What's new about oral treatments in Multiple Sclerosis? Immunogenetics still under question.

Multiple Sclerosis (MS) is a chronic pathology affecting the Central Nervous System characterized by inflammatory processes that lead to demyelination and neurodegeneration. In MS treatment, disease modifying therapies (DMTs) are essential to reduce disease progression by suppressing the inflammatory response responsible for promoting lesion formation. Recently, in addition to the classical injectable DMTs like Interferons and Glatiramer acetate, new orally administered drugs have been approved for MS therapy: dimethyl fumarate, teriflunomide and fingolimod. These drugs act with different mechanisms on the immune system, in order to suppress the harmful inflammatory process. An additional layer of complexity is introduced by the influence of polymorphic gene variants in the Human Leukocyte Antigen region on the risk of developing MS and its progression. To date, pharmacogenomic studies have mainly focused on the patient's response following admission of injectable drugs. Therefore, greater consideration must be made to pharmacogenomics with a view to developing more effective and personalized therapies. This review aims to shed light on the mechanism of action of the new oral drugs dimethyl fumarate, teriflunomide and fingolimod, taking into account both the importance of immunogenetics in drug response and pharmacogenomic studies.

HLA class III genes involvement in Kawasaki disease: a case-control study in Caucasian population.

Kawasaki disease (KD) is an acute, multisystemic, febrile vasculitis of unknown aetiology, which affects young children mainly under 5 years of age. The clinical variability has until now prevented to decrypt KD aetiological factors. Recently, the importance of genetics and the pivotal role of the immune system have emerged. To investigate in this direction, genomic DNA from 74 Caucasian KD cases and 440 healthy controls has been analysed to characterize functional polymorphisms of relevant HLA class III genes: AGER -429 and -374, TNF -857, -308 and -238, HSPA1A +190, HSPA1B +1267 and HSPA1L +2437. Allele, genotype and haplotype frequencies were therefore compared with the chi-squared test and Fisher's exact test. Our data showed significant deviations between patients with Kawasaki disease and controls concerning the TNF -308 polymorphism genotype (GG: P = 0.0449) and allele (G,A: P = 0.0433) and -238 polymorphism genotype frequencies (AA: P = 0.0351). Moreover, we found differences concerning the HSPA1A +190 polymorphism (GC: P = 0.0317) and the HSPA1L +2437 polymorphism (TT: P = 0.0072; TC: P = 0.0250; T: P = 0.0037; C: P = 0.0037). The calculation of TNF -238 and HSPA1L haplotype frequencies also pointed out a statistically significant decrease in patients of CG haplotype (P = 0.0001), which could have a role in protecting from the inflammatory processes that characterize the disease progression. The results obtained point to a possible involvement of the entire HLA class III region in KD susceptibility.

Response to oxidative stress of peripheral blood mononuclear cells from multiple sclerosis patients and healthy controls.

The complex scenario of multiple sclerosis (MS) pathology involves several mechanisms, including oxidative stress response. The heat shock proteins (HSPs) are important for the protection of the cells; however, their role in MS is not clear. The present research is focused on the response of peripheral blood mononuclear cells (PBMCs) to oxidative stress and to the involvement of HSP70-2 (a protein coded by the HSPA1B gene, located in the MHC class III). To this aim, we challenged PBMCs from MS patients and healthy controls with hydrogen peroxide. Specifically, PBMCs mitochondrial activity, HSP70-2 protein expression and the production of intracellular reactive oxygen species were assessed. These parameters were also related to the HSP70-2 rs1061581 polymorphism, which is linked to the risk of developing MS. Moreover, mitochondrial activity and HSP70-2 protein levels were also related to disease severity. Overall, our results indicate that PBMCs, from both MS patients and healthy controls, may display a similar response towards an oxidative insult; within this context, HSP70-2 does not seem to be central in the protection of PBMCs. Nevertheless, the HSP70-2 rs1061581 polymorphism is related to ROS levels and appears to have a role in the different expression of HSP70-2 under oxidative stimulus.

Unraveling a new player in multiple sclerosis pathogenesis: The RNA-binding protein HuR.

