-SSP) method. The frequency of the DQA1*0501 and DQB1*02 alleles was higher in celiac patients than in controls. The DQA1B1 (*0501; *02) haplotype was present in 46 (83.6%) patients and only in 12 (24%) controls. The remaining 9 celiac patients which were negative for DQA1B1 (*0501;*02) carried the DQA1B1 (*03;*0302) haplotype. We found an excess homozygosity of the DQB1*02 allele and the DQA1B1 (*0501;*02) haplotype in the patients. No statistically significant correlation was found between the homozygosity of this haplotype or the DQB1*02 allele and an earlier onset of the disease.     

Genetic differences in HLA-DQA1* and DQB1* allelic distributions between celiac and control children in Santiago, Chile.

Celiac disease is a permanent gluten intolerance strongly associated with HLA class II antigens. The over presentation of particular HLA alleles and haplotypes has been described in several populations. Different lines of evidence obtained during the last years suggest that a particular HLA-DQ heterodimer, encoded by the DQA1*0501 and DQB1*0201 genes in cis or trans conformation, confers the primary disease susceptibility. We report the HLA class II allelic distribution and DQA1/ DQB1 genotypes in 62 Chilean celiac patients compared with 124 control subjects in Santiago, Chile. We found a pronounced increase of the "susceptible" alleles :DQA1*0501 (0.480 vs 0.169, Pc < 0.0005), DQB1*0302 (0.430 vs 0.242, Pc = 0.002) and DQB1*0201 (0.250 vs 0.125, Pc = 0.037) in celiac patients in comparison with control children. As for "protective" alleles, we detected a high frequency of DQA1*0101 (0.310 vs 0.160, Pc = 0.01), DQA1*0201 (0.105 vs 0.010, Pc < 0.0075) and DQB1*0301 (0.250 vs 0.100, Pc = 0.010) in controls. In relation to risk haplotypes, the main combination observed was the conformation DQ8 (DQB1*0302/DQA1*0301) over DQ2 (DQB1*0201/DQA1*0501). In conclusion, results show that celiac disease in Chilean patients is primarily associated with DQ8 conformation. This is concordant with the high frequency of DR4 alleles (in linkage disequilibrium with DQB1*0302) detected in Amerind groups in Chile, where DQB1*0302 is more frequent than DQB1*0201.     

DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases

Abstract: DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA 1*0302, DQB 1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB 1*0701, DQA 1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3, DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4, DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7, DQ2-DQCAR 111–121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.     

Celiac disease among Ashkenazi Jews from Israel: A study of the HLA class II alleles and their associations with disease susceptibility

The immunogenetics of celiac disease demonstrates a highly significant association with the HLA class II alleles DQA1*0501 DQB1*0201 encoded in either a cis- or trans-configuration. In Northern Europe, these alleles are found in linkage disequilibrium with DRB1*0301 while in Southern Europe an additional secondary association through linkage disequilibrium is seen with the combination DRB1*1101/0701. This study examines 34 Ashkenazi Jews with celiac disease and 36 ethnically matched controls to determine alleles at the DRB, DQA1, DQB1, and DPB1 loci using SSO probes in conjunction with gene amplification by the PCR. The results confirm a highly significant association with the DQA1*0501 DQB1*0201 allelic combination (71% celiac vs 8% control individuals; p = 0.00005; χ² = 21.4). Of celiac subjects, 29% were negative for the proposed DQ susceptibility alleles, the majority of whom were DRB1*0402 positive (20% overall celiac group). No additional susceptibility was associated at the DRB3 and DPB loci. This study confirms that the MHC-linked celiac disease susceptibility among Ashkenazi Jews is closely associated with the presence of the combination of alleles DQA1*0501 DQB1*0201. However, within this population of relatively high-prevalence celiac disease, 30% of celiac patients do not carry these alleles and are therefore not covered by a single “unifying” hypothesis.     

