183 research outputs found

    A case-control analysis of common variants in GIP with type 2 diabetes and related biochemical parameters in a South Indian population

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    <p>Abstract</p> <p>Background</p> <p>Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, which plays a crucial role in the secretion of insulin upon food stimulus and in the regulation of postprandial glucose level. It also exerts an effect on the synthesis and secretion of lipoprotein lipase, from adipocytes, important for lipid metabolism. The aim of our study was to do a case-control association analysis of common variants in <it>GIP </it>in association with type 2 diabetes and related biochemical parameters.</p> <p>Method</p> <p>A total of 2000 subjects which includes 1000 (584M/416F) cases with type 2 diabetes and 1000 (470M/530F) normoglycemic control subjects belonging to Dravidian ethnicity from South India were recruited to assess the effect of single nucleotide polymorphisms (SNPs) in <it>GIP </it>(rs2291725, rs2291726, rs937301) on type 2 diabetes in a case-control manner. The SNPs were genotyped by using tetra primer amplification refractory mutation system-PCR (ARMS PCR). For statistical analysis, our study population was divided into sub-groups based on gender (male and female). Association analysis was carried out using chi-squared test and the comparison of biochemical parameters among the three genotypes were performed using analysis of covariance (ANCOVA).</p> <p>Result</p> <p>Initial analysis revealed that, out of the total three SNPs selected for the present study, two SNPs namely rs2291726 and rs937301 were in complete linkage disequilibrium (LD) with each other. Therefore, only two SNPs, rs2291725 and rs2291726, were genotyped for the association studies. No significant difference in the allele frequency and genotype distribution of any of the SNPs in <it>GIP </it>were observed between cases and controls (<it>P </it>> 0.05). Analysis of biochemical parameters among the three genotypes showed a significant association of total cholesterol (<it>P </it>= 0.042) and low density lipoprotein (LDL) with the G allele of the SNP rs2291726 in <it>GIP </it>(<it>P </it>= 0.004), but this was observed only in the case of female subjects. However this association does not remain significant after correction for multiple testing by Bonferroni's inequality method.</p> <p>Conclusion</p> <p>No statistically significant association was observed between any of the SNPs analysed and type 2 diabetes in our population. But the analysis of biochemical parameters indicates that the G allele in rs2291726 may be a putative risk allele for increased LDL cholesterol and further studies in other population needs to be carried out for ascertaining its role in cholesterol metabolism and subsequent cardiovascular risk.</p

    Gene set of nuclear-encoded mitochondrial regulators is enriched for common inherited variation in obesity

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    There are hints of an altered mitochondrial function in obesity. Nuclear-encoded genes are relevant for mitochondrial function (3 gene sets of known relevant pathways: (1) 16 nuclear regulators of mitochondrial genes, (2) 91 genes for oxidative phosphorylation and (3) 966 nuclear-encoded mitochondrial genes). Gene set enrichment analysis (GSEA) showed no association with type 2 diabetes mellitus in these gene sets. Here we performed a GSEA for the same gene sets for obesity. Genome wide association study (GWAS) data from a case-control approach on 453 extremely obese children and adolescents and 435 lean adult controls were used for GSEA. For independent confirmation, we analyzed 705 obesity GWAS trios (extremely obese child and both biological parents) and a population-based GWAS sample (KORA F4, n = 1,743). A meta-analysis was performed on all three samples. In each sample, the distribution of significance levels between the respective gene set and those of all genes was compared using the leading-edge-fraction-comparison test (cut-offs between the 50(th) and 95(th) percentile of the set of all gene-wise corrected p-values) as implemented in the MAGENTA software. In the case-control sample, significant enrichment of associations with obesity was observed above the 50(th) percentile for the set of the 16 nuclear regulators of mitochondrial genes (p(GSEA,50) = 0.0103). This finding was not confirmed in the trios (p(GSEA,50) = 0.5991), but in KORA (p(GSEA,50) = 0.0398). The meta-analysis again indicated a trend for enrichment (p(MAGENTA,50) = 0.1052, p(MAGENTA,75) = 0.0251). The GSEA revealed that weak association signals for obesity might be enriched in the gene set of 16 nuclear regulators of mitochondrial genes

    The PPARGC1A Gly482Ser polymorphism is associated with left ventricular diastolic dysfunction in men

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    <p>Abstract</p> <p>Background</p> <p>The Gly482Ser polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 alpha (<it>PPARGC1A</it>) has been demonstrated to be associated with diabetes, obesity and hypertension, all of which are important risk factors for left ventricular diastolic dysfunction.</p> <p>Methods</p> <p>The <it>PPARGC1A </it>Gly482Ser polymorphism was genotyped in a community-based cohort of 499 men and 533 women, who also underwent an echocardiographic examination to determine their left ventricular diastolic function. The association between the polymorphism and the presence of diastolic dysfunction was evaluated using logistic regression models.</p> <p>Results</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was significantly associated with a lower risk of diastolic dysfunction in men, but not in women. In a model adjusting for potential confounders (age, body mass index, leisure time physical activity, hypertension and diabetes) the results were still significant and substantial (odds ratio 0.13, 95% confidence interval 0.03–0.54, p for trend = 0.004). The results were consistent in a series of models, and they imply a multiplicative, protective effect of the Ser allele, with lower risk of diastolic dysfunction for each copy of the allele.</p> <p>Conclusion</p> <p>The Ser allele of the <it>PPARGC1A </it>Gly482Ser polymorphism was associated with decreased risk of diastolic left ventricular dysfunction in men, but not in women, in our large community-based sample. It was associated with a substantially decreased risk, even after adjustment for potential confounders. The clinical importance of the findings has to be established in further studies.</p

    Polymorphism of the FABP2 gene: a population frequency analysis and an association study with cardiovascular risk markers in Argentina

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    <p>Abstract</p> <p>Background</p> <p>The FABP2 gene encodes for the intestinal FABP (IFABP) protein, which is expressed only in intestinal enterocytes. A polymorphism at codon 54 in exon 2 of the FABP2 gene exchanges an Alanine (Ala), in the small helical region of the protein, for Threonine (Thr). Given the potential physiological role of the Ala54Thr FABP2 polymorphism, we assess in this study the local population frequency and analyze possible associations with five selected markers, i.e. glycemia, total cholesterol, body mass index (BMI), hypertension, and high Cardiovascular Risk Index (CVR index).</p> <p>Methods</p> <p>We studied 86 men and 116 women. DNA was extracted from a blood drop for genotype analysis. Allele frequencies were calculated by direct counting. Hardy Weinberg Equilibrium was evaluated using a Chi-square goodness of fit test.</p> <p>For the polymorphism association analysis, five markers were selected, i.e. blood pressure, Framingham Risk Index, total cholesterol, BMI, and glycemia.</p> <p>For each marker, the Odds Ratio (OR) was calculated by an online statistic tool.</p> <p>Results</p> <p>Our results reveal a similar population polymorphism frequency as in previous European studies, with <b>q = 0.277 </b>(95% confidence limits 0.234–0.323). No significant association was found with any of the tested markers in the context of our Argentine nutritional and cultural habits. We did, however, observe a tendency for increased Cholesterol and high BMI in Thr54 carriers.</p> <p>Conclusion</p> <p>This is the first study to look at the population frequency of the Thr54 allele in Argentina. The obtained result does not differ from previously reported frequencies in European populations. Moreover, we found no association between the Thr54 allele and any of the five selected markers. The observed tendency to increased total cholesterol and elevated BMI in Thr54 carriers, even though not significant for p < 0.1 could be worth of further investigation to establish whether the Thr54 variant should be taken into consideration in cardiovascular prevention strategies.</p

    Vitamin D levels and susceptibility to asthma, elevated immunoglobulin E levels, and atopic dermatitis: A Mendelian randomization study.

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    BACKGROUND: Low circulating vitamin D levels have been associated with risk of asthma, atopic dermatitis, and elevated total immunoglobulin E (IgE). These epidemiological associations, if true, would have public health importance, since vitamin D insufficiency is common and correctable. METHODS AND FINDINGS: We aimed to test whether genetically lowered vitamin D levels were associated with risk of asthma, atopic dermatitis, or elevated serum IgE levels, using Mendelian randomization (MR) methodology to control bias owing to confounding and reverse causation. The study employed data from the UK Biobank resource and from the SUNLIGHT, GABRIEL and EAGLE eczema consortia. Using four single-nucleotide polymorphisms (SNPs) strongly associated with 25-hydroxyvitamin D (25OHD) levels in 33,996 individuals, we conducted MR studies to estimate the effect of lowered 25OHD on the risk of asthma (n = 146,761), childhood onset asthma (n = 15,008), atopic dermatitis (n = 40,835), and elevated IgE level (n = 12,853) and tested MR assumptions in sensitivity analyses. None of the four 25OHD-lowering alleles were associated with asthma, atopic dermatitis, or elevated IgE levels (p ≥ 0.2). The MR odds ratio per standard deviation decrease in log-transformed 25OHD was 1.03 (95% confidence interval [CI] 0.90-1.19, p = 0.63) for asthma, 0.95 (95% CI 0.69-1.31, p = 0.76) for childhood-onset asthma, and 1.12 (95% CI 0.92-1.37, p = 0.27) for atopic dermatitis, and the effect size on log-transformed IgE levels was -0.40 (95% CI -1.65 to 0.85, p = 0.54). These results persisted in sensitivity analyses assessing population stratification and pleiotropy and vitamin D synthesis and metabolism pathways. The main limitations of this study are that the findings do not exclude an association between the studied outcomes and 1,25-dihydoxyvitamin D, the active form of vitamin D, the study was underpowered to detect effects smaller than an OR of 1.33 for childhood asthma, and the analyses were restricted to white populations of European ancestry. This research has been conducted using the UK Biobank Resource and data from the SUNLIGHT, GABRIEL and EAGLE Eczema consortia. CONCLUSIONS: In this study, we found no evidence that genetically determined reduction in 25OHD levels conferred an increased risk of asthma, atopic dermatitis, or elevated total serum IgE, suggesting that efforts to increase vitamin D are unlikely to reduce risks of atopic disease

    Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function

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    <p>Abstract</p> <p>Background</p> <p>Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.</p> <p>Methods</p> <p>Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor <it>(PPAR)</it>-complex genes involved in the transcriptional regulation of fatty acid metabolism.</p> <p>Results</p> <p>By linear regression analysis, 7 SNPs (4 in <it>PPARA</it>, 2 in <it>PPARGC1A</it>, 1 in <it>PPARG</it>) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of <it>P </it>values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in <it>PPARGC1A </it>and none in <it>PPARA </it>or <it>PPARG</it>. In the gene-gene analysis, significant interactions were found between rs4253655 in <it>PPARA </it>and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in <it>PPARGC1A</it>, and between rs1151996 in <it>PPARG </it>and rs4697046 in <it>PPARGC1A </it>(p = 0.01).</p> <p>Conclusions</p> <p>Myocardial metabolism <it>PPAR</it>-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.</p
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