Autoimmune Type 1 Diabetes Genetic Susceptibility Encoded by Human Leukocyte Antigen DRB1 and DQB1 Genes in Tunisia

Human leukocyte antigen (HLA) class II genes contribute to the genetic susceptibility to type 1 diabetes (T1D), and susceptible alleles and haplotypes were implicated in the pathogenesis of T1D. This study investigated the heterogeneity in HLA class II haplotype distribution among Tunisian patients with T1D. This was a retrospective case control study done in Monastir in central Tunisia. The subjects comprised 88 T1D patients and 112 healthy controls. HLA-DRB1 and -DQB1 genotyping was done by PCR-sequence-specific priming. Significant DRB1 and DQB1 allelic differences were seen between T1D patients and controls; these differences comprised DRB1*030101 and DQB1*0302, which were higher in T1D patients than in control subjects, and DRB1*070101, DRB1*110101, DQB1*030101, and DQB1*060101, which were lower in T1D patients than in control subjects. In addition, the frequencies of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 were higher in T1D patients than in control subjects, and the frequencies of DRB1*070101-DQB1*0201 and DRB1*110101-DQB1*030101 haplotypes were lower in T1D patients than in control subjects. Multiple logistic regression analysis revealed the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 and the negative association of only DRB1*070101-DQB1*0201 haplotypes with T1D. Furthermore, a significantly increased prevalence of DRB1*030101-DQB1*0201 homozygotes was seen for T1D subjects than for control subjects. Our results confirm the association of specific HLA-DR and -DQ alleles and haplotypes with T1D in Tunisians. The identification of similar and unique haplotypes in Tunisians compared to other Caucasians highlights the need for evaluating the contribution of HLA class II to the genetic susceptibility to T1D with regard to haplotype usage and also to ethnic origin and racial background.Type 1 (insulin-dependent) diabetes (T1D) is the most prevalent form of diabetes in children and young adults (12, 17) and results from autoimmune CD4⁺ and CD8⁺ T-cell-directed destruction of insulin-producing pancreatic ß islet cells, leading to irreversible hyperglycemia and related complications (4, 22). In addition to environmental factors, there is a strong genetic component to T1D pathogenesis, of which the human leukocyte antigen (HLA) locus, in particular the class II region (DR and DQ), account for 40 to 50% of T1D familial clustering (13, 30). This was evidenced by the enrichment of DR3, DR4, DQ2, and DQ8, and the lower prevalence of DR15 or DQ6.2 alleles among T1D patients, thereby assigning a susceptible or protective role for these alleles in T1D pathogenesis, respectively (3, 16, 21).The fact that not all carriers of a specific high-risk DR or DQ variant develop the disease and the strong linkage disequilibrium between select DRB1 and DQB1 alleles (28) indicate that the pathogenesis of T1D results from the complex interaction between several genes within the class II region, in which specific DRB1-DQB1 haplotypes contribute to disease susceptibility. Accordingly, the enrichment or decreased prevalence of select DRB1-DQB1 haplotypes in T1D patients imparts disease susceptibility or protection, respectively (3, 18, 24). This susceptibility or protection effect disappears when a different DRB1 or DQB1 allele replaces the specific allele in the haplotype (29). The contribution of specific HLA haplotypes toward T1D susceptibility depends on the ethnic/racial background (26), which was highlighted by the positive association of DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302 haplotypes with T1D among Caucasians (3, 16) compared to DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 haplotypes and T1D in Japanese (18), while DRB1*1501-DQB1*0602 appeared to be protective of T1D in all populations (3, 16, 18). This indicates that association of a specific class II allele and DRB1-DQB1 haplotype with T1D must be evaluated in the context of the specific ethnic/racial background (26).We previously reported an association between HLA DRB1 and DQB1 alleles and haplotypes in Tunisian T1D patients (n = 50) and control subjects (n = 50) and identified two susceptible haplotypes (DRB1*030101-DQB1*0201 and DRB1*040101-DQB1*0302), but no protective haplotypes (27). Using haplotype estimation and regression analysis, here, we extend our investigation of HLA class II and T1D risk on a large sample size by confirming the association of these haplotypes and identified an additional T1D-protective haplotype.     

