Common Familial Effects on Ischemic Stroke and Myocardial Infarction: A Prospective Population-Based Cohort Study.

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.

DNA mismatch repair gene MSH6 implicated in determining age at natural menopause.

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.

Familial effects on ischemic stroke: the role of sibling kinship, sex, and age of onset.

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 Death Registers 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; P<0.001). Familial risk was higher in full (relative risk, 1.64; 95% confidence interval, 1.50-1.81; P<0.001) than in half (relative risk, 1.41; 95% confidence interval, 1.10-1.82; P=0.007) 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; P<0.001). 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.

A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.

BACKGROUND: The 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 FINDINGS: The 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)). CONCLUSIONS: Our 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.

Is uric acid protective or deleterious in acute ischemic stroke? A prospective cohort study.

Contrasting observations have been made between serum urate and ischemic stroke outcomes in studies involving Caucasian populations. To assess the hypothesis that urate is associated with stroke outcomes, a prospective follow-up study was performed in a cohort of Asian patients with ischemic stroke. Patients diagnosed with transient ischemic attack, first or recurrent ischemic stroke were included in this study. Serum urate, measured using high-performance liquid chromatography, was correlated with 12-month functional and vascular stroke outcomes. Poor functional outcome was defined as a modified Rankin scale exceeding 2 and vascular outcome was defined as a composite of recurrent stroke, myocardial infarction or vascular death during the study period. A total of 503 patients of mean age 63 (SD 12) years were included. A U-shaped relationship between urate quartiles and poor functional outcomes was demonstrated. More patients with low (<280microM) and high (>410microM) urate levels had poor functional outcomes (36% and 27% respectively), compared to those with urate levels between 340 and 410microM (14%). No significant relationship was observed between urate and vascular outcomes. Depending on its level, serum urate may exhibit protective and deleterious effects on stroke outcomes.

Allantoin in human plasma, serum, and nasal-lining fluids as a biomarker of oxidative stress: avoiding artifacts and establishing real in vivo concentrations.

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.

Ethnicity does not affect the homocysteine-lowering effect of B-vitamin therapy in Singaporean stroke patients.

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. The magnitude of tHcy reduction by B-vitamin treatment was consistent across ethnic groups (Chinese -3.8+/-4.5, Malay -4.9+/-4.2, and Indian -3.3+/-3.6 micromol/L) despite ethnic differences in MTHFR genotype and baseline folic acid (FA) and vitamin B(12) (vitB(12)) concentrations. CONCLUSIONS: Ethnicity does not appear to affect the tHcy-lowering effect of B-vitamins, despite differences in dietary intake and prevalence of MTHFR polymorphisms. This suggests that the effect of B-vitamins in lowering tHcy is generalizable across Asian populations. However, due to relatively small numbers of non-Chinese studied, confirmation in other populations is required.