Lack of clear and univocal genotype-phenotype correlation in familial Mediterranean fever patients: A systematic review.

Familial Mediterranean fever (FMF) is the most common autosomal recessive autoinflammatory disease. To date, following the isolation of more than 280 MEFV sequence variants, the genotype-phenotype correlation in FMF patients has been intensively investigated; however, an univocal and clear consensus has not been yet reached. Thus, the aim of this systematic review was to analyze the available literature findings in order to provide to scientific community an indirect estimation of the impact of genetic factors on the phenotypic variability of FMF. This systematic review has been conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. The p.M694V mutation was reported to have a relatively severe clinical course, similarly, patients homozygous for M694I and M680I, or carrying a combination of both at codons 694 and 680, have a severe disease. Also, patients homozygous for M694V and V726A variants experienced more severe clinical picture. Conversely, heterozygous p.V726A and p.E148Q genotypes have been correlated with a milder disease course. At present, doubts remain on the potential pathogenic role of E148Q variant. The heterogenity in clinical FMF manifestations reflects the changes occuring in repertoire of mutations. We believe that clinical criteria and gene tests, enhancing each other, could better support the diagnosis of FMF.

Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance?

BACKGROUND: Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. OBJECTIVE: To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. METHODS: A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. RESULTS: 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. CONCLUSIONS: The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF.

TLR4 and NOD2/CARD15 genetic polymorphisms and their possible role in gastric carcinogenesis.

UNLABELLED: The aim of this study was to evaluate the role of TLR4 and NOD2/CARD15 genes in gastric carcinogenesis. PATIENTS AND METHODS: We investigated the allelic frequencies of TLR4 (D299G and T399I) and NOD2/CARD15 (R702W, G908R, and L1007finsC) SNPs in 87 asymptomatic serologically H. pylori-positive individuals (Group I), in 63 patients with antrum-predominant gastritis (Group II) and in 60 patients with corpus-predominant gastritis or pangastritis (Group III). RESULTS: There was significant difference in allelic frequencies of TLR4 D299G SNP in Group II (p=0.02; OR 2.97) as well as in Group III (p=0.001; OR 4.80). Significant difference of T399I SNP allele frequency was only found in Group III (p=0.009; OR 3.73). The allele frequencies of NOD2/CARD15 G908R and of L1007insC SNP were higher in Group III (p=0.003, OR 5.18; p=0.03; OR 3.66, respectively). CONCLUSION: TLR4 and NOD2/CARD15 genes are associated with high risk Group III patients and, therefore, they appear to play a role in gastric carcinogenesis.

Molecular analysis of the CART gene in overweight and obese Italian children using family-based association methods.

AIM: In our study, we evaluated if CART gene A1475G and DeltaA1457 polymorphisms could be associated with obesity. PATIENTS AND METHODS: We recruited 133 Italian trios from among 103 (50 males and 53 females) overweight children (mean age 10.5 years, range 6-14 years; mean BMI 26.1 +/- 3.2 kg/m(2)), and 30 (16 males and 14 females) obese children (mean age 9.0 years, range 6-11 years; mean BMI 32.3 +/- 2.0 kg/m(2)). We also selected 187 non-obese unrelated controls. RESULTS: The allele frequencies of the A1475G single nucleotide polymorphism (SNP) were significantly higher in overweight children (0.07) than in control children (0.02) (p = 0.03) and control adults (0.02) (p = 0.02). Moreover, the allele frequencies were significantly different between obese children (0.08) and control children (0.02) (p = 0.03), and between obese children (0.08) and control adults (0.02) (p = 0.02). The DeltaA1457 SNP showed no significant association with overweight/obesity. TDT statistic revealed a preferential transmission of the 1475G allele from heterozygous parents to overweight children (p < 0.01) and to obese children (p < 0.05). No statistically significant excess transmission of the DeltaA1457 allele was found. CONCLUSION: Our results supported the hypothesis that inherited variations of the CART gene could influence the development of obesity also in Italian children.

Investigation of the eotaxin gene -426C-->T, -384A-->G and 67G-->a single-nucleotide polymorphisms and atopic dermatitis in Italian children using family-based association methods.

BACKGROUND: Eotaxin plays an important role in atopic dermatitis (AD) as a potent chemoattractant and activator of eosinophils and T-helper 2 lymphocytes. AIM: To investigate whether single-nucleotide polymorphisms of the eotaxin gene are associated with AD, we investigated the genotype and allelic frequencies of -426C-->T, -384A-->G, and 67G-->A SNPs in 130 Italian families. METHODS: In total, 130 children with either the extrinsic allergic or intrinsic nonallergic forms of AD (EAD and IAD) were recruited from 130 families. Genotyping was performed using PCR and restriction fragment length polymorphism analysis. RESULTS: A significant difference was observed in the genotype frequency of the -426C-->T SNP between children with EAD and those with IAD (P = 0.01), and between children with EAD and controls (P = 0.01). The allele frequencies of the -426C-->T SNP were significantly different between children with EAD and those with IAD (P < 0.01), and between children with EAD and controls (P < 0.01). For children with EAD, the genotype frequency of the -426C-->T SNP was no different between the groups with mild, moderate and severe SCORAD (P = NS). No significant association was observed between the -384A-->G and 67G-->A SNPs and the two groups of children with EAD and IAD compared with the control group. In 32 trios selected from 68 EAD families, the transmission disequilibrium test showed a preferential transmission of the -426T allele from the parents to affected offspring (P < 0.01). CONCLUSIONS: Our results suggest that in our group of children with AD, the eotaxin gene may play a crucial role in the development of extrinsic AD, probably with other genetic factors.