BACKGROUND: ELAV-like proteins are a small family of RNA-binding proteins that are fundamental players in post-transcriptional mechanisms and are involved in the pathogenesis of neurologic and psychiatric disorders. HuR, the ubiquitously expressed member of the family, is also implicated in sustaining inflammation and inflammatory diseases, supporting the production of pro-inflammatory cytokines. Inflammation plays a central role in Multiple Sclerosis (MS), which represents the most common cause of permanent physical disability in young adults. MS is a chronic autoimmune disease affecting the Central Nervous System, with a complex aetiology involving genetic, environmental and epigenetic factors. No data are available on the potential entanglement of HuR in MS pathogenesis in patients. In the present work, we aimed at exploring HuR protein levels in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to healthy controls. To further elucidate the possible involvement of HuR in MS, we also investigated the relationship between this specific RNA-binding protein and HSP70-2 protein, also considering the HSP70-2 rs1061581 polymorphism, given that HSP70-2 mRNA has been reported as a HuR target and this specific polymorphism to be associated with MS risk. METHODS: Alleles and genotypes for HSP70-2 rs1061581 polymorphism were assessed, by using a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, followed by digestion with restriction enzyme, in MS patients and healthy controls. PBMCs from a subgroup of patients and controls were used to evaluate HuR and HSP70-2 protein content by Western blot. RESULTS: PBMCs from 52 MS patients had a lower HuR and higher HSP70-2 protein content compared to 43 healthy controls. An increase of 100 units of HuR significantly decreased the risk of developing MS by 9.8% (OR: 0.902, 95% CI: 0.83-0.98), controlling for HSP70-2 protein expression, HSP70-2 rs1061581 genotype, age and sex. Moreover, holding HuR levels, an increase of 100 units of HSP70-2 protein significantly increased the MS risk by 18.1% (OR: 1.181, 95% CI: 1.03-1.36) and the genetic susceptibility of developing MS for HSP70-2 rs1061581 GG carriers is confirmed. Of interest, MS patients with a moderate to severe form of MS (MSSS ≥ 3) showed a trend towards a reduction of HuR protein levels compared to patients with mild disease severity (MSSS < 3). CONCLUSIONS: HuR protein levels are reduced in MS patients compared to healthy subjects, and the protein amount may continue to decline with disease progression, suggesting a putative role of this RNA-binding protein. Moreover, our results suggest that MS pathology may have disrupted the link between HuR and its target transcript HSP70-2. It will be important to further explore the exact role of HuR in MS, considering the complex interplay with other RNA-binding factors and target mRNAs.

CR1 genotype and haplotype involvement in coronary artery disease: the pivotal role of hypertension and dyslipidemia.

Inflammation plays a pivotal role in the pathogenesis of atherosclerosis and coronary syndromes. Atherosclerosis is a complex multifactorial disorder. Data indicate that the complement proteins play a crucial role in the link between inflammation and atherogenesis. Thus, there is evidence supporting the role of complement activation in atherogenesis. Complement receptor 1 (CR1) is a membrane protein found on different cells involved in various activities of the complement system. We demonstrated the possible involvement of CR1 in atherosclerosis studying the allele and genotype frequencies of the CR1 Pro1827Arg, CR1 His1208Arg exon 22 and int27 HindIII polymorphisms in a sample of patients with angiographically documented coronary artery disease (CAD) (n=550) and in healthy controls (n=380) matched for age, gender and ethnicity. Our data showed no significant deviations between the two groups with regard to either allele or genotype frequencies. After stratification according to risk factors, our analysis revealed a reduced frequency of the GG genotype of the Pro1827Arg polymorphism in patients with CAD and dyslipidemia vs the controls (p=0.031) and of the GG and LL genotypes in CAD patients with dyslipidemia vs CAD patients without dyslipidemia regarding the Pro1827Arg and CR1 HindIII intron 27 polymorphisms (GG, p=0.019; LL, p=0.184). We analyzed the haplotype frequencies of CR1. A decrease in CAD patients carrying the CAC haplotype compared to controls (p=0.043) and a decrease in the CAC haplotype in CAD patients with hypertension vs healthy controls (p=0.029) were demonstrated. Our data showed a possible involvement of CR1 gene polymorphisms in the predisposition to the development of this disease.

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.

MHC variation, mate choice and natural selection: the scent of evolution.

