Urate is the terminal product of purine metabolism in primates, including humans. Urate is also an efficient scavenger of oxidizing species and is thought to be an important antioxidant in human body fluids. Allantoin, the major oxidation product of urate, has been suggested as a candidate biomarker of oxidative stress because it is not produced metabolically. Although urate is converted to allantoin under strongly alkaline pH, such conditions have been used in the past to facilitate extraction of allantoin. We evolved a method for the determination of allantoin concentrations in human plasma and serum by gas chromatography-mass spectrometry without such artifact. With this method, we show that alkaline conditions do indeed cause breakdown of urate, leading to significant overestimation of allantoin concentration in human samples. By using our alternative method, serum samples from 98 volunteers were analyzed, and allantoin levels were found to be significantly lower than was previously reported. The in vivo utility and sensitivity of our method was further evaluated in human nasal-lining fluids. We were able to demonstrate an ozone-induced increase in allantoin, in the absence of increases in either ascorbate or glutathione oxidation products.
The length of female reproductive lifespan is associated with multiple adverse outcomes, including breast cancer, cardiovascular disease and infertility. The biological processes that govern the timing of the beginning and end of reproductive life are not well understood. Genetic variants are known to contribute to ∼50% of the variation in both age at menarche and menopause, but to date the known genes explain <15% of the genetic component. We have used genome-wide association in a bivariate meta-analysis of both traits to identify genes involved in determining reproductive lifespan. We observed significant genetic correlation between the two traits using genome-wide complex trait analysis. However, we found no robust statistical evidence for individual variants with an effect on both traits. A novel association with age at menopause was detected for a variant rs1800932 in the mismatch repair gene MSH6 (P = 1.9 × 10−9), which was also associated with altered expression levels of MSH6 mRNA in multiple tissues. This study contributes to the growing evidence that DNA repair processes play a key role in ovarian ageing and could be an important therapeutic target for infertility.
BackgroundThe effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk.Methodology/Principal FindingsThe study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs) in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint P trend = 1.2×10−6).ConclusionsOur study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.
Background and Purpose-Increased total homocysteine (tHcy) is a risk factor for stroke. This study examines whether the efficacy of B-vitamins in reducing tHcy is modified by ethnicity in a Singaporean ischemic stroke population. Methods-505 patients (419 Chinese, 41 Malays and 45 Indians) with ischemic stroke were randomized to receive placebo or B-vitamins. Fasting blood samples collected at baseline and 1 year were assayed for tHcy. MTHFR polymorphisms were genotyped. Results-Ethnicity did not independently determine tHcy at baseline.
Background-Previous studies on familial risk of ischemic stroke have supported genetic influence on the disease incidence. This study aimed to characterize these familial effects in a nationwide population-based study by taking into account sibling relations, sex of siblings, and age of onset, with respect to ischemic stroke incidence. Methods and Results-Incident ischemic stroke cases identified from the Swedish Hospital Discharge and Cause of DeathRegisters between 1987 and 2007 were linked to their stroke-free siblings (study participants), forming an exposed sib-pair. Each exposed sib-pair was matched up to 5 unexposed sib-pairs from the Multi-Generation Registry by birth and calendar years. Incident ischemic stroke risk was assessed using hazard estimates obtained from stratified Cox regression analyses. A total of 30 735 exposed and 152 391 unexposed study participants were included in the analyses. The overall risk of incident ischemic stroke when exposed was significantly increased (relative risk, 1.61; 95% confidence interval, 1.48 -1.75; PϽ0.001). Familial risk was higher in full (relative risk, 1.64; 95% confidence interval, 1.50 -1.81; PϽ0.001) than in half (relative risk, 1.41; 95% confidence interval, 1.10 -1.82; Pϭ0.007) siblings. Familial risk of early ischemic stroke almost doubled when exposed to early ischemic stroke (relative risk, 1.94; 95% confidence interval, 1.41-2.67; PϽ0.001). Conclusions-There was a 60% increased risk for ischemic stroke in individuals having a sibling with prior stroke. The familial effect was even higher for full-sibling relations. Familial effects were observed in both male and female individuals, and no differential effects depending on the sex of either of the siblings were found. (Circ Cardiovasc Genet. 2012;5:226-233.)Key Words: epidemiology Ⅲ family history Ⅲ heritability Ⅲ ischemic stroke Ⅲ sex T he evidence for ischemic stroke being a heritable disease has increased over the years, with increasing number of studies showing familial aggregation of stroke. Family and twin studies have suggested genetic influence in the susceptibility to ischemic stroke, 1-5 but the number of genetic variants associated with stroke is modest. 6 -8 Twin studies provide data suggesting strong familial inheritance of stroke risk. [1][2][3][4][5] Concordance rates of stroke are significantly higher in monozygotic twins compared with dizygotic twins of approximately 5-fold increase in stroke prevalence between the 2. 1,2 Clinical Perspective on p 233Paternal and maternal history of stroke has been associated with increased stroke risk. 3 Self-reported family history may be highly inaccurate owing to significant reporting or misclassification bias when compared with a validated family history. A systematic review found few studies carried out with detailed stroke phenotype, consideration of the number of affected or unaffected relatives, and influence of family history on stroke development. 9 A population-based study carried out in Sweden a few years ago teased out the difference of...
