Mariaclara Cuccia

Plasma Levels of Soluble Receptor for Advanced Glycation End Products and Coronary Artery Disease in Nondiabetic Men

Objective—The receptor for advanced glycation end products (RAGE) is a cell surface receptor whose signaling pathway has been implicated in atherogenesis. RAGE has an endogenous secretory receptor form, called soluble RAGE (sRAGE), that could exert antiatherogenic effects by acting as a decoy. We sought to determine whether a decreased plasma level of sRAGE could be independently associated with the prevalence of coronary artery disease (CAD) in nondiabetic men. Methods and Results—Plasma levels of sRAGE were determined in 328 nondiabetic male patients with angiographically proved CAD and in 328 age-matched healthy controls. The concentration of sRAGE in plasma was significantly lower (P<0.0001) in CAD cases [median (interquartile range): 966 (658–1372) pg/mL] than in control subjects [1335 (936–1954) pg/mL]. In logistic regression analysis, the multivariate-adjusted odds ratio for the presence of CAD was 6.719 (95% confidence interval, 3.773 to 11.964; P<0.0001) when the lowest quartile of the sRAGE level was compared with the highest quartile. Conclusions—Our findings indicate that low levels of sRAGE in plasma are independently associated with the presence of CAD in nondiabetic men and suggest that sRAGE is one of the clinically important molecules associated with atherosclerosis.

Age of onset in vitiligo: relationship with HLA supratypes.

HLA class I (A, B, C), class II (DR, DQ) histoglobulins and HLA class III (C4A, C4B and Bf) complement factors were analysed in 87 patients with vitiligo and in controls. Two HLA supratypes seem to mark different age of onset of vitiligo: HLA‐BfS, C4A3, C4B1, DR5 (W11), DQW3 is characteristic of the pediatric form; while HLA‐BfS, C4A3, C4B1, DR7, DQW2 marks the adult form of disease. The importance of defining HLA supratype, not single alleles, is discussed.

Family study of non-responsiveness to hepatitis B vaccine confirms the importance of HLA class III C4A locus.

Non-responsiveness to hepatitis B virus (HBV) vaccine in adults is strongly associated with HLA-C4AQ0,DRB1*0301,DQB1*02 haplotype. This association was also demonstrated in neonates who failed to mount a humoral response to challenge with HBV vaccine. About 4% of vaccinated newborns do not reach a protective antibody level (⩾10 mIU/ml) at seroconversion and 0.4% is a non-responder even after receiving a fourth dose of vaccine (true non-responders (TNR)); while 3.6% achieved an antibody level ⩾10 mIU/ml (slow responders (SR)) only when reboostered with the fourth dose. In the present study we extend the vaccination and HLA typing to 91 family members of probands to understand better the possible parent-to-child transmission of this trait. A transmission disequilibrium test (TDT), performed in 27 families, showed that the C4AQ0 allele was almost always transmitted to probands, both TNRs and SRs. Although not statistically significant, the highest LOD score was obtained with C4A locus: 1.58. These results suggest the presence of a region regulating immune response against HBV vaccination near to or coincident with the C4A locus.

Inflammation and Atherosclerosis: The Role of TNF and TNF Receptors Polymorphisms in Coronary Artery Disease

Inflammation plays an important role in the pathogenesis of atherosclerosis and coronary syndromes; moreover, various lines of evidence suggest that genetic factors contribute significantly to the risk of coronary artery disease (CAD). Through its effects on endothelial function, coagulation, insulin resistance and lipid metabolism, the proinflammatory cytokine TNF could be involved in cardiovascular pathophysiology. The aim of our study is to analyze whether TNF gene promoter (-308 G/A; −857 G/A) and TNF receptor polymorphisms (TNFR1 MspA1 I exon 1 and TNFR2 Nla III exon 6) show involvement in CAD predisposition in a group of Italian patients compared with healthy controls. Genotyping was performed by PCR-RFLP. Consecutive Italian patients with angiographically proven CAD (n= 248) were compared with controls (n=241), matched for age, sex and geographical origins. CAD patients showed a higher frequency of the TNF −308 A allele than healthy controls (p=0.046). After stratification according to risk factors for CAD, our analysis revealed that CAD patients with diabetes (p=0.042) and CAD patients without hypertension (p=0.0495) displayed a higher frequency of the TNF −308 AA genotype compared with healthy controls. Our data stress the inflammatory nature of CAD and show a possible involvement of TNF −308G/A promoter polymorphisms in the predisposition to the development of this disease. The less frequent A allele seems to be a predisposing factor for development of CAD in particular pathological settings associated with the disease itself, such as diabetes.

