An assessment of public health surveillance of Zika virus infection and potentially associated outcomes in Latin America.

BACKGROUND: We evaluated whether outbreaks of Zika virus (ZIKV) infection, newborn microcephaly, and Guillain-Barré syndrome (GBS) in Latin America may be detected through current surveillance systems, and how cases detected through surveillance may increase health care burden. METHODS: We estimated the sensitivity and specificity of surveillance case definitions using published data. We assumed a 10% ZIKV infection risk during a non-outbreak period and hypothetical increases in risk during an outbreak period. We used sensitivity and specificity estimates to correct for non-differential misclassification, and calculated a misclassification-corrected relative risk comparing both periods. To identify the smallest hypothetical increase in risk resulting in a detectable outbreak we compared the misclassification-corrected relative risk to the relative risk corresponding to the upper limit of the endemic channel (mean + 2 SD). We also estimated the proportion of false positive cases detected during the outbreak. We followed the same approach for microcephaly and GBS, but assumed the risk of ZIKV infection doubled during the outbreak, and ZIKV infection increased the risk of both diseases. RESULTS: ZIKV infection outbreaks were not detectable through non-serological surveillance. Outbreaks were detectable through serologic surveillance if infection risk increased by at least 10%, but more than 50% of all cases were false positive. Outbreaks of severe microcephaly were detected if ZIKV infection increased prevalence of this condition by at least 24.0 times. When ZIKV infection did not increase the prevalence of severe microcephaly, 34.7 to 82.5% of all cases were false positive, depending on diagnostic accuracy. GBS outbreaks were detected if ZIKV infection increased the GBS risk by at least seven times. For optimal GBS diagnosis accuracy, the proportion of false positive cases ranged from 29 to 54% and from 45 to 56% depending on the incidence of GBS mimics. CONCLUSIONS: Current surveillance systems have a low probability of detecting outbreaks of ZIKV infection, severe microcephaly, and GBS, and could result in significant increases in health care burden, due to the detection of large numbers of false positive cases. In view of these limitations, Latin American countries should consider alternative options for surveillance.

Cardiovascular Disease Risk Factors in Hispanic Adolescents in South Texas.

OBJECTIVES: Despite a national crisis of increased prevalence of obesity and type 2 diabetes mellitus in adolescents, especially among Hispanics, there is a paucity of data on health indicators among farmworker adolescents and their peers. The main aim of this study was to estimate the prevalence of cardiovascular disease risk factors in a population of Hispanic adolescent students in south Texas. The study also aimed to compare the prevalence of these risk factors between students enrolled in the Migrant Education Program (MEP) and other students, and between boys and girls. METHODS: In partnership with the Weslaco (Texas) Independent School District and the Migrant Education Department, a cohort study was conducted from 2007 to 2010 to estimate the prevalence of overall obesity (body mass index ≥85th percentile for age and sex), abdominal obesity (waist circumference ≥75th percentile for age, sex, and ethnicity), acanthosis nigricans (AN), and high blood pressure (HBP; ≥90th percentile for age, height, and sex or systolic/diastolic BP ≥120/80 mm Hg) among MEP students compared with other students from two south Texas high schools. Multilevel logistic regression was used to assess the relation between sex and our main outcomes of interest while accounting for within-school nesting of participants. RESULTS: Among 628 sampled students, 508 (80.9%) completed the consent procedure and participated in the study. Of these, 257 were MEP students and 251 were non-MEP peers. Approximately 96.7% of participants were Hispanic and 50.0% were boys. Analyses of data across the years comparing MEP students and non-MEP students show an average prevalence of 44.8% versus 47.7% for overall obesity, 43.2% versus 43.7% for abdominal obesity, 24.7% versus 24.7% for AN, and 29.2% versus 32.8% for HBP. Across recruitment and follow-up years, the prevalence of overall obesity, abdominal obesity, and HBP was 1.3 to 1.5, 1.2 to 1.8, and 2.9 to 4.6 times higher in boys than in girls, respectively. In contrast, the prevalence of AN varied little by sex. CONCLUSIONS: The high prevalence of cardiovascular risk factors in both groups suggests a compelling need for comprehensive, culturally targeted interventions to prevent future cardiovascular diseases in these high-risk Hispanic adolescents, especially among boys. There were not, however, substantial differences between MEP students and other students. These findings also support the feasibility of conducting future epidemiologic studies among adolescent farmworkers and their families, as well as culturally appropriate school or community-based interventions.

Food insecurity and dyslipidemia in a representative population-based sample in the US.

