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

OBJECTIVES: 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.

Distinctive HLA-II association with primary biliary cholangitis on the Island of Sardinia.

BACKGROUND: The HLA DRB1*08 allele associated with primary biliary cholangitis (PBC) among Caucasians is of low frequency in the Sardinian population. OBJECTIVE: The aim of our study was to type a cohort of PBC patients from the island of Sardinia for HLA class II antigens. METHODS: Twenty Sardinian patients affected by PBC, 14 with autoimmune hepatitis (AIH) and 89 healthy controls (HCs) were typed for HLA class II alleles by dot-blot analysis. RESULTS: The PBC-associated HLA DRB1*08 allele was detected in none of the studied individuals. The DRB1*0301-DQB1*0201 was the prevalent HLA haplotype, detected in 19 (47.5%) out of 40 PBC haplotypes (OR = 3.0; 95% CI 1.5-6.2) and in 11 (39.3%) out of 28 AIH haplotypes (OR = 2.2; 95% CI 0.94-5.0), but in only 41 (23%) out of 178 HC haplotypes. Moreover, PBC patients showed an increased frequency of homozygosity for the DQB1*0201 allele (35% compared with 6.7% of the HCs; OR = 7.5; 95% CI 2.2-25.7). The frequency of the DRB1*11 allele in the PBC group was about half of that seen in the Sardinian HCs (7.5% vs 15.7%) (p = ns). CONCLUSIONS: Our study confirmed the low frequency of the HLA DRB1*08 allele among Sardinians, either in the general population or PBC patients. The high prevalence of the HLA DRB1*0301-DQB1*0201 haplotype is a distinctive genetic feature of PBC among Sardinians. Our study strengthens the hypothesis that still unknown genetic, epigenetic, and environmental factors must be involved in the pathogenesis of different HLA-associated liver diseases, and it represents a pathfinder that warrants exploration in a future extensive study.

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.

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.

Antitissue transglutaminase antibodies outside celiac disease.

BACKGROUND: Tissue transglutaminase enzyme-linked immunosorbent assay (tTG-ELISA) has recently been proposed as a simple and fast screening test for celiac disease (CD). The rate of false-positive and false-negative tests with tTG-ELISA, however, has not been definitively established. Therefore, the aim of our study was to investigate anti-tTG antibodies (TGA) not only in untreated patients with CD and in healthy controls, but also in a large group of patients with other autoimmune diseases. METHODS: The presence of TGA was investigated in sera from 111 patients with untreated CD, 96 patients with other autoimmune conditions (28 with autoimmune liver disease, 46 with insulin-dependent diabetes mellitus, 10 with inflammatory bowel syndrome, 12 with type 1 polyglandular syndrome) and from 100 healthy controls using guinea pig tTG-ELISA (gp-TG/ELISA) and highly purified recombinant human tTG-ELISA (h-TG/ELISA). Western blotting with guinea pig tTG was also performed. RESULTS: Ninety-four patients with CD who tested positive for antiendomysial antibodies (AEA) and one who tested negative for AEA showed antibodies against the gp-TG. Among the controls, 50% of patients with autoimmune liver disease and 6.5% of patients with insulin-dependent diabetes mellitus tested positive with gp-TG/ELISA. Western blotting experiments revealed that the high rate of positive tests observed using ELISA among the control group sera is attributable to impurities in the gp-TG preparation. However, h-TG/ELISA tests were positive for the sera from all patients who tested positive for AEA and from one control who tested negative for AEA, whereas h-TG/ELISA tests were negative for all CD patients who tested negative for AEA and for other controls who tested negative for AEA. CONCLUSIONS: The frequency of false-negative and false-positive tests represents the major limit to the use of gp-tTG/ELISA. However, because h-TG/ELISA is both simple and fast, it could be used in large screening programs for CD.