Carlo Carcassi

HLA-dependent hypersensitivity to nevirapine in Sardinian HIV patients.

Background:Hypersensitivity reaction to nevirapine, which in some cases can be fatal, shows a higher prevalence in Sardinia in comparison with other Italian regions. Objective:This study demonstrates that hypersensitive reaction to nevirapine in Sardinian HIV-infected patients is associated with the HLA Cw8-B14 haplotype. These two HLA class I antigens are in strong linkage disequilibrium in the Sardinian population. Methods:Forty-nine Sardinian HIV-positive patients treated with nevirapine were studied. Thirteen (26%), developed a hypersensitive reaction thus requiring the drug to be discontinued. HLA class I and II molecular typing was performed in both nevirapine-hypersensitive and nevirapine-tolerant patients. To avoid biased representation of the allele frequencies in the two groups of treated patients, molecular typing was also performed in 82 HIV-positive patients who had not been treated with nevirapine. Results:Considerable overlap was observed for the clinical, immunological and demographic characteristics of the 13 hypersensitive patients and 36 tolerant patients. Clinical parameters included viral load, status of HIV infection, CD4 and CD8 cell counts, hepatitis C virus/hepatitis B virus co-infections. Forty-six percent (6/13) of the nevirapine-hypersensitive subjects had the HLA-Cw8 and HLA-B14(65) antigens compared with 5% (2/36) of the nevirapine-tolerant group (P = 0.004; Pc = 0.05). Conclusion:In agreement with other recent reports, the utility of HLA typing in HIV patients to identify genetic factors that may confer susceptibility to drug-induced hypersensitive reaction was confirmed. A careful choice of antiretroviral therapy in susceptible individuals should significantly reduce the risk of severe hypersensitive reaction.

HLA-G Gene Polymorphism in Human Placentas: Possible Association of G*0106 Allele with Preeclampsia and Miscarriage

Abstract Definite causes for several pathologies of pregnancy remain unknown. In light of several recent studies, however, diminished or aberrant HLA-G expression may be associated with certain complication of pregnancy and be linked to HLA-G polymorphism. We analyzed DNA from 60 normal placentas (controls), 140 placentas from miscarriage, 36 placentas from preeclampsia, 76 placentas from fetal hypotrophy, and 34 placentas with hypoxia for variations in coding regions (allelic groups G*0101 to G*0107) and the 14-bp deletion/insertion into the 3′-untranslated region. No statistically significant differences were observed in the distribution of allelic group between pathological placentas and controls with the exception of G*0106 allele frequency in preeclamptic compared with control placentas (21.2% and 6.6%, respectively). A greater frequency of this allele also was observed in the two subgroups of miscarriage and hypoxia compared with that in controls. In addition, presence of the 14-bp sequence was prominent in preeclampsia compared with controls (60.8% vs. 35%, respectively), and homozygotes with deletion were not detected in the pathology. The results suggest that the G*0106 allele, which is coupled with the presence of the 14-bp sequence, contributes and/or is a relevant marker in some specific complications of pregnancy, especially preeclampsia.

HLA-DPB1 alleles association of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus.

Our objective was to determine the HLA-DPB1 allele associations of anticardiolipin (aCL) and anti-beta2 GPI (aβ2 GPI) antibodies, and of clinical manifestations of the antiphospholipid syndrome (APS), in systemic lupus erythematosus(SLE). We studied 577 European patients with SLE. aCL and aβ2 GPI antibodies were measured by ELISA. Molecular typing of HLA-DPB1 locus was performed by polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. aCL showed positive association with -DPB1*1501 (P 0.005, OR 7.4), and -DPB1*2301 (P 0.009, OR 3.3). aβ2 GPI showed positive association with -DPB1*0301 (P 0.01, OR 1.9), and -DPB1*1901 (P 0.004, OR 8.1). In addition, livedo reticularis was associated with -DPB1*1401, and Raynaud’s phenomenon with -DPB1*2001. In conclusion, HLA-DPB1 locus may contribute to the genetic predisposition to develop antiphospholipid antibodies and clinical manifestations of the APS in patients with SLE.

Chronic myeloid leukemia: a prospective comparison of interphase fluorescence in situ hybridization and chromosome banding analysis for the definition of complete cytogenetic response, a study of the GIMEMA CML WP

In chronic myeloid leukemia, different methods are available to monitor the response to therapy: chromosome banding analysis (CBA), interphase fluorescence in situ hybridization (I-FISH), and real-time quantitative polymerase chain reaction (RT-Q-PCR). The GIMEMA CML WP (Gruppo Italiano Malattie Ematologiche Adulto Chronic Myeloid Leukemia Working Party) has performed a prospective study to compare CBA and I-FISH for the definition of complete cytogenetic response (CCgR). Samples (n = 664) were evaluated simultaneously by CBA and I-FISH. Of 537 cases in CCgR, the number of positive nuclei by I-FISH was less than 1% in 444 cases (82.7%). Of 451 cases with less than 1% positive nuclei by I-FISH, 444 (98.4%) were classified as CCgR by CBA. The major molecular response rate was significantly greater in cases with I-FISH less than 1% than in those with I-FISH 1% to 5% (66.8% vs 51.6%, P < .001) and in cases with CCgR and I-FISH less than 1% than in cases with CCgR and I-FISH 1% to 5% (66.1% vs 49.4%, P = .004). I-FISH is more sensitive than CBA and can be used to monitor CCgR. With appropriate probes, the cutoff value of I-FISH may be established at 1%. These trials are registered at http://www.clinicaltrials.gov as NCT00514488 and NCT00510926.