OBJECTIVE: The association of food insecurity with dyslipidemia has not been firmly established. The main objective of this study was to assess whether food insecurity was associated with dyslipidemia. METHOD: A population-based sample of 1,663 adults from the 2008-2011 Survey of the Health of Wisconsin was used. Food insecurity was defined as an affirmative response to either of the questions: (1) "In the last 12months, have you been concerned about having enough food for you or your family?" (2) "In the last 12months, have your food choices been limited because there wasn't enough money?" High total cholesterol was defined as total cholesterol (TC) >240mg/dL or taking prescribed lipid-lowering medication. Low high-density lipoprotein cholesterol (HDL-C) was defined as <40mg/dL in men and <50mg/dL in women. RESULTS: Food insecurity was not associated with high TC either among men or women. Food insecurity was associated with a higher likelihood of low HDL-C among women (adjusted odds ratio [AOR]: 2.31 {95% confidence interval [CI]: 1.42, 3.76}), but not among men. Obesity appears to be a partial mediator of the association among women (P from the Sobel test=0.01). CONCLUSION: These findings suggest that food insecurity may contribute to an increased risk of low HDL-C in women.

Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.

BACKGROUND: The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. METHODS: We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks). FINDINGS: The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 µmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 µmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. INTERPRETATION: In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Validation of RT-qPCR test for SARS-CoV-2 in saliva specimens.

BACKGROUND: Saliva samples may be an easier, faster, safer, and cost-saving alternative to NPS samples, and can be self-collected by the patient. Whether SARS-CoV-2 RT-qPCR in saliva is more accurate than in nasopharyngeal swaps (NPS) is uncertain. We evaluated the accuracy of the RT-qPCR in both types of samples, assuming both approaches were imperfect. METHODS: We assessed the limit of detection (LoD) of RT-qPCR in each type of sample. We collected paired NPS and saliva samples and tested them using the Berlin Protocol to detect SARS-CoV-2 envelope protein (E). We used a Bayesian latent class analysis (BLCA) to estimate the sensitivity and specificity of each test, while accounting for their conditional dependence. RESULTS: The LoD were 10 copies/mL in saliva and 100 copies/mL in NPS. Paired samples of saliva and NPS were collected in 412 participants. Out of 68 infected cases, 14 were positive only in saliva. RT-qPCR sensitivity ranged from 82.7 % (95 % CrI: 54.8, 94.8) in NPS to 84.5 % (50.9, 96.5) in saliva. Corresponding specificities were 99.1 % (95 % CrI: 95.3, 99.8) and 98.4 %(95 % CrI: 92.8, 99.7). CONCLUSIONS: SARS-CoV-2 RT-qPCR test in saliva specimens has a similar or better accuracy than RT-qPCR test in NPS. Saliva specimens may be ideal for surveillance in general population, particularly in children, and in healthcare or other personnel in need of serial testing.

Antihypertensive effects of aspirin: what is the evidence?

Nonsteroidal anti-inflammatory drugs are known to increase blood pressure and blunt the effect of antihypertensive drugs. Surprisingly, it has been suggested recently that aspirin lowers blood pressure and could be used for preventing hypertension. This review summarizes published data on the effects of aspirin on blood pressure. Trials suggesting that aspirin administered at bedtime lowers blood pressure are uncontrolled, unmasked, and potentially biased. They also conflict with cohort studies showing an 18% increase in the risk of hypertension among aspirin users. Fortunately, short-term use of aspirin does not seem to interfere with antihypertensive drugs. Regardless of its effect on blood pressure, low-dose aspirin effectively prevents cardiovascular events in patients with and without hypertension, but its benefits should be carefully weighed against a potential increase in the risk of adverse effects such as gastric bleeding and hemorrhagic stroke, as well as a small increase in the risk of hypertension.

Indoor charcoal smoke and acute respiratory infections in young children in the Dominican Republic.

The authors investigated the effect of charcoal smoke exposure on risks of acute upper and lower respiratory infection (AURI and ALRI) among children under age 18 months in Santo Domingo, Dominican Republic (1991-1992). Children living in households using charcoal for cooking (exposed, n = 201) were age-matched to children living in households using propane gas (nonexposed, n = 214) and were followed for 1 year or until 2 years of age. Fuel use and new episodes of AURI and ALRI were ascertained biweekly through interviews and medical examinations. Household indoor-air concentration of respirable particulate matter (RPM) was measured in a sample of follow-up visits. Incidences of AURI and ALRI were 4.4 and 1.4 episodes/child-year, respectively. After adjustment for other risk factors, exposed children had no significant increase in risk of AURI but were 1.56 times (95% confidence interval: 1.23, 1.97) more likely to develop ALRI. RPM concentrations were higher in charcoal-using households (27.9 microg/m(3) vs. 17.6 microg/m(3)), and ALRI risk increased with RPM exposure (10-microg/m(3) increment: odds ratio = 1.17, 95% confidence interval: 1.02, 1.34). Exposure to charcoal smoke increases the risk of ALRI in young children, an effect that is probably mediated by RPM. Reducing charcoal smoke exposure may lower the burden of ALRI among children in this population.