Clear cell hidradenocarcinoma--a case report with unusual in situ malignant changes

Clear cell hidradenocarcinoma is a rare tumour, the histogenesis of which has been much debated in the past. However, it is now considered a tumour of sweat gland origin. Presented herewith is a report of a case with unusual histological features of in situ malignant changes within sweat glands. These changes very closely simulate lobular cancerisation of the breast. On reviewing the English literature on the histopathology of sweat gland tumours, we have not found similar histological findings. These histological findings provide supportive evidence of the sweat gland origin of these tumours.     

HLA class II haplotypes distinctly associated with vaso-occlusion in children with sickle cell disease

We investigated the association of HLA class II alleles and haplotypes with sickle cell anemia vaso-occlusive crisis (VOC). DRB1*100101 was positively associated, while DRB1*140101, DRB1*150101, and DQB1*060101 were negatively associated, with VOC. Both susceptible (DRB1*100101-DQB1*050101) and protective (DRB1*110101-DQB1*030101 and DRB1*150101-DQB1*060101) haplotypes were identified, indicating that HLA class II haplotypes influence VOC risk.     

Acute splenic sequestration in female children with sickle cell disease in the North of Jordan

The objective of this study was to evaluate the rate of acute splenic sequestration (ASSC) in patients with sickle beta-thalassaemia and sickle cell anaemia, the risk of recurrence in those who survive the first episode, and the relationship between ASSC episodes and subsequent hypersplenism. All patients with confirmed diagnosis of sickle cell disease at a tertiary referral teaching hospital, between January 1994 and December 2002 were interviewed and had their medical records reviewed. Seventy-seven patients with sickle cell disease were identified. Their ages ranged between 2 and 18 years (mean, 10.1 years). There were 35 females and 38 males. Thirty-seven (50.6%) had sickle beta-thalassaemia, and 36 (49.4%) had homozygous sickle cell anaemia. Of these, 26 had high level of Hb F and 11 had normal level of fetal haemoglobin (Hb F). Twenty-one patients (28%) had 63 episodes of acute splenic sequestration. Thirty-seven episodes were experienced by 12 patients with sickle beta-thalassaemia; of these 11 were major attacks with one fatality. Twenty-six episodes were experienced by nine patients with sickle cell anaemia. Splenomegaly and hypersplenism were greater in the acute splenic sequestration group than in the rest of the sickle cell anaemia patients, and the differences were extremely significant. ASSC was found in nine siblings of sickle beta-thalassaemia group, while none were found in the sickle cell anaemia group. The mean age of the first episode was significantly higher in sickle beta-thalassaemia, with significant differences in the levels of Hb F, Hb S, size of spleen and severity of crisis between both groups. In the sickle cell anaemia group the only significant difference between patients with and these without acute splenic sequestration was the difference in the size of spleen. In this study, the rate of ASSC in the sickle beta-thalassaemia patients was 32%, in contrast to 25% in the sickle cell anaemia patients. The risk of recurrence was about 70% in those who survived their first episodes. There was a close relationship between ASSC and subsequent hypersplenism. Important predictable factors for ASSC in sickle beta-thalassaemia patients were the presence of splenomegaly of more than 5 cm below the costal margin, history of acute splenic sequestration in siblings and high Hb F. Most of first episodes in sickle cell anaemia occur under the age of 2 years, while in sickle beta-thalassaemia the majority of patients have their first crisis at the age of > or =3.5 years.     

HLA DRB1*130101-DQB1*060101 haplotype is associated with acute chest syndrome in sickle cell anemia patients

We investigated the association of human leukocyte antigens (HLA) class II alleles and haplotypes with the pathogenesis of acute chest syndrome (ACS) in 186 sickle cell anemia (SCA) patients, of whom 58 had documented ACS (new pulmonary infiltrate, fever, and other associated clinical events) and 128 with a negative history of ACS, serving as controls. HLA DRB1* and -DQB1* genotyping was performed by polymerase chain reaction–sequence-specific priming. Of the DRB1* and DQB1* alleles analyzed, only DRB1*130101 ( Pc  < 0.001) was positively associated with ACS. DRB1*130101-DQB1*060101 haplotype was more prevalent among ACS patients ( P  = 0.018), thus conferring disease susceptibility. Specific HLA alleles and haplotypes may influence ACS risk in SCA patients, and specific HLA genotypes may be useful markers for identifying high-risk SCA ACS patients.