Hierarchy of baby-linked immunogenetic risk factors in the vertical transmission of hepatitis C virus

Mother-to-infant transmission of Hepatitis C Virus (HCV) represents the major cause of pediatric HCV infection today. Immunogenetic influence has been poorly investigated and mainly confined to HLA-class II serological polymorphisms. Among 290 parities, 135 from Pavia and 155 from Bergamo, of HCV-RNA-infected Italian women, 21 babies (7.24%) were HCV-RNA positive at birth and steadily positive over 20 months of life. All the 21 infected babies and 44 randomly selected uninfected ones, born to HCV-RNA+ mothers but steadily negative for HCV-RNA during a follow-up of 2 years, and their mothers were investigated for HLA-G, -C, -DRB1, -DQA1 and -DQB1 genomic polymorphisms. Among the different covariates, HLA-Cw*07, -G*010401, -DRB1*0701, -DRB1*1401 and homozigosity for HLA-G 14bp deletion can be considered as risk factors for HCV vertical transmission. On the contrary, protection was conferred by the HLA-DQB1*06, -G*0105N, -Cw*0602, DRB1*1104 and -DRB1*1302 alleles. Our initial question was: has the immunogenetic profile any role in the protection of the fetus growing in an infected milieu and, if so, is it independent from the other non-immunogenetic parameters? The answer to both questions should be yes.

The morphologic spectrum of dilated cardiomyopathy and its relation to immune-response genes.

Endomyocardial biopsies from 174 patients with dilated cardiomyopathy (DC) were examined. Eight patients with histologically proven myocarditis were excluded from the study. A peculiar pattern of oversized and bizarre nuclei was observed in only some of the remaining patients. Two groups were identified: those with and without this feature (groups A and B, respectively). Myocyte width, nuclear diameter and nuclear/sarcoplasmic ratio were significantly higher in group A. The mean respective values were 36 +/- 5 mu, 14 +/- 3 mu and 0.41 +/- 0.08 for group A versus 20 +/- 8 mu, 7 +/- 2 mu and 0.37 +/- 0.08 for group B. Interstitial fibrosis was similarly present in groups A and B. Endocardial thickness was significantly increased in all patients, with group A showing the highest mean value. The morphologic features showed no correlation with the clinical condition of the patients at time of presentation. HLA typing was performed in 50 consecutive patients, 38 from group A and 12 from group B. DR4 and DR5 antigens were significantly more frequent in DC patients than in a normal population control (400 blood donors), while DR3 was less frequent. Group A was more strongly associated with the DR5 antigen than group B (55.3 vs 25.0%, respectively). It was less strongly associated with the DR4 antigen compared with group B (21.5 vs 41.7%, respectively). No difference was observed between the 2 groups concerning negative association with the DR3 antigen. Endomyocardial biopsies from DC patients reveal marked morphologic changes from patient to patient.(ABSTRACT TRUNCATED AT 250 WORDS)

The 374T/A RAGE Polymorphism Protects Against Future Cardiac Events in Nondiabetic Patients with Coronary Artery Disease