Genome‐wide association studies have successfully identified many novel genetic loci for various human complex diseases and quantitative traits. There are several important factors contributing to the feasibility of this approach; one of them is the rapid advancement in high‐throughput single nucleotide polymorphisms (SNPs) genotyping technologies which has enabled researchers to comprehensively interrogate the entire human genome. Almost all the studies that have been published up to date used commercially available whole‐genome genotyping arrays from Illumina® and Affymetrix®. The most prominent feature of these high‐throughput genotyping platforms is the ability to interrogate several hundred thousands to one million SNPs simultaneously in a microarray. The application of genotyping arrays is not only limited to association studies, but it has also been applied to many other human genetic studies. However, the rapid developments of sequencing technologies have started replacing the microarray experiments for both structural and functional genomics studies. Key concepts: Over the past three years, GWAS have been playing an important role in identifying novel genetic loci for various human complex diseases and quantitative traits. The paradigm shift in genetic approach to GWAS has been attributed to several important developments, notably the rapid advancement in high‐throughput SNPs genotyping technologies. High‐throughput SNPs genotyping technologies had enabled researchers to interrogate several hundred thousands to one million SNPs simultaneously in a microarray. GWAS is a comprehensive and agnostic approach in the search for unknown disease variants, as such; the ability to interrogate large number of SNPs covering the entire human genome is a prerequisite to this study design. Currently, Illumina® and Affymetrix® are the only two companies in the market who design and provide whole‐genome genotyping arrays for human genetic studies. There are two commonly adopted approaches in SNPs selection for whole‐genome genotyping arrays: direct and indirect. Direct approach focuses on selecting SNPs that are of putative functional importance. In contrast, indirect approach selects SNPs despite their functionality. Genome coverage is an estimate of the proportion of SNPs (using the International HapMap data as reference) that can be captured by the SNPs which directly genotyped in an array with a preset r 2 threshold. Expeditious developments of sequencing technologies have started threatening the market of microarray. Currently, the three next‐generation sequencing platforms are Illumina® Genome Analyzer, Roche® 454 GS‐FLX Sequencer and ABI® SOLiD Sequencer. Sequencing approach has been quickly adopted for various applications in structural and functional genomic studies, for example, ChIP‐Seq, transcriptome profiling (RNA‐Seq) and paired‐end sequencing method to detect structural variations.
Background: Recent genome-wide association studies suggest some overlap of genetic determinants of ischemic stroke (IS) and myocardial infarction (MI). This study aimed to assess shared familial risk between IS and MI in a large, population-wide cohort study.Methods: Study participants free of IS and MI and their affected siblings were extracted from the Swedish Hospital Discharge and Cause of Death Registers between 1987 and 2007, forming an exposed sib-pair. They were matched by birth year of both siblings and calendar period to up to five unexposed sib-pairs. Stratified Cox regression analyses were used to assess familial risk of MI and IS in those exposed to having a sibling with IS (n = 31,659) and MI (n = 62,766), respectively, compared to unexposed (n = 143,728 and 265,974).Results: The overall risk of MI when exposed to having a sibling with IS was statistically significantly increased (RR, 1.44; 95% CI, 1.34–1.55, p < 0.001) to a similar extent as risk of IS when exposed to having a sibling with MI (RR, 1.41; 95% CI, 1.32–1.50, p < 0.001). The familial risks were similar in full siblings for both groups (RR for MI, 1.46; 95% CI, 1.35–1.58, p < 0.001; and RR for IS, 1.40; 95% CI, 1.30–1.40, p < 0.001) and half siblings (RR for MI, 1.29; 95% CI, 1.05–1.59, p < 0.001; and RR for IS, 1.38; 95% CI, 1.16–1.65, p < 0.001).Conclusion: This large, population-wide study indicates that there is considerable overlap of familial risk between IS and MI.
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