Expression of HSP-65 in jejunal epithelial cells in patients clinically suspected of coeliac disease

BACKGROUND: Coeliac disease (CD) can be classified both clinically and biologically an autoimmune disease. A close relationship obtains between heat shock proteins (HSPs) and numerous autoimmune diseases. HSPs are overexpressed when protecting the host against environmental insult. We sought here to establish whether dietary gluten is such a stress stimulus in patients clinically suspected of CD, and whether the expression of HSP-65 associates with densities of intraepithelial gammadelta+ T cells and/or with expression of mucosal HLA-DR. METHODS: Seventy-eight children with clinical suspicion of CD underwent a jejunal biopsy. Monoclonal antibodies were used to stain jejunal epithelial HSP-65, intraepithelial lymphocytes and mucosal HLA-DR. Serum IgA-class endomysial autoantibodies (EMA) were measured by an indirect immunofluorescence method. CD susceptibility HLA DQA1*0501 and DQB1*0201 alleles (HLA DQ2) were determined. RESULTS: Enhanced expression of epithelial cell mitochondrial HSP-65 was found in 80% (16/20) of coeliacs and in 24% (14/58) of children excluded for the disease, but in only 7% (2/28) of control subjects (p < 0.001, p = 0.049, respectively). Children with enhanced expression of HSP-65 had significantly higher gammadelta+ T cell densities than those with normal HSP-65 expression. A clear association between HSP-65 and serum IgA-class EMA were also ascertained in patients with normal jejunal mucosal morphology. HLA DQ2 positivity did not correlate with the HSP-65 expression. CONCLUSIONS: Gluten might be an environmental insult not only in CD patients but also in some patients excluded for the disease on biopsy. Enhanced expression of epithelial cell stress proteins might be an indicator of such an insult.     

Celiac disease and endocrine autoimmunity – the genetic link

Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley and rye. The prevalence of celiac disease is increased in patients with monoglandular and/or polyglandular autoimmunity and their relatives. Between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5 to 7% of patients with autoimmune thyroid disease and/or type 1 diabetes are IgA anti-tissue transglutaminase antibody positive. The close relationship between celiac disease and endocrine autoimmunity is largely explained by sharing a common genetic background. The HLA antigens DQ2 (DQA1*0501-DQB1*0201) and/or DQ8 (DQA1*0301-DQB1*0302), that are tightly linked to DR3 and DR4, respectively, are the major common genetic predisposition. Moreover, functional single nucleotide polymorphisms of various genes that are involved in immune regulation have been identified as “overlap” susceptibility genes for both celiac disease and monoglandular or polyglandular autoimmunity. While plausible, it remains to be established how far a gluten free diet may prevent or ameliorate glandular autoimmunity. In conclusion, all patients with celiac disease should be screened for type 1 diabetes and/or autoimmune thyroid disease. Conversely, patients with the above autoimmune endocrine disorders should be also screened for celiac disease.     

Preferential presentation of herpes simplex virus T-cell antigen by HLA DQA1*0501/DQB1*0201 in comparison to HLA DQA1*0201/DQB1*0201

The HLA DQA1 locus is polymorphic. Haplotypes containing HLA DQA1*0501, but not HLA DQA1*0201, together with HLA DQB1*0201 are associated with Grave's disease and celiac sprue. In this report, we demonstrate a functional correlate of DQA1 polymorphism. T cells infiltrating a herpes simplex virus (HSV) lesion from a HLA DQ 2,7 individual yielded a virusspecific CD4+ clone restricted by DQ2. Presentation of viral peptide and protein segregated with DQA1 allele, because cell lines bearing DQA1*0501/DQB1*0201 heterodimers presented antigen in proliferation and cytotoxicity assays much more efficiently than cell lines bearing DQA1*0201/DQB1*0201. Binding of viral peptide to cell lines bearing DQA1*0201, in comparison to DQA1*0501, was only moderately reduced and may not explain this effect. Truncation and substitution analyses of peptide binding and T-cell activation were performed to determine which viral peptide residues contacting TCR might therefore be presented in an altered conformation by DQA1*0201/DQB1*0201. Residues 432, 435, 437, 438, and 440 (position P1, P4, P6, P7, and P9) contributed to DQ2 binding, whereas residues 431, 433, 434, and 436 (positions P-1, P2, P3, and P5) contributed to TCR contact. Differential presentation of peptide by HLA DQ2 heterodimers varying at the DQA1 locus may have relevance to host defense and the pathogenesis of HLA DQ2-associated autoimmune diseases. Human Immunology 53, 195-205 (1997).     

