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Presence of DQ2.2 Associated with DQ2.5 Increases the Risk for Celiac Disease 时间:2017-06-14 08:44   来源:未知   作者:admin   点击: 次 Abstract:Background. Celiac disease (CD) is a genetically determined immune-mediated disorder in which gluten immunogenic peptides are presented to CD4 T cells by HLA-DQ2.5, DQ8, DQ2.2, and their combinations. Our aim is to establish a risk gradient for celiac disease based on HLA-DQ profile in a brazilian representative population and the relevance of DQ2.2 in celiac disease development. Materials and Methods. 237 celiac patients and 237 controls (both groups with 164 females and 73 males) were included. All samples were tested for the presence of predisposing HLA-DQ alleles using the PCR-SSP method. Results were considered significant when . Disease risk was expressed as 1 : for each HLA-DQ category described at this study. Results. DQ2.5 and/or DQ8 were detected in 224 celiac patients (94.5%) and 84 controls (35.4%). Eight celiac patients (3.4%) and 38 controls (16%) disclosed only DQ2.2. Even though DQ2.2 (β2/β2 or β2/x) showed a low CD risk of 1 : 251 and 1 : 550, respectively, the genotype DQ2.5/DQ2.2 (β2/β2) showed high CD risk of 1 : 10 (). The disease risk gradient ranged from 1 : 3014 to 1 : 7. Conclusion. Our study allowed the determination of a risk gradient for celiac disease development in at-risk population, showing that DQ2.2 variant was relevant when associated with DQ2.5.
1. Introduction
Celiac disease (CD) is a genetically determined immune-mediated disorder, in which individuals carrying specific HLA haplotypes (DQ2 and/or DQ8) mount an immunologic response to the ingestion of gluten that leads to a broad range of clinical signs and symptoms. Gastrointestinal disorders are the most common manifestations and include chronic diarrhea, abdominal distention, and nutrients malabsorption. However, extraintestinal manifestations are also frequent and include numerous conditions such as dermatitis herpetiformis, anemia, dental enamel hypoplasia, osteoporosis, and neurologic problems [1].
CD activity is characterized by the production of IgA anti-endomysial antibody (IgA-EmA) and IgA anti-transglutaminase antibody (IgA-tTG), which are good markers of the active phase of the disease and are usually used as a first step in its diagnosis. In most cases, a definitive diagnosis requires a jejunal biopsy showing typical histologic abnormalities such as villous atrophy, crypt hyperplasia, and lymphocytic infiltration [2].
In the general population of Europe, United States, and countries predominantly populated by individuals of European origin, the prevalence of CD is approximately 1%. In Brazil, several prevalence studies performed to date revealed significant differences around the country, probably consequent to genetic and environmental factors and possibly also due to interlaboratory assay variability [3–7]. Although multicenter epidemiological studies that could yield reliable information on CD prevalence in Brazil are still lacking, the existing reports suggest that the disease prevalence in this country is similar to the general prevalence found in other areas of the world [2, 4, 5, 7].
  Virtually all CD patients carry the alleles that code for DQ2 and/or DQ8 molecules or at least for one chain of the DQ2 heterodimer, normally β chain, encoded by DQB1*02 allele. The occurrence of CD in the absence of these at-risk DQ factors is extremely rare [8]. The presence of these molecules does not predict with accuracy that CD will develop, since they are present in 25 to 50% of the general population, although the vast majority of these individuals will never develop the disease [9].
  Consequently, in view of the nearly 100% negative predictive value, the HLA typing has been used as a screening tool in high-risk population such as carriers of type 1 diabetes, Down syndrome, or Turner syndrome [10]. HLA typing has also been used as a prognostic factor of the disease severity [11, 12] and sex distribution [13] and as an accessory element in the diagnosis of difficult cases [14]. Finally, the HLA-DQ typing to determine the future risk of CD has been extensively discussed, although its practical usage remains not clinically defined. Genetic testing of individuals could eliminate more than 60% of the population considered to have a low CD-risk (DQ2 or DQ8 negative) from future antibody testing, and the identification of high-risk individuals would allow a prospective screening, enabling an early therapeutic intervention [15].
  As far as we know, no previous study has focused on the frequency of CD predisposing HLA genotypes in affected and nonaffected individuals in a Brazilian population. Consequently, our aim in the present study is to determine the frequency of CD predisposing DQ genotypes in celiac and nonceliac subjects and establish a CD-risk gradient focusing on the prevalence of DQ2.2, in Brazil.