Peripheral tissue release of interleukin-6 in patients with chronic kidney diseases: effects of end-stage renal disease and microinflammatory state.

To examine if uremia influences muscle interleukin-6 (IL-6) metabolism we studied the exchange of IL-6 across the forearm in 16 patients with chronic kidney disease (CKD) (stages 3 and 4), in 15 hemodialysis (HD)-treated end-stage renal disease (ESRD) patients (n=15), and in six healthy controls. In addition, we performed an analysis of both IL-6 protein and IL-6 mRNA expression in muscle of CKD (stage 4) patients showing evidence of inflammation and in controls. A release of IL-6 from the forearm was observed in patients with elevated IL-6 plasma levels. Arterial IL-6 was directly related to released IL-6 (r=0.69; P<0.004) in HD patients. Both IL-6 protein and IL-6 mRNA expression were increased in muscle of inflamed CKD patients vs controls (P<0.05). Although muscle net protein balance was similar in all patients, it was significantly more negative in HD patients with high than in those with low IL-6 plasma levels (P<0.05). In addition, net protein balance was related to the forearm release of IL-6 in HD patients only (r=0.47; P<0.038). These data demonstrate that IL-6 expression is upregulated in muscle, and that muscle tissue, by releasing this cytokine, may contribute to the inflammatory response in HD patients. The release of IL-6 from peripheral tissues is associated with an increase in muscle protein loss in HD patients, suggesting that muscle release of IL-6 is linked to protein catabolism in these patients. The release of IL-6 from peripheral tissues may act as a signal for the inflammatory response and contribute to functional dysregulation in uremia.

Gender and the progression of chronic renal diseases: does apoptosis make the difference?

Several studies in patients with chronic kidney diseases have shown that men have a more rapid disease progression than women. Also, with ageing, men exhibit greater decrements in renal function and increased glomerular sclerosis than women. Data from meta-analysis studies indicate that women with several non-diabetic renal diseases such as membranous nephropathy, IgA nephropathy and polycystic kidney disease present a slower progression, but in diabetic renal disease this is not yet established. Thus, men appear to be at greater risk for renal injury than are women, but the underlying mechanisms are unknown. Sex hormones may mediate the effects of gender on chronic renal disease, through the interaction with the renin-angiotensin system, the modulation of nitric oxide synthesis and the downregulation of collagen degradation. New observations indicate that androgens may contribute to continuous loss of kidney cells though the stimulation of apoptotic pathways. Apoptosis is an unique type of programmed cell death which is activated in several chronic kidney diseases. Studies in vitro indicate that androgens prime a Fas/FasL dependent apoptotic pathway in kidney tubule cells. This apoptotic cell death pathway is receptor-linked and interacts with the mitochondrial pathway, which may be activated by other mechanisms, such as toxins and ischemia. Therefore, the mechanisms to cell death which are primed by androgens may interact with others occurring in several conditions leading to the loss of renal cells. These findings are consistent with a role for androgens to promote chronic renal injury in men.

Molecular analysis of sequence variants in the Fcepsilon receptor I beta gene and IL-4 gene promoter in Italian atopic families.

BACKGROUND: The genetic variants in the Fcepsilon receptor I beta gene (Glu237Gly) and the T allele of the (C590T) polymorphism of interleukin (IL)-4 gene promoter were reported to be associated with atopy. But the data of the studies in different populations are contrasting with one another. METHODS: A group of 25 Italian nuclear families were studied. In each family at least two allergic subjects were present. The allergic children were 65 and the allergic relatives were 35. One hundred and three nonallergic unrelated controls included outpatiens with no history of atopy. The (C590T) promoter polymorphism of the IL-4 and the genetic variant Glu237Gly of Fcepsilon RI beta genes were analysed by the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: A significant difference was observed in the genotype frequency at codon 237 of the Fcepsilon RI beta gene between allergic children and nonatopic control (P < 0.01) and in the allergic relatives (P < 0.001). In the children, the Glu237Gly polymorphism was also associated with elevated circulating levels of immunoglobulin E. The -590C/T allele of IL-4 promoter gene showed no association with atopy. CONCLUSIONS: In our study, the Glu237Gly polymorphism of the Fcepsilon RI beta gene was associated with atopy. Our results have not pointed out an association between the (C590T) promoter polymorphism of the IL-4 gene and atopy. These data suggest the potential role of the Fc RI beta gene in the development of the allergy.