ICA+ relatives with DQA1*0102/DQB1*0602 have expected 0602 sequence and DR types

The HLA haplotype DQA1*0102/DQB1*0602 reportely confers protection from type 1 diabetes. DQA1*0102/DQB1*0602 is present in more than 7% of ICA positive relatives screened as part of the Diabetes Prevention Trial--type 1. The presence of autoantibodies in these subjects suggests that the mechanism that protects DQB1*0602 subjects from diabetes occurs after the disease process has been initiated. However, as previously suggested, the method used to type the DQB1*0602 alleles may have lacked the sensitivity to identify alleles similar, but not identical, to DQB1*0602. In addition unusual extended haplotypes may be presented that could help account for the presence of diabetes autoantibodies. We therefore sequenced and performed extended haplotyping on samples from ICA+ relatives with DQA1*0102/DQB1*0602. In this group, sequencing confirmed DQB1*0602 in 149/150, and 152/165 have the common DRB1*1501-DQB1*0602 haplotype. Thus, high resolution typing of class II alleles either by PCR-based oligotyping or nucleotide sequencing fail to indicate any unusual genetic characteristics about these antibody-positive relatives, of which few are expected to progress to clinical disease.     

Molecular characterization of HLA class II genes in celiac disease patients of Latin American caucasian origin

Abstract: In the present study, the polymorphic domain of HLA class II genes present in a pediatric population of Argentinian celiac disease patients was analyzed by hybridization to sequence-specific oligonucleotides and DNA sequencing. Sixteen out of 16 DR5/7 heterozygous patients bore the DQA1*0501 and DQB1*0201 alleles implicated in the DQ2 risk specificity. The second exon of DQA1, DQB1 and DRB1 genes from 2 DR5/7 patients was characterized by DNA sequencing. The following alleles were found in both patients: DRB1*1101 and DRB1*0701; DQB1*0301 and DQB1*0201; DQA1*0501 and DQA1*0201. Previous serological analysis in this population had shown the presence of DQ2 in 95% of the patients (40% in controls) and a negative association with DQ1 haplotypes, suggesting the presence of other "permissive" or neutral alleles. The following HLA-DQB1 alleles, besides DQB1*0201, were identified in 31 CD patients: DQB1*0301, 0302, 0401 and 0402. All these alleles share a common pattern of residues between positions 84 and 90, and distinct from that present in DQ1-related alleles.     

HLA class II alleles associated with celiac disease susceptibility in a Southern European population

Susceptibility to celiac disease in Northern Europe is associated with the human leukocyte antigens (HLA) B8, DR3 and DQ2, which exist together on an extended haplotype. The strong predominance of this haplotype within the Northern European celiac populations, together with the linkage disequilibrium which occurs between these loci, does not allow identification of the gene(s) primarily associated with disease susceptibility. Studies from Southern Europe using both serology and examination of restriction fragment length polymorphisms (RFLP) have demonstrated associations with DR3, DR7 and DQ2, suggesting that the DQ locus is primarily involved. We investigated 43 celiac patients and 41 healthy controls from Rome, Italy, using sequence-specific oligonucleotide (SSO) probes, in conjunction with gene amplification by the polymerase chain reaction (PCR), to determine alleles at the DRB, DQA1, DQB1 and DPB1 loci: 19% of celiac patients possessed the alleles DRB1*0301 DRB3*0101, 33% DRB1*0301 DRB3*0201 and 33% of celiac patients were heterozygous for DRB1*1101-1201/DRB1*0701. The strongest association with celiac disease susceptibility was the combination of alleles DQA1*0501 DQB1*0201 (91% celiac patients vs. 12% controls; p = 0.000002). There was no additional susceptibility associated with alleles at the DPB locus. This study confirms the hypothesis that susceptibility is associated with a particular combination of DQ alleles and the ethnic variation in DR frequencies is secondary to linkage disequilibrium with these DQ alleles.     

Oligotyping of Italian celiac patients with the 11th International Histocompatibility Workshop reagents.