The Major Histocompatibility Complex (MHC) is considered a system completely defined and only connected with the immune response. However, in addition to the well-known correlation between MHC and the non-self recognition, the MHC region controls a lot of other functions: the recognition of genetic individuality in social relationships, the mate choice and the feto-maternal interplay. Starting from protocordates, the first MHC function was the individual self-identification inside a group, but then it turned into an inter-individual recognition system, which could transmit information about the MHC genotypes. In mammals, the MHC system is functionally and physically linked to the olfactory receptors: when smelling each other, we are able to make a direct genetic analysis through the nose. The MHC individual genetic recognition system plays a fundamental role, both in mate choice and in foeto-maternal selection, from the very start of implantation. All these data suggest that the MHC polymorphism is driven not only by pathogen selection, but also by sexual reproductive-mechanisms. Questions remain about the relative involvement of these two selective forces in MHC evolution.

The Bov-A2 retroelement played a crucial role in the evolution of ruminants.

The Bov-A2 is one of the most common short interspersed nucleotide elements (SINEs) in ruminants. The genomic distribution and evolution of this retroelement were analysed in order to highlight its possible functional role. Several regions containing an entire Bov-A2 were amplified and polymorphisms were identified by direct sequencing of the amplification products. The obtained sequences were used together with entire Bov-A2 sequences of the public database to analyse their evolutionary pathway. A site-specific micro-recombination followed by gene conversion or unequal crossing-over might be responsible for the high amount of genetic variation of Bov-A2 sequences. Short cDNAs copied by the reverse transcriptase might be the donor sequences for the micro-recombination, according to the RT-mutatorsome mechanism of the somatic hyper-mutation (SHM) process in the hypervariable regions of immunoglobulin and major histocompatibility complex (MHC) genes. The Bov-A2 is generally present in the non-coding regions of several genes preferentially expressed during the cell response to environmental stresses or activation signals. In particular, the presence of Bov-A2 sequence in the 3' untranslated regions of mRNAs involved in cell growth and differentiation during the immune response might be related to an important functional role in the post-transcriptional regulation of gene expression. This hypothesis is supported by the similarity between the conserved "core" sequences motives CACTn (n = 3, 4, 3) of Bov-A2 and elements affecting the messengers stability as several microRNAs (miRNAs). Using primers based on the "core" sequence and bovine, ovine and human cDNAs in RT-PCR experiments, we demonstrate that the mRNAs containing the "core" sequence are present at high levels in lymphocytes only after their activation. Our results suggest the existence of a system based on environmental and epigenetic signals that is able to spread and mutate the Bov-A2 sequence in the genes expressed during the response to cellular activation signals. By means of this adaptive system a reverse flow of information from environment to genes might reinforce and diversify the stress response at cellular and individual levels.

Pro-inflammatory variants of DRB1 and RAGE genes are associated with susceptibility to pediatric type 1 diabetes: a new hypothesis on the adaptive role of autoimmunity.

Functional polymorphisms of two MHC genes (DRB1 and RAGE) were analysed in Italian pediatric patients with Type 1 diabetes and in a control group. The diabetic condition is related positively to the positive electric charge of the pocket 4 of pro-inflammatory DRB1 alleles (R = 0.5072, P = 0.0001) and negatively to at least one anti-inflammatory RAGE allele (R = -0.2200, P = 0.0106). The association DRB1-disease decreases from high risk positively charged alleles to low risk negatively ones. A multiple regression model including the effect of electric charges at positions 70 and 74 of the DRB1 explains more than 31% of the variability of our data. The addition of the RAGE dependent variables does not increase the significance of the model. Our results confirm that the interaction between a negatively charged amino acid of insulin autoantigenic peptides and a positively charged DRB1 is the key event triggering the autoimmune process. The linkage disequilibrium between RAGE and DRB1 is the main cause of the association between the variants of RAGE and the initial outcome of the disease. However, since RAGE ligands increase during the disease progression, the observed association suggests that the proinflammatory RAGE and DRB1 polymorphisms synergize to activate the immune response which leads to the complications of diabetes. These evidences support a new hypothesis that considers the largely unexplored role of the MHC genes in genetic adaptation to a variable environment and in the maintenance of the metabolic biodiversity. A mechanism based on the maternal immunization against the negatively charged autoantigens, such as the insulin peptide B9-23, and on the fetal-maternal interaction might transform the physiological adaptation into adaptive changes of the genetic population structure. According to the "thrifty-genotype" hypothesis, "thrifty DRB alleles" with a positive charge are responsible for the susceptibility to diabetes and for an efficient storage of caloric intake in arctic climates with scarce food availability while "non-thrifty DRB alleles" with a negative or neutral charge are advantaged in tropical climates with constant food supply.

Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients.

BACKGROUND/OBJECTIVES: Increasing evidence suggests the importance of neuroinflammation in the pathogenesis of Alzheimer's disease (AD), which is a complex neurodegenerative disorder. Complement activation occurs in the brain of patients with AD and seems to contribute to an important local inflammatory state. Increased expression of the fourth serum complement component 4 (C4) has been observed in AD patients in many studies. This protein has two isoforms, encoded by two genes: C4A and C4B localized to the HLA class III region. These genes exhibit copy number variations (CNVs) and this different gene copy number can influence C4 protein levels. We focalized our attention on these two genes, determining the distribution of CNVs in AD patients, compared with healthy controls, in order to analyse their possible involvement in AD pathogenesis. METHODS: We investigated 191 AD patients and 300 healthy controls. The C4A and C4B copy numbers were assessed by quantitative PCR (qPCR). RESULTS: The results obtained showed a statistically significant increase in the number of copies for both C4A and C4B in AD patients, compared with healthy controls (p<0,001). CONCLUSION: The presence of high C4A and C4B copy numbers in AD patients could explain the increased C4 protein expression observed in AD patients, thus highlighting a possible role for C4A and C4B CNVs in the risk of developing AD.

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.

-374T/A polymorphism of the RAGE gene promoter in relation to severity of coronary atherosclerosis.

BACKGROUND: We have recently reported that homozygosity for the minor A-allele of RAGE (receptor for advanced glycation end products) -374T/A polymorphism may exert a protective effect toward the development of angiographic coronary artery disease (CAD). Here we focused on the putative involvement of this functional RAGE polymorphism on the severity of coronary atherosclerosis as assessed by angiography. METHODS: In a total of 234 consecutive Caucasian patients with angiographically proven CAD, the severity of coronary atherosclerosis was assessed by the number of diseased vessels (greater than 50% stenosis). Genotyping for the -374T/A variant was performed by means of PCR-RFLPs. RESULTS: The mean number of diseased vessels was significantly lower in patients with the AA genotype (1.47+/-0.68) than in those with the AT or TT genotype (1.88+/-0.82, p=0.029). After confounding variables were controlled for, the number of diseased vessels remained significantly different in the AA genotype carriers from that in the AT or TT carriers (p=0.041, ANCOVA). CONCLUSIONS: Our data suggest that the RAGE -374T/A polymorphism is one of the likely candidate determinants for the genetic variance of disease phenotype in coronary atherosclerosis.

The Possible Involvement of HLA Class III Haplotype (RAGE, HSP70 and TNF Genes) in Alzheimer's Disease.

In the central nervous system Hsp70s seems to have a protective role in repair and removal of cellular proteins damaged by stress conditions. A protective role of Hsp70 was also shown in Alzheimer Disease. The HSP70-1 +190 G/C polymorphism is located in the gene 5'UTR region and it is implicated in alteration of the transcription binding factor; HSP70-2 +1267 A/G causes a silent mutation in the coding region and it seems to influence the mechanism of mRNA translation; HSP70-hom +2437 A/G causes a substitution Met → The (M493T) in the coding region and it seems to influence the bond with the substrate and therefore on the chaperone activity of hsp70. The aim of our study will be to investigate Alzheimer susceptibility to Hsp70 polymorphisms, taking into account our previous findings on HLA class III region, and to hypothesize a role of HLA class III haplotype configuration based on the variants of three genes: RAGE, HSP70 and TNF. We studied these polymorphisms with PCR-RFLP and PCR-TSP. We investigated 173 AD patients and 211 control subjects. Our results have shown a statistically significant decrease of the C allele frequency of the HSP70-1 +190 G/C polymorphism in AD patients vs controls (P value = 0,018), as well as the G allele of HSP70-2 +1267 G/A (p value = 0,02). We focalized our attention on haplotype reconstruction. We have observed a significant statistically decrease of GGT haplotype frequency (empirical p-value=0.0133 ); GAT haplotype was statistically significant increase in AD patients compared with control (empirical p-value=0.007). The total HLA class III haplotype are reconstructed. The causative haplotypes are the following ones: TTGATGGG ( p value =0,005; empirical p =0,0042); TTGATAGG (p value =0,45; empirical p =0,034). Patients with these haplotypes may show an earlier onset of the disease than patients with TTGGTGGG (p value=0,0138; empirical p =0,0102); TTCGTGGG (p value=0,021; empirical p =0,017); TTCGTGGA (p value =0,058; empirical p =0,043) haplotypes. The overall variation of the haplotypes formed by the RAGE and TNF and HSP70 variants influenced the presence of the AD phenotype (omnibus association LR test p-value 0.00185), HSP701 and HSP702 showed independent effect on AD risk after adjusting for the effect of the entire haplotype (conditional LR test p-value=0.0114 and p-value=0.0044 respectively). These data confirm the involvement of HLA class III in AD.

Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?

We investigated whether molecular defects in the CYP21 gene were detectable in two common sex chromosome aberrations, the Turner and the Klinefelter syndromes. We found abnormal 17-hydroxyprogesterone levels after adrenal stimulation in 26/60 (43.3%) patients affected by these chromosome aberrations, as compared with only 11/68 (16.2%) normal controls (P=0.0014, odds ratio 4.0). Screening of the CYP21 gene identified a single Val281Leu missense mutation in exon 7 in 9/63 (14.3%) of the patients, all nine of whom were heterozygote carriers; the mutation frequency was significantly higher than in the general population (P=0.007, odds ratio=3.5). The hormonal and molecular data indicate that these common sex chromosome aberrations are associated with a remarkably high frequency of steroidogenic defects. It may be hypothesised that reduced levels of steroid 21-hydroxylase could confer a survival advantage, leading to a successful pregnancy.

Evaluation of gene expression in human lymphocytes activated in the presence of melatonin.

The effect of melatonin on the expression of genes previously correlated to T lymphocyte activation (HLA-DRB, thymosin beta 10 (beta-Tim)) and to Lymphokine Activated Killer (LAK) activity (beta-Tim, Tumour Rejection Antigen (TRA 1), nRap 2) was investigated in phytohemagglutinin (PHA)-stimulated human lymphocyte cultures. The aim was to find an enhancing effect of this substance on anti-tumoral immune defences as suggested by studies on tumour progression in mice and clinical immunotherapy trials in humans. mRNA obtained from melatonin-treated and -untreated PHA-stimulated lymphocytes was retrotranscribed and amplified by RT-PCR using primers based on the sequences of the selected genes. The results suggest that melatonin does not increase T and LAK cell responses: in fact, a reduction in the transcription of all the considered genes was observed. These data are correlated with the antiproliferative effect of melatonin observed in in vitro treated lymphocytes.

HLA and sarcoidosis: new pathogenetic insights.

Many theories have been presented to account for the immunological and epidemiological features of sarcoidosis; several lines of study support the prevailing opinion that an environmental agent, possibly microbial in origin, may cause sarcoidosis in a genetically predisposed host. Many polymorphic genes have been suggested to contribute to this genetic susceptibility: genes encoding angiotensin converting enzyme, vitamin D receptor, and interleukin-1, T-cell receptor genes, Gm and Km immunoglobulin genes and, most relevant, HLA genes (classical and non classical). There is also some evidence of an HLA-associated protection against sarcoidosis. The main action of disease-associated HLA molecules is to present specific antigenic peptides in such a way that the recognizing T-lymphocytes initiate an inflammatory response with peculiar pathological consequences. Other, so-called, non-classical HLA genes coding for proteins involved in antigen processing and presentation, namely TAP, LMP and DM, seem to contribute. Particular alleles of the tumor necrosis factor gene cluster (TNFA, LTA, LTB) are known to be associated with peculiar clinical forms of sarcoidosis. For instance, Löfgren's syndrome, which is an acute form of pulmonary sarcoidosis with frequent spontaneous remission, is marked by the TNFA*2, HLA-DR3 haplotype. How many HLA genes are involved is still unknown, but it is now clear that the HLA region is strongly implicated in the development of sarcoidosis. Probably, the future lies in isolating and sequencing the putative peptide bound to susceptible MHC molecules which, activating reactive T-cells, is responsible for disease initiation and/or exacerbation. However, the investigative approach should not be confined only to genomic sequences: the temporal and spatial expression of gene products, the post-transcriptional modification of the protein products will be fundamental in determining the basic functional context of developing sarcoidosis.