Association of blood and hair mercury with blood pressure and vascular reactivity.

BACKGROUND: Some studies suggest that high levels of blood and hair mercury (Hg) increase the risk of atherothrombotic diseases, an effect that may be explained by oxidative damage to the vascular endothelium. OBJECTIVES: We tested whether high Hg levels impair the vasodilating function of the vascular endothelium or increase blood pressure. METHODS: We measured the association between high blood and hair Hg and brachial artery flow mediated vasodilation (FMD%), middle cerebral artery reactivity to CO2 (MCAR%) and hypertensive status in 101 participants in the Wisconsin Sleep Cohort Study (mean age of 59.4 years; 52.5% male). Whole blood total Hg and hair total Hg were tested using inductively coupled plasma mass spectrometry and cold vapor atomic fluorescence spectrometry, respectively. RESULTS: Geometric mean blood and hair Hg were 1.16 microg/L and 270.1 ng/g. Blood and hair Hg were not significantly associated with FMD% and MCAR%. However, after adjustment for other risk factors, people in the upper quartile of blood Hg were 1.9 times (P=0.23) more likely to be hypertensive and those in the upper quartile of hair Hg were more than 4 times more likely (P=0.02). CONCLUSION: High hair and blood Hg levels do not seem to influence vascular reactivity, but may increase the risk of hypertension.

Zika virus infection and risk of Guillain-Barré syndrome: A meta-analysis.

OBJECTIVE: Findings from studies of the association between Zika virus (ZIKV) infection and Guillain-Barré syndrome (GBS) are inconsistent. I conducted a systematic review and meta-analysis to clarify the nature of this association. METHODS: I searched PubMed, Scopus, Cochrane, CINAHL, Web of Science, Scielo, and DOAJ for case report, ecological, and analytic studies with "Zika" and "Guillain-Barré syndrome" as keywords, published up to July 1stth 2018. I evaluated if ZIKV infection status influenced the diagnosis of GBS (detection bias) in case-report and analytic studies; assessed if changes in weekly number of cases of ZIKV infection during outbreaks were followed by changes in number of GBS cases 1-8 weeks later; gauged the likelihood of selection, confounding, information, sparse data, and time-dependent bias (i.e. when ZIKV infection was ascertained after GBS onset) in analytic studies; and calculated the average ZIKV-GBS odds ratio (OR) in studies without time-dependent bias. RESULTS: In case reports, ZIKV infection prevalence in GBS cases was 2.4 to 25 times higher than expected. Changes in the number of ZIKV-infection cases during outbreaks were not consequentially followed by changes in the number of GBS cases (OR: 1.01; 95% CI: 0.99-1.03). Major biases were likely in all but one analytic study, which showed a non-significant ZIKV-GBS association. The average ZIKV-GBS OR in studies without time-dependent bias was 1.57 (95% CI: 0.86-2.86). INTERPRETATION: These findings indicate the available evidence is insufficient to claim ZIKV infection causes GBS. Therefore, stakeholders may want to reconsider current ZIKV-GBS public health and patient care recommendations.

Inflammation markers and risk of developing hypertension: a meta-analysis of cohort studies.

OBJECTIVE: To systematically assess the association of circulating inflammation markers with the future risk of hypertension. METHODS: We did a systematic literature search of PubMed and Scopus, from database inception to July 10, 2018. Prospective and retrospective cohort studies evaluating the association of circulating C reactive protein (CRP), high-sensitive CRP (hs-CRP), interleukin 6 (IL-6) and IL-1ß to the risk of developing hypertension in the general population were included. The relative risks (RRs) for the top versus bottom tertiles of circulating biomarkers were calculated using a fixed-effects/random-effects model. A potential non-linear dose-response association was tested. RESULTS: Fourteen prospective cohort studies, two retrospective cohort studies and five nested case-control studies involving 142 640 participants and 20 676 cases were identified. The RR for the third versus first tertiles of circulating CRP was 1.23 (95% CI 1.11 to 1.35; I2=59%, n=12). The association remained unchanged after adjustment for body mass index. The RRs for other biomarkers were as follows: hs-CRP (RR 1.20, 95% CI 1.02 to 1.37; I2=74%, n=7), IL-6 (RR 1.51, 95% CI 1.30 to 1.71; I2=0%, n=5), and IL-1ß (RR 1.22, 95% CI 0.92 to 1.51; I2=0%, n=3). A non-linear dose-response meta-analysis demonstrated that the risk of hypertension increased linearly with increasing circulating inflammation markers, even within the low-risk and intermediate-risk categories. CONCLUSIONS: Higher levels of circulating CRP, hs-CRP and IL-6, but not IL-1ß, were associated with the risk of developing hypertension. The association persisted in subgroups of studies defined by major sources of heterogeneity.