Mapping of the Major Psoriasis-Susceptibility Locus (PSORS1) in a 70-Kb Interval around the Corneodesmosin Gene (CDSN)

Numerous putative susceptibility loci have been described for psoriasis. Among the loci confirmed in the literature, PSORS1 (the major histocompatibility complex at 6p21.3) has the strongest effect. Recent studies have highlighted a 200-kb candidate region. However, this region has not been well delimited, mainly because of the strong linkage equilibrium among the associated alleles. To finely map PSORS1, we set up a study using 17 polymorphic markers in a 525-kb interval around the human leucocyte antigen C locus (HLA-C). The results uncovered five loci with alleles strongly associated with psoriasis (Sidak-corrected P [P(c)] values from 1.8 x 10(-7) to .003), all structured in a psoriasis-susceptibility haplotype (PSH). Subsequent analysis of extended haplotypes showed that the PSH was not only present on the traditional psoriasis-susceptibility extended haplotypes (HLA-Cw6-B57, HLA-Cw6-B37, and HLA-Cw6-B13) but also on a haplotype of Sardinian origin (HLA-Cw7-B58) found to be associated with psoriasis (Pc=.0009) because of an ancestral recombination with one of the susceptibility haplotypes carrying the HLA-Cw6 allele. Comparisons of the regions identical by descent among associated and nonassociated haplotypes highlighted a minimum region of 70 kb not recombinant with PSORS1, around the corneodesmosin (CDSN) gene.

The human leucocyte antigen-G 14-basepair polymorphism correlates with graft-versus-host disease in unrelated bone marrow transplantation for thalassaemia

The presence of the 14‐bp insertion polymorphism of the human leucocyte antigen (HLA)‐G gene (HLA‐G) promotes immune tolerance through increased synthesis of HLA‐G molecules. We investigated this polymorphism in a large cohort of 53 thalassaemia patients transplanted from an unrelated donor. Sixteen patients (30·2%) homozygous for the 14‐bp deletion had a higher risk of developing acute graft‐versus‐host disease (aGvHD) than patients homozygous for the 14‐bp insertion (−14‐bp/−14‐bp vs +14‐bp/+14‐bp: Relative Risk = 15·0; 95% confidence interval 1·59–141·24; P = 0·008). Therefore, the 14‐bp polymorphism could be an important predictive factor for aGvHD following bone marrow transplantation.

Long-term health-related quality of life evaluated more than 20 years after hematopoietic stem cell transplantation for thalassemia

The principal aim of our study was to investigate whether patients transplanted more than 20 years ago for β-thalassemia major had a different health-related quality of life (HRQoL) compared with the general population. The Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) were received from 109 ex-thalassemia patients who underwent hematopoietic stem cell transplantation (HSCT) during the 1980s and 1990s. Adjusted comparisons were performed separately for patient age at HSCT and the presence or absence of graft-versus-host disease (GVHD). Sociodemographic and clinical variables were also analyzed. The median age of our cohort at HSCT and the time of the survey was 12 years (range, 1-36) and 34 years (range, 21-48), respectively, with a median follow-up age of 22.8 years (range, 11.7-30.3). Statistical analysis of data collected more than 20 years after HSCT showed that the long-term HRQoL of ex-thalassemia patients was very similar to that of the general population. Clinical meaningful differences were only found for the general health (GH) scale (-8.9; 95% CI, -15.0 to 2.7, P = .005). Mental health, education level, employment status, marital status, living arrangements, and birth rate were compatible with normal living patterns. The development of GVHD and older age at transplantation were important impairing factors. Additional analyses performed to evaluate HRQoL in an age-sex-matched cohort of 124 patients receiving conventional treatment of β-thalassemia revealed poorer outcomes compared with the cohort of transplanted patients.

HLA antigen distribution in different clinical subgroups demonstrates genetic heterogeneity in lichen planus.

Summary HLA‐A, B, Cw, DR and DQ antigens were serologically determined in 105 patients suffering from lichen planus (LP). Of these patients, 87 had idiopathic LP and 18 had secondary LP. In the first group, 43 had cutaneous LP without mucosal lesions, 17 had cutaneous LP with mucosal lesions and 27 had purely mucosal LP. No HLA antigen was found to be significantly associated with secondary LP or with mucosal idiopathic LP. In cutaneous idiopathic LP with or without mucosal lesions, the HLA‐DR1 and DQ1 antigen frequency was significantly increased, and that of HLA‐DQ3 significantly decreased. Among the HLA‐DR1 cutaneous idiopathic LP patients, 78.5% carried the DRB1*0101 allele, and 214% the DRBI*0102 allele, compared with 35.7 and 67.8%, respectively, of the HLA‐DR1 controls. Our data demonstrate that idiopathic LP is influenced by HLA‐associated genetic susceptibility and resistance factors not involved in secondary LP, and that cutaneous idiopathic LP is a genetically and therefore pathogenetically different condition from purely mucosal idiopathic LP.

High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis

Orrù S, Manolakos E, Orrù N, Kokotas H, Mascia V, Carcassi C, Petersen MB. High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis.

HLA and Multiple Skin Carcinomas

The presence of HLA-associated genetic factors in patients with multiple skin carcinomas was investigated. 43 patients affected by multiple basal and squamous cell carcinomas and 220 healthy age-matched controls were typed for 72 HLA-A, B, C, DR antigens. A negative association of B-17 (mostly B-58) and a positive association of Cw-3 and DR-1 was observed in patients with multiple basal cell carcinomas; a similar negative association with B-58 and positive association with DR-1 was seen in patients with squamous cell carcinomas. The results of this study suggest the presence of resistance factors to the development of skin cancers associated with B-17 (B-58) antigen.