Relationship between the -374T/A RAGE gene polymorphism and angiographic coronary artery disease.

The receptor for advanced glycation end products (RAGE) is thought to play a critical role in diabetic atherosclerosis. Accordingly, a functional -374T/A polymorphism in RAGE gene promoter has been associated with macrovascular complications in type 1 diabetic patients. However, the extent to which this common variant influences the risk of coronary artery disease (CAD) in the general population remains to be determined. We genotyped the -374T/A RAGE polymorphism in 259 non-diabetic individuals, of whom 175 had angiographically documented coronary artery disease (CAD patients) and 84 had normal coronary angiography (CAD-free control subjects). Homozygosity for the -374A allele was found in 9.7% of the CAD patients versus 22.6% of the CAD-free subjects (p=0.005). By means of a multiple logistic regression analysis, the AA genotype of the -374T/A polymorphism was shown to be independently associated with a reduced risk of CAD (adjusted odds ratio 0.33, 95% CI 0.15 to 0.73; p=0.006). Our observations suggest that the -374T/A polymorphism of the RAGE gene may reduce susceptibility to CAD, thus exerting a protective effect on coronary risk. Future pathophysiological studies may be worthwhile to clarify the mechanisms behind this association.

Parental GM and HLA genotypes and reduced birth weight in patients with Turner's syndrome.

We investigated a possible influence on birth weight in Turner's syndrome of many clinical, hormonal, genetic and immunogenetic variables. We considered 97 patients with Turner's syndrome. Patients with parents with identical GM (Gamma heavy chains Marker) phenotype had a significantly lower birth weight than those with parents with different GM phenotype. Karyotype other than 45,X, HLA (Human Leukocyte Antigen) parental sharing, mother-patient compatibility and elevated 17-hydroxyprogesterone (17OHP) serum level after adrenocorticotropin hormone (ACTH) and absence of heart and kidney malformations and lymphedema were associated with a lower birth weight, but not significantly. Multiple interactions showed that the presence of an identical GM phenotype in parents, together with other conditions (karyotype other than 45,X, adrenal dysfunction, HLA parental sharing, mother-child compatibility, KM(3) [Kappa light chains Marker] phenotype) resulted in a further decrease of birth weight. These data might suggest a negative effect of genetic similarity on intrauterine growth in Turner's syndrome.

[Chronic fatigue syndrome: a review]. / La sindrome da stanchezza cronica.

Chronic fatigue sindrome is a relatively unknown and underdiagnosed entity in Italy where its epidemiology remains uncertain, as well as its etiology, although it causes important disability in those affected. Classification criteria by Fukuda are available to diagnose the syndrome. Its epidemiology indicates that it is probably more frequent in Northern countries and it is described in Gulf War veterans. Etiological hypotheses include infectious diseases, immunology and neurology. Among these hypotheses sickness behavior mimes certain aspects of this syndrome and is characterized by a cytokine imbalance in the central nervous system and in the periphery. There are no valid therapies available at the moment. In the laboratory of Immunogenetics, we are constituting a biological bank of the syndrome to study the immunogenetic aspects of the disease in the hope of delucidating some of the obscure areas of its etiopathogenesis.

Are Hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation?

Genetic and environmental factors contribute to disease Multiple Sclerosis (MS) susceptibility, the most prevalent neurological pathology affecting young individuals in Western countries. We focused our attention on HSP70-2, an inducible chaperon induced under stress conditions. Genotype analysis of HSP70-2 (+1267 A/G) polymorphism revealed a significant association between the minor allele G and presence of MS (OR:1.31, 95% CI: 1.02-1.69, P = 0.039). In addition, Hsp70-2 protein content in vitro from PBMC was significantly lower in MS patients with GG genotype compared to AA genotype, indicating an implication of the G allele of HSP70-2 gene polymorphism in the development of MS.