Risk factors for acute myocardial infarction in Latin America: the INTERHEART Latin American study.

BACKGROUND: Current knowledge of the impact of cardiovascular risk factors in Latin America is limited. METHODS AND RESULTS: As part of the INTERHEART study, 1237 cases of first acute myocardial infarction and 1888 age-, sex-, and center-matched controls were enrolled from Argentina, Brazil, Colombia, Chile, Guatemala, and Mexico. History of smoking, hypertension, diabetes mellitus, diet, physical activity, alcohol consumption, psychosocial factors, anthropometry, and blood pressure were recorded. Nonfasting blood samples were analyzed for apolipoproteins A-1 and B-100. Logistic regression was used to estimate multivariate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Persistent psychosocial stress (OR, 2.81; 95% CI, 2.07 to 3.82), history of hypertension (OR, 2.81; 95% CI, 2.39 to 3.31), diabetes mellitus (OR, 2.59; 95% CI, 2.09 to 3.22), current smoking (OR, 2.31; 95% CI, 1.97 to 2.71), increased waist-to-hip ratio (OR for first versus third tertile, 2.49; 95% CI, 1.97 to 3.14), and increased ratio of apolipoprotein B to A-1 (OR for first versus third tertile, 2.31; 95% CI, 1.83 to 2.94) were associated with higher risk of acute myocardial infarction. Daily consumption of fruits or vegetables (OR, 0.63; 95% CI, 0.51 to 0.78) and regular exercise (OR, 0.67; 95% CI, 0.55 to 0.82) reduced the risk of acute myocardial infarction. Abdominal obesity, abnormal lipids, and smoking were associated with high population-attributable risks of 48.5%, 40.8%, and 38.4%, respectively. Collectively, these risk factors accounted for 88% of the population-attributable risk. CONCLUSIONS: Interventions aimed at decreasing behavioral risk factors, lowering blood pressure, and modifying lipids could have a large impact on the risk of acute myocardial infarction among Latin Americans.

Predictors of persistence with antihypertensive therapy: results from the NHANES.

BACKGROUND: More than 40% of treated hypertensives in the United States do not have their blood pressure under control. This is partly owing to non-persistence with prescribed medication, which occurs within 1 year in 32-53% of newly treated patients. Knowledge of factors related to non-persistence is limited, partly because previous studies have being conducted mostly in elderly patients enrolled in a single health insurance. METHODS: Weighted logistic regression was used to identify factors associated with non-persistence in hypertensive patients from National Health and Nutrition Examination Surveys III (NHANES III) and NHANES 1999-2002 who had been prescribed antihypertensive medication. RESULTS: Of 6100 participants, 903 were non-persistent (sampling weighted national prevalence of 12.5%), even though they had elevated blood pressure. Non-persistence was 12 times higher in patients <30 years than in those > or =50 years old (P < 0.001), 31% higher in men than in women (P = 0.01), and 43% higher in Hispanics, as compare to other racial groups (P = 0.03). Patients with low income were almost two times more likely to be non-persistent (P < 0.001). Having no health insurance increased non-persistence by 88% (P = 0.002), and patients who did not visit their doctor during the last year were 10 times more likely to be non-persistent than those who made at least one medical visit (P < 0.001). CONCLUSIONS: In addition to young age, factors related to access to health care and medications (low income, health insurance, and visits to the doctor) were the main predictors of non-persistence. Policies that improve access to health care and patient follow-up may be of great impact in maintaining persistence.

Population-based case-control study of renin-angiotensin system genes polymorphisms and hypertension among Hispanics.

The effect of polymorphisms of the RAS genes on the incidence of hypertension seems to be population-dependent. We studied the effects of the angiotensinogen T174M and M235T, angiotensin converting enzyme insertion/deletion (ACE I/D), and angiotensin II receptor 1 (AT1R) A1166C gene polymorphisms on the risk of hypertension among Hispanics. We selected all cases (n=256) and 257 age and sex group-matched controls from a random sample of free living Colombians (n=2,989). Logistic regression was used to estimate the independent effect of each polymