Recombination frequencies of human leukocyte antigen loci in hematological malignancies among Turkish population.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) is a treatment option with growing performance for leukaemia, aplastic anaemia and genetic disorders. The frequency of MHC (Major Histocompatibility Complex) gene locus recombination is increased at loci close to the telomeres and in the female gender. The aim of the present study is to document the recombination events by pedigree diagrams with the primary goal to determine the frequency of recombination in a different ethnic population from mostly reported studies. METHODS: Altogether 9545 allogeneic HSCT recipients and their family-based potential donors (n:36231) were included in this retrospective study. RESULTS: Recombinations were determined in 118 (F/M:50/68) out of 9545 families enrolled on the study. These were present in 40 of the patients and 78 of healthy donors. The frequency of recombinations was 0.42% and 0.22%, in patients and donors, respectively. Of the 118 recombinations, 60 were detected in A locus (13 inpatients), 14 in B locus (3 inpatients) and 42 in DR locus (22 inpatients). In our study, due to recombinations in HLA (Human Leukocyte Antigen)-A,-B,-DR loci, we found that some patient-donor pairs became 6/5 matched instead of 6/6 (n:45), eliminating the allogeneic HSCT possibility for the patients from the full-matched siblings. CONCLUSION: To our knowledge, this is the first study reporting the recombination frequencies in HLA loci among Turkish population and thus, providing informative data to the clinicians regarding the cross-over possibilities in Turkish patients with haematological malignancies.

The HLA-Cw12 Allele Is an Important Susceptibility Allele for Psoriasis and Is Associated with Resistant Psoriasis in the Turkish Population.

BACKGROUND: Psoriasis is a multifactorial immune-mediated inflammatory disease triggered by both genetic and environmental factors. The strong association between psoriasis and HLA-C⁎06 allele has been demonstrated in various races. The HLA-C⁎12 allele is closely related to the HLA-C⁎06 family of alleles and shares identical sequences. To the best of our knowledge, there is no information about the relationship between HLA-C⁎12 and psoriasis in the Turkish population. The present study aims to determine this relationship. METHODS: This case control study involved 150 patients with plaque-type psoriasis and 145 age- and gender-matched healthy individuals. Severity of psoriasis was measured using the PASI scores of all patients and joint involvement was investigated with CASPAR criteria. HLA-C alleles were determined with a Tepnel-Lifecodes system. RESULTS: HLA-C⁎06, HLA-C⁎12, and HLA-C⁎04 alleles were most commonly observed in psoriasis patients. HLA-C⁎06 and HLA-C⁎12 were significantly more frequent in the psoriasis group. HLA-C⁎06 was 4.11 times more common in psoriasis patients. An increase in PASI (Psoriasis Area Severity Index) scores was compatible with HLA-C⁎12 positivity. A need for systemic treatment was highly noticeable in patients with the HLA-C⁎12 allele. CONCLUSIONS: HLA-C⁎12 was found as the second most frequent allele with psoriasis in Turkish population and was associated with severe psoriasis. Our study is limited as we could not investigate other potentially related alleles other than HLA-C alleles and risk factors increasing severity of psoriasis.

High soluble CD30 levels and associated anti-HLA antibodies in patients with failed renal allografts.

INTRODUCTION: Serum soluble CD30 (sCD30), a 120-kD glycoprotein that belongs to the tumor necrosis factor receptor family, has been suggested as a marker of rejection in kidney transplant patients. The aim of this study was to evaluate the relationship between sCD30 levels and anti-HLA antibodies, and to compare sCD30 levels in patients undergoing hemodialysis (HD) with and without failed renal allografts and transplant recipients with functioning grafts. METHODS: 100 patients undergoing HD with failed grafts (group 1), 100 patients undergoing HD who had never undergone transplantation (group 2), and 100 kidney transplant recipients (group 3) were included in this study. Associations of serum sCD30 levels and anti-HLA antibody status were analyzed in these groups. RESULTS: The sCD30 levels of group 1 and group 2 (154 ± 71 U/mL and 103 ± 55 U/mL, respectively) were significantly higher than those of the transplant recipients (group 3) (39 ± 21 U/mL) (p<0.001 and p<0.001). The serum sCD30 levels in group 1 (154 ± 71 U/mL) were also significantly higher than group 2 (103 ± 55 U/mL) (p<0.001). Anti-HLA antibodies were detected in 81 (81%) and 5 (5%) of patients in groups 1 and 2, respectively (p<0.001). When multiple regression analysis was performed to predict sCD30 levels, the independent variables in group 1 were the presence of class I anti-HLA antibodies (ß = 0.295; p = 0.003) and age (ß = -0.272; p = 0.005), and serum creatinine (ß = 0.218; p = 0.027) and presence of class II anti-HLA antibodies (standardized ß = 0.194; p = 0.046) in group 3. CONCLUSIONS: Higher sCD30 levels and anti-HLA antibodies in patients undergoing HD with failed renal allografts may be related to higher inflammatory status in these patients.

FGF-23 associated with the progression of coronary artery calcification in hemodialysis patients.

BACKGROUND: Disordered mineral metabolism is implicated in the pathogenesis of vascular calcification in hemodialysis (HD) patients. Fibroblast growth factor 23 (FGF-23) is the main regulator of phosphate metabolism. In this prospective study, we aimed to investigate the association of serum FGF-23 with progression of coronary artery calcification in HD patients. METHODS: Seventy-four HD patients (36 male/38 female, mean age: 52 ± 14 years) were included. Serum FGF-23 levels were measured by ELISA. Coronary artery calcification score (CACS) was measured twice with one year interval. Patients were grouped as progressive (PG) (36 patients-48%) and non-progressive (NPG). RESULTS: Age, serum phosphorus, baseline and first year CACS were found to be significantly higher in the PG compared to NPG group. Serum FGF-23 levels were significantly higher in PG [155 (80-468) vs 147 (82-234), p = 0.04]. Patients were divided into two groups according to baseline CACS (low group, CACS ≤ 30; high group, CACS > 30). Serum FGF-23 levels were significantly correlated with the progression of CACS (ΔCACS) in the low baseline CACS group (r = 0.51, p = 0.006), but this association was not found in high baseline CACS group (r = 0.11, p = 0.44). In logistic regression analysis for predicting the PG patients; serum FGF-23, phosphorus levels and baseline CACS were retained as significant factors in the model. CONCLUSIONS: Serum FGF-23 was found to be related to progression of CACS independent of serum phosphorus levels. FGF-23 may play a major role in the progression of vascular calcification especially at the early stages of calcification process in HD patients.

Association of cytokine gene polymorphisms (IL6, IL10, TNF-α, TGF-ß and IFN-γ) and Graves' disease in Turkish population.

INTRODUCTION: Cytokines play a crucial role in the pathogenesis of autoimmune thyroid disease, and recent studies have demonstrated an association between cytokine gene polymorphisms and Graves' Disease (GD) in different ethnic groups. The aim of the present study was to investigate the relationship of interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-ß), and interferon-gamma (INF-γ) gene polymorphisms in the development of GD in Turkish population. MATERIAL AND METHODS: A total of 224 subjects were included in the study comprising of 100 patients with GD (70 female, 30 male; mean age, 43.9 ±13.8 years) and 124 healthy subjects (81 female, 43 male); mean age, 37.8 ±10.2 years) without antithyroid autoantibodies or family history of autoimmune disorders. Genotyping was conducted by using PCR and sequence-specific primers. RESULTS: Statistical analysis showed a significant association between high TNF-α -308GA and IL-6 -174CC gene polymorphisms in patients with GD compared to control subjects (p=0.016, p=0.044, respectively). However, no significant differences were observed between GD and control subjects for IL-10, TGF-ß, and INF-γ gene polymorphisms. CONCLUSION: TNF-α-308GA and IL-6 -174CC gene polymorphisms are involved in susceptibility to GD in Turkish population. The polymorphism hypothesis in pro-inflammatory cytokines might be involved in predisposition to GD.

Association of HLA phenotypes of end-stage renal disease patients preparing for first transplantation with anti-HLA antibody status.

