Both biochemical and genetic evidence have implicated the genes for TNF-alpha (TNFA) and lymphotoxin-alpha (LTA) in atopic asthma. Here, we report for the first time the association of their genotypes and haplotypes with atopic asthma in Indian populations. We genotyped seven single nucleotide polymorphisms, encompassing the two genes, in patients and control subjects in two independent cohorts. Serum TNF-alpha levels of selected individuals were measured and correlated with genotypes and haplotypes. The A allele of the TNFA-863C > A polymorphism was associated with reduced risk of asthma (P = 0.002 and 0.007 in Cohorts A and B, respectively), reduced TsIgE levels (P = 0.0024 and P = 0.0029 in Cohorts A and B, respectively), and reduced serum TNF-alpha levels (P < 0.05). A marginal association was also observed for LTA_NcoI polymorphism with asthma and TsIgE levels. Furthermore, analysis using HAPLO. STATS showed significant differences in the major haplotype frequencies (> 3%) between patients and control subjects (P = 0.002 and P = 0.006 for Cohorts A and B, respectively). Individually, the haplotype GATCCG was the most frequent in patients (P = 0.0029 and P = 0.0025 for Cohorts A and B, respectively), and was associated with high TsIgE and serum TNF-alpha levels, whereas AACACG was the most frequent in the control subjects (P = 0.0032 and P = 0.022 for Cohorts A and B, respectively), and was associated with low TsIgE and serum TNF-alpha levels. We also report here that the C > A substitution at position -863 of the TNFA influences the binding of nuclear proteins in electrophoretic mobility shift assay experiments. Thus, the TNFA-863C > A polymorphism in the promoter region of TNFA may influence TNF-alpha expression and affect TsIgE levels and susceptibility to asthma.

OBJECTIVE: Tumor necrosis factor-a (TNF-a) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. Recently, the A allele of a polymorphism in the 5H -¯anking region of the TNF-a gene (G7308A) has been reported to be more frequent in obese than in lean subjects and has also been associated with increased expression of this cytokine in fat tissue and in¯uences fat mass and insulin resistance. We, therefore, examined the relationship between this variant and obesity in a German Caucasian population. SUBJECTS AND METHODS:We genotyped 176 index subjects recruited within the framework of the BErG (Berlin Erna Èhrung Geschwister)-Study for the TNF-a-G7308A polymorphism. Subjects were characterized for weight, height, waist and hip circumference, body mass index (BMI), body composition, glucose tolerance, leptin and angiotensinogen levels. RESULTS: The frequency of the 7308A allele (0.18) was similar to that reported previously and genotype distribution was in Hardy ± Weinberg equilibrium (GG, n 118; GA, n 53; AA, n 5). There was a signi®cant difference in allele frequencies of the polymorphism by BMI quartiles (I,`27.3 kgam 2 ; II, 27.3 ± 31.9 kgam 2 ; III, 31.9 ± 36.5 kgam 2 ; IV, b 36.5 kgam 2 , in each quartile n 44) with 7308A allele carriers having a higher BMI than G allele carriers (P 0.013). Despite previous smaller studies that have related insulin resistance to the G7308A polymorphism, we found no relationship between glucose and insulin response during an oral glucose tolerance test (OGTT) and the polymorphism. Furthermore, none of the plasma parameters were related to the polymorphism. CONCLUSION: Our ®ndings support the hypothesis that the G7308A polymophism of the TNF-a gene is associated with BMI. The G7308A polymorphism may, therefore, represent a genetic marker for increased susceptibility for obesity in Caucasians.

The integrin alpha(v)beta3 has been shown to act as the receptor for internalization of foot-and-mouth disease virus (FMDV) (A12), with attachment being through a highly conserved RGD motif located on the G-H loop of viral capsid protein VP1. In addition, however, we have recently shown that efficient infection of culture-grown cells by FMDV (O1BFS) requires binding to cell surface heparan sulfate. In this study, we have used a solid-phase receptor binding assay to characterize the binding by FMDV to purified alpha(v)beta3 in the absence of heparan sulfate and other cell surface components. In this assay, FMDV (O1BFS) successfully replicated authentic ligand binding by cellular alpha(v)beta3 in terms of its high affinity, dependence on divalent cations, and activation by manganese ions. Virus binding to this preparation of alpha(v)beta3 was exquisitely sensitive to competition by short RGD-containing peptides (50% inhibition at < 10(-8) M peptide), and this inhibition was highly sequence specific, with the equivalent RGE peptide being at least 10(4) fold less effective as a competitor. Representative viruses of the other six serotypes of FMDV bound to alpha(v)beta3 in a similar RGD-specific manner, although significant differences in sensitivity to RGD peptides suggest that the affinity of the different FMDV serotypes for alpha(v)beta3 is influenced, in part, by the variable amino acid residues in the VP1 G-H loop on either side of the RGD.

Two key findings regarding the cardiovascular risks associated with obesity have emerged in recent years: one relates to the importance of visceral obesity as a risk factor for cardiovascular disease, and the other to the recognition that adipose tissue can be regarded as a large endocrine organ that directly contributes to cardiovascular risk by secreting a number of molecules known to modulate vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system. Therefore, abdominal fat deposition, which is characterized by increase in waist circumference, should be the target of clinical intervention in obese individuals.