Oligotyping for HLA-DRB1, DQA1 and DQB1 specificities has been performed on PCR-amplified DNA from 55 Italian celiac children, living in Rome, and 50 blood donors. 52.6% of CD patients were DR3;DQA1*0501;DQB1*0201-positive versus 14% of controls (RR = 6.85) and 34.5% were DR5,7;DQA1*DQB1*0201-positive versus 2% of controls (RR = 25.86). 7 patients (12.7%) were negative for the DQA1*0501/B1*0201 dimer: 3 of them were DR4 (5.4%) and the others typed as DR1,5; 1,7; 5,7 and w6,7. No patient was negative for both DQA1*0501 and DQB1*0201 alleles.     

A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan

To investigate the correlation between clinical features and HLA DR/DQ genetic variability in myasthenia gravis (MG), we evaluated HLA DR/DQ allele frequencies in 87 Japanese patients with childhood-onset disease. HLA genotypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303 were significantly higher in patients than in healthy controls (P(c) < 0.0001, RR = 5.5; P(c) < 0.0001, RR = 8.5, for two genotypes, respectively). Patients who had a significantly higher likelihood of the HLA types DRB1*1302/DQA1*0102/DQB1*0604 or DRB1*0901/DQA1*0301/DQB1*0303 belonged to the latent general type (LG) of MG; this is clinically ocular type, but shows myasthenic electromyographic findings in extremity muscles. The LG type of MG was observed in 78% of patients exhibiting the clinically ocular type; this group comprised approximately 75% of patients with childhood-onset MG. These date suggest that LG type of MG may present a particular subset of childhood-onset MG, which is associated with the specific HLA subtypes DRB1*1302/DQA1*0102/DQB1*0604 and DRB1*0901/DQA1*0301/DQB1*0303.     

Allelic distribution and the effect of haplotype combination for HLA type II loci in the celiac disease population of the Valencian community (Spain)

The association between human leukocyte antigen (HLA) class II antigens and celiac disease (CD) was analyzed in a Spanish population. No association with DRB1*04 and DQB1*0302 was noted. The main associated haplotype (70.8%) was DRB1*03–DQB1*0201–DQA1*0501(DR3–DQ2), followed by DRB1*07–DQB1*0202–DQA1*0201 (DR7–DQ2) haplotype, which is associated with DRB1*11–DQB1*0301–DQA1*0505 (DR11–DQ7). The combinations of DR3–DQ2 with DR7–DQ2, and DR7–DQ2 with DR11–DQ7, present a twofold risk compared with each haplotype in homozygosis. An independence test in DR3-DQ2 haplotype found that association with CD was attributable to the whole haplotype, but for DR7-DQ2 was secondary to DQB1/DQA1. There is no need of a double gene dosage to increase the risk. CD-associated alleles typing demonstrates a very high negative predictive value to exclude CD in risk groups.     

Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives

The occurrence of other autoimmune diseases in celiac disease families has not been previously reported in a North American population. We investigated the familial aggregation of rheumatoid arthritis (RA), juvenile rheumatoid arthritis/juvenile idiopathic arthritis (JRA/JIA), hypothyroidism, insulin dependent diabetes mellitus (IDDM), and alopecia areata (AA) among individuals in families with celiac disease (CD). Family history information, obtained from questionnaires from the University of California Irvine Celiac Disease study, was reviewed for reports of RA, JRA/JIA, hypothyroidism, IDDM, and AA in celiac disease cases and their first-degree relatives. Reports of disease were compared with prevalence data from the literature and analyzed by calculating the standardized ratio (SR) with 95% confidence limits. We analyzed: (1) subjects with confirmed celiac disease or dermatitis herpetiformis (205 probands and 203 affected first-degree relatives) and (2) first-degree relatives of celiac disease cases (n=1272). We found a significantly increased number of cases, relative to the expected number, of IDDM in both groups and hypothyroidism among subjects with celiac disease. JRA/JIA was increased among first-degree relatives of celiacs. These results indicate that the presence of IDDM within our celiac disease families may be due to shared genetic susceptibility predisposing to these diseases or autoimmune diseases in general.