Dataset Information

Effects of six functional SNPs on the urinary 8-isoprostane level in a general Japanese population; Shimane COHRE Study.

ABSTRACT: Oxidative stress is an important risk factor for cardiovascular diseases. Although a variety of genetic factors are assumed to contribute to the regulation of oxidative stress, evidence in human populations is insufficient. In this study, we therefore evaluated the effects of six functional single-nucleotide polymorphisms (SNPs) on the oxidative stress under a cross-sectional study design. Participants of the health examination in two neighboring counties were recruited in a mountainous region of Shimane prefeture, Japan (n=1092). As a marker for the oxidative stress, the urinary 8-isoprostane (IsoP) was measured by ELISA. The six SNPs were genotyped using the Taqman method. None of the SNPs showed a significant effect on the IsoP level. However, the Generalized Multiple Dimensionality Reduction (GMDR) method identified that the combination of the two SNPs, MTHFR C677T and eNOS T-786C, showed a significant effect on the IsoP level in this population. The linear regression analysis confirmed that the high risk genotype identified in the GMDR was an independent factor influencing the IsoP even after adjustment of confounding factors. This result suggested that GMDR analysis might be useful to identify concealed effects of combined SNPs.

SUBMITTER: Suyama Y

PROVIDER: S-EPMC3825119 | biostudies-other | 2011

REPOSITORIES: biostudies-other

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Effects of six functional SNPs on the urinary 8-isoprostane level in a general Japanese population; Shimane COHRE Study.

Suyama Yoji Y Matsuda Chikashi C Isomura Minoru M Hamano Tsuyoshi T Karino Kenji K Yamasaki Masayuki M Yamaguchi Shuhei S Shiwaku Kuninori K Masuda Junichi J Nabika Toru T

Disease markers 20110101 6

Oxidative stress is an important risk factor for cardiovascular diseases. Although a variety of genetic factors are assumed to contribute to the regulation of oxidative stress, evidence in human populations is insufficient. In this study, we therefore evaluated the effects of six functional single-nucleotide polymorphisms (SNPs) on the oxidative stress under a cross-sectional study design. Participants of the health examination in two neighboring counties were recruited in a mountainous region o ...[more]

PMID: 21725157

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Project description:BackgroundEpidemiological evidence has shown that serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations, a diagnostic biomarker for heart failure, are positively associated with cardiovascular risk. Since NT-proBNP in serum is excreted in urine, it is hypothesized that urinary NT-proBNP concentrations are correlated with serum concentrations and linked with cardiovascular risk in the general population.MethodsA total of 3060 community-dwelling residents aged ≥ 40 years without history of cardiovascular disease (CVD) were followed up for a median of 8.3 years (2007-2015). Serum and urinary concentrations of NT-proBNP at baseline were compared. The hazard ratios (HRs) and their 95% confidence intervals (CIs) for the association between NT-proBNP concentrations and the risk of developing CVD were computed using the Cox proportional hazards model.ResultsThe median values (interquartile ranges) of serum and urinary NT-proBNP concentrations at baseline were 56 (32-104) pg/mL and 20 (18-25) pg/mL, respectively. There was a strong quadratic correlation between the serum and urinary concentrations of NT-proBNP (coefficient of determination [R2] = 0.72): urinary concentrations of 20, 27, and 43 pg/mL were equivalent to serum concentrations of 55, 125, and 300 pg/mL, respectively. During the follow-up period, 170 subjects developed CVD. The age- and sex-adjusted risk of CVD increased significantly with higher urinary NT-proBNP levels (P for trend < 0.001). This association remained significant after adjustment for traditional cardiovascular risk factors (P for trend = 0.009). The multivariable-adjusted risk of developing CVD almost doubled in subjects with urinary NT-proBNP of ≥ 43 pg/mL as compared to those with urinary NT-proBNP of ≤ 19 pg/mL (HR 2.07, 95% CI 1.20-3.56).ConclusionsThe present study demonstrated that urinary NT-proBNP concentrations were well-correlated with serum concentrations and were positively associated with cardiovascular risk. Given that urine sampling is noninvasive and does not require specially trained personnel, urinary NT-proBNP concentrations have the potential to be an easy and useful biomarker for detecting people at higher cardiovascular risk.