BACKGROUND The -374T/A polymorphism of the Receptor for Advanced Glycation End products (RAGE) may exert a protective effect toward the development of atherosclerosis. No data are currently available on the potential prognostic role of this polymorphism in patients with angiographically proven coronary artery disease (CAD). Hereto we sought to address this issue in a large consecutive cohort of patients undergoing coronary revascularization. METHODS A total of 643 CAD patients who underwent myocardial revascularization were followed for 4.2 years (interquartile range: 2.2-8.1 years). The rates of major cardiac adverse events (death, nonfatal myocardial infarction, and unstable angina) were compared according to the -374T/A RAGE polymorphism. RESULTS During a median follow-up period of 4.2 years, the study endpoint was reached by 126/643 patients (19.6%). We observed adverse cardiac events in 13.4% of patients with AA, 17.5% of those with AT, and 24.2% of those with TT genotype (p <0.05). In univariate Cox proportional hazard analysis, the AA genotype was significantly related to a better outcome in nondiabetic patients (hazard ratio: 0.47, 95% CI: 0.20-0.96; p <0.05). No association was found with adverse events in diabetic subjects. After allowance for potential confounders, the AA genotype remained a significant prognostic factor in the nondiabetic group (adjusted HR: 0.41, 95% CI: 0.17-0.94, p <0.05). CONCLUSIONS The -374T/A RAGE polymorphism is an independent protective factor for cardiac events in nondiabetic patients with CAD. The effect of this genetic variant seems to be attenuated in diabetics, who have chronic RAGE upregulation.

Specific polymorphisms of cytokine genes are associated with different risks to develop single-system or multi-system childhood Langerhans cell histiocytosis.

Cytokines and chemokines determine mobilisation of Langerhans cells and their dysregulation is implicated in the pathogenesis of Langerhans cell histiocytosis (LCH). Twenty point mutations of 12 different cytokine genes were studied in 41 Italian children, 15 with single‐system (SS) and 26 with multi‐system disease. The allele and genotype distributions of interleukin‐4 (IL‐4) and interferon‐γ (IFNγ) were significantly different in patients vs. 140 controls (P = 0.007, and P = 0.018). Older children with single‐system disease shared the ‘anti‐inflammatory profile’ determined by the intermediate producer genotype IFNγ +874A/T (P = 0.029) and the high‐producer genotypes IL‐4 –590C/T and T/T (P = 0.029). Our findings suggest that specific cytokine gene variants affect susceptibility to LCH and its clinical heterogeneity.

Adrenocorticotrophin stimulation and HLA polymorphisms suggest a high frequency of heterozygosity for steroid 21‐hydroxylase deficiency in patients with Turner's syndrome and their families

OBJECTIVE Following the chance observation of congenital adrenal hyperplasia in a patient with Turners syndrome we decided to evaluate the incidence of 21‐hydroxylase deficiency (21‐OHD) in patients with Turners syndrome and in their relatives.

Polymorphic markers in MHC class II/III region: a study on Italian patients with myasthenia gravis

With an Italian case series of 81 Italian patients and 130 controls, we analysed associations between myasthenia gravis (MG) and genetic polymorphisms in the MHC class II/III region. Increases in the frequency of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype, which is likely part of the 8.1 ancestral haplotype, were maximal in females with early onset (EO) MG vs. controls [p<0.05, relative risk (RR)=9.9]. These patients showed neither a significantly high frequency of thymic hyperplasia, nor high levels of serum anti-acethylcholine receptor antibodies. The DRB1*03 allele was absent in patients with thymoma; however, in comparison with controls, occurrence of this marker was frequent in MG patients (p<0.005; RR=6.2), more frequent in females (p<0.005; RR=7.8) and most frequent in EOMG female patients (p<0.005; RR=15.1). Analysis of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype and its recombinants showed that the MHC region between C4 and TNF might contain genes that influence susceptibility to MG in females. Polymorphic markers within the supratype, e.g. TNF-B*1 and C4A*Q0, might contribute to pathogenetically significant abnormalities in immune responses in a subset of female MG patients. The combined effect of other intervening genes cannot be excluded.