HLA-DQB1*0201 homozygosis predisposes to severe intestinal damage in celiac disease

OBJECTIVE: Celiac disease (CD) is a T-lymphocyte-mediated small intestinal enteropathy triggered and maintained by dietary gluten, with a strong genetic component mapping to the HLA genes encoding for the class II DQ(alpha1*0501, beta1*02) molecule. Damage of the small intestine may cause a variety of clinical signs ranging from isolated long-standing iron-deficiency anemia refractory to iron supplementation to forms of severe malnutrition that may become life threatening. However, patients carrying the typical intestinal lesions of CD and presenting no symptoms at all (silent CD) are also a common clinical observation. Since it is commonly assumed that clinical signs and symptoms tend to correlate with the severity of the intestinal damage, the purpose of this study was to investigate whether particular HLA class II genotypes might also influence the extent of intestinal damage and consequently the clinical presentation of the disease. MATERIAL AND METHODS: We retrospectively compared histological grading of celiac disease intestinal biopsies with HLA haplotype, age at onset of disease and clinical signs and symptoms. RESULTS: Our findings showed that homozygosis for the DQB1*0201 allele is associated with a higher severity of the histological score (p<0.008). Of note for the clinician, this work also suggests that the same type 3c of intestinal damage causes a different clinical syndrome, depending on the patient's age. CONCLUSIONS: The genetic predisposition at the HLA-DQB1 locus influences the severity of the mucosal damage in a dose-dependent manner, but not the clinical presentation, of celiac disease

High frequency of low-risk human leukocyte antigen class II genotypes in latent celiac disease

Human leukocyte antigen (HLA) class II genotypes in latent celiac disease, a clinical variant of celiac disease (CD) have been scarcely studied. The aim of this work was to investigate whether latent CD and CD share similar frequencies of HLA class II genotypes. HLA class II genotypes of CD patients compared with controls were subdivided in the following at-risk groups: DQB1*02/DQB1*02 (43.0%, odds ratio [OR] 8.02, p < 0.0001), DQB1*0302/DQB1*02 (12.2%, OR 2.77, p = 0.0002), DQB1*02/DQB1*X (39.2%, OR 1.23, p = 0.1903), DQB1*0302/DQB1*X (3.4%, OR 0.35, p = 0.0064) and DQB1*X/DQB1*X (0.8%, OR 0.01, p = 0.0001) where X is neither DQB1*0302 nor DQB1*02. Next, HLA class II genotypes of 21 latent CD patients were compared with the above at-risk groups. Only one latent CD patient (4.8%) was found in the high risk DQB1*02/DQB1*02 group, three (14.3%) were DQB1*0302/DQB1*02, one (4.8%) was DQB1*0302/DQB1*X and the remaining 16 (76.2%) showed the DQB1*02/DQB1*X genotype. Noteworthy, the only 1 patient with the DQB1*02/DQB1*02 high risk genotype did not carry the DR3-DQB1*02/DR3-DQB1*02 or the DR3-DQB1*02/DR7-DQB1*02 but the uncommon DR3-DQB1*02/DR4-DQB1*02 genotype. These data suggest that latent CD is prevalently associated with low-risk HLA class II genotypes

Decline of lactase activity and c/t-13910 variant in Sardinian childhood

Our study aims to determine the age of onset of adult-type hypolactasia in Sardinians, and to establish the age at which genotyping of the C/T-13910 variant can be used reliably in the diagnosis of lactose malabsorption. PATIENTS AND METHODS: A lactose breath hydrogen test was given to 383 randomly selected patients, from 3 to 19 years old. RESULTS: The C/C-13910 genotype was found in 90% of patients; the frequency of the positive lactose breath hydrogen test increased with age and reached a prevalence of 85% at 9 years. CONCLUSIONS: In Sardinians, adult-type hypolactasia becomes phenotypically evident in all individuals older than 9 years, suggesting that this should be considered the minimum age at which the genetic test for lactase nonpersistence should be applied

GENETIC TESTING IMPROVES THE DIAGNOSIS OF ADULT TYPE HYPOLACTASIA IN THE MEDITERRANEAN POPULATION OF SARDINIA

Recently, the C/T-13910 polymorphism on chromosome 2q21 in North-European populations has been found completely associated with lactase activity and its genetic typing proposed as first-stage screening test for adult hypolactasia. However, the C/T-13910 variant in some sub-Saharan African groups is not a predictor of lactase persistence. In this work, we wanted to verify if in the Mediterranean island of Sardinia, located in Southern Europe, the C/T-13910 polymorphism may be useful or not for the diagnosis of adult type hypolactasia. DESIGN: Validation study of a genetic testing for adult type hypolactasia in Sardinians. SETTING: Brotzu Hospital and Microcitemico Hospital, Cagliari, Italy. SUBJECTS: The sample consisted in 84 Sardinian individuals (63 women and 21 men; range 20-73 years) selected from a group of 832 patients. METHODS: Genetic testing was compared to an improved test obtained by a combination of different breath hydrogen tests and clinical assessment. RESULTS: We found that all 49 individuals with lactose malabsorption, demonstrated by a combination of different breath hydrogen tests and clinical assessment, carried the C/C-13910 genotype associated with lactase non-persistence, 23 individuals with lactose normal absorption carried the C/T-13910 genotype associated with lactase persistence and only one person with the above phenotype showed a discordant C/C-13910 genotype. The genetic testing showed very high sensitivity, specificity, positive and negative predictive values of 100, 95.8, 98 and 100%, respectively. CONCLUSIONS: Sardinians, unlike some ethnic groups in sub-Saharan Africa, show the same genetic association of hypolactasia with the C/T-13910 variant as other North-European populations. The genetic testing for the C/T-13910 variant may contribute to improving the diagnosis of adult type hypolactasia