Project description:A genome-wide eQTL analysis was performed in whole blood samples collected from 76 Japanese subjects. RNA microarray analysis was performed for 3 independent samples that were genotyped in a genome-wide scan. The correlations between the genotypes of 534,404 autosomal single nucleotide polymorphisms (SNPs) and the expression levels of 30,465 probes were examined for each sample. The SNP-probe pairs with combined correlation coefficients of all 3 samples corresponding to P < 3.10 × 10-12 (i.e., Bonferroni-corrected P < 0.05) were considered significant. SNP-probe pairs with a high likelihood of cross-hybridization and SNP-in-probe effects were excluded to exclude false positive results. We identified 102 cis-acting and 5 trans-acting eQTL regions. The cis-eQTL regions were widely distributed both upstream and downstream of the gene, as well as within the gene. RNA microarray data obtained from 3 independent samples originally recruited for other studies investigating the gene expression levels in psychiatric disorders were used in the present study. For the purpose of the present analyses, genomic DNA was collected from 24 subjects (13 men and 11 women, mean age [SD] = 39.9 [7.6] years) in sample 1, 24 subjects in sample 2 (12 men and 12 women, 34.1 [11.5] years), and 28 subjects (14 men and 14 women, 41.4 [11.8] years) in sample 3. Some of the subjects had depressive symptoms, but all were physically healthy and without clinically significant systemic disease (e.g., malignant disease, diabetes mellitus, hypertension, renal failure, or endocrine disorders). Subjects were recruited from the outpatient clinic of the National Center of Neurology and Psychiatry Hospital, Tokyo, Japan, through advertisements in free local information magazines or through our website announcement. All the subjects were biologically unrelated Japanese individuals who resided in the same geographical area (western Tokyo). The study protocol was approved by the ethics committee at the National Center of Neurology and Psychiatry, Japan. Written informed consent was obtained from every subject after the study was explained to them. Venous blood was collected between 1100 and 1200 h in PAXgene tubes (Qiagen, Valencia) from each subject and was incubated at room temperature for 24 h for RNA stabilization. RNA was extracted from whole blood according to the manufacturer’s guidelines by using the PAXgene Blood RNA System Kit (PreAnalytix GmbH, Hombrechtikon, Switzerland). The RNA was quantified by optical density readings at A260nm by using the NanoDrop ND-1000 (Thermo Scientific, Rockford). Gene expression analysis was performed using Agilent Human Genome 4 × 44 K arrays (Agilent Technologies, Santa Clara). Raw signal data for each of the 3 independent samples were analyzed separately by the GeneSpring GX software (Agilent Technologies). Data were filtered according to the expression level for quality control to eliminate genes that were below the 20th percentile threshold. The expression value of each gene was normalized to the median expression value of all genes in each chip. A total of 30,465 probes were included in the analysis. Genomic DNA was obtained from venous blood samples. Genotyping was performed by Riken Genesis (Yokohama, Japan) using the Illumina HumanOmni1-Quad BeadChip (Illumina, Inc., San Diego). A total of 713,495 autosomal SNPs were assessed for quality using the PLINK v1.07 software. All SNPs with a call rate below 95%, a deviation from Hardy-Weinberg equilibrium at an error level of P < 0.001, or a minor allele frequency of less than 10% were excluded. The remaining 534,404 SNPs were used for further analysis.

Dataset Information

Effects of six functional SNPs on the urinary 8-isoprostane level in a general Japanese population; Shimane COHRE Study.

Publications

Effects of six functional SNPs on the urinary 8-isoprostane level in a general Japanese population; Shimane COHRE Study.

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