Patients with pre-transplantation high levels of panel reactive antibody (PRA) have an increased risk of graft failure, and renal transplantation in sensitized patients remains a highly significant challenge worldwide. The influence of anti-human leukocyte antigen (HLA) antibodies on the development of rejection episodes depends on patient-specific clinical factors and differs from patient to patient. The HLA typing of the recipient might influence the development of anti-HLA antibodies. Some HLA antigens appear to be more immunogenic than others. The aim of this study is to demonstrate the distribution of HLA phenotypes in PRA-positive and PRA-negative end-stage renal disease (ESRD) patients on the basis of having sensitizing events or not. Our study included 642 (mean age: 41.54; female/male: 310/332) ESRD patients preparing for the first transplantation and who are on the cadaveric kidney transplantation waiting list of Istanbul Medical Faculty in 2008-2009. Class I HLA-A,B typing was performed by complement-dependent cytotoxicity (CDC) method, whereas class II HLA-DRB1 typing was performed by low-resolution polymerase chain reaction (PCR)-sequence-specific primer (SSP). All serum samples were screened for the presence of IgG type of anti-HLA class I- and II-specific antibodies by enzyme-linked-immunosorbent assay (ELISA). PRA-negative group consisted of 558 (86.9%) and PRA-positive group included 84 (13.1%) patients. We have found statistically significant frequency of HLA-A3 (p=0.018), HLA-A66 (p=0.04), and HLA-B18 (p=0.006) antigens in PRA-positive patients and DRB1*07 (p=0.02) having the highest frequency in patients with sensitizing event history but no anti-HLA development suggesting that DRB1*07 might be associated with low risk of anti-HLA antibody formation.

Impact of HLA on the underlying primary diseases in Turkish patients with end-stage renal disease.

The number of patients with end stage renal disease (ESRD) is increasing faster than the number of renal transplantations performed per year worldwide. Of the primary diseases leading to ESRD, diabetic nephropathy is the leading cause. The purpose of the present study is to investigate the association of HLA with the primary diseases leading to ESRD in Turkish patients. A total of 3230 individuals comprising 587 ESRD patients and 2643 healthy controls were enrolled into the study. Class I HLA-A, -B typing was performed by CDC method, while class II HLA-DRB1 typing was performed by low resolution PCR-SSP. We found a significant negative association between almost all A locus antigens and primary disease groups classified as chronic glomerulonephritis and hypertensive nephrosclerosis (p < 0.05). HLA-B58 and HLA-DRB1*03 significantly correlated with amyloidosis and diabetic nephropathy, respectively. Determination of HLAs as risk factors for primary diseases leading to ESRD might be beneficial in preventing progression to ESRD and recurrence of the primary disease post-transplantation.

The prevalence of manifest and latent celiac disease in type 1 diabetes mellitus.

BACKGROUND/AIMS: Celiac disease and type 1 diabetes mellitus are both autoimmune diseases which have a common genetic predisposition. The aim of this study was to determine the prevalence of manifest and latent celiac disease in type 1 diabetic patients. METHODS: Anti-endomysium IgA was tested by indirect immunofluorescence using sections of human umbilical cord for screening in 100 adult patients with type 1 diabetes mellitus and in 80 age and sex matched controls with no known disease. Distal duodenal biopsy, human leukocyte antigen typing, urinary D-xylose excretion test, stool analysis, biochemistry profile, blood counts, serum ferritin level and small intestinal radiography were performed in anti-endomysium IgA positive cases. Small bowel biopsy specimens consistent with celiac disease were defined as manifest celiac disease, while positive antiendomysium IgA and normal intestinal histology with the presence of human leukocyte antigen class II antigens consistent with the disease were defined as latent celiac disease. RESULTS: Anti-endomysium IgA was positive in eight diabetic patients, while it was negative in all controls. Celiac disease was found in a total of six (6%) patients, four with manifest and two with latent disease. Only one patient had symptoms. CONCLUSIONS: The prevalence of celiac disease is increased in patients with type 1 diabetes mellitus. Since many patients may be asymptomatic, it is suggested that all diabetic patients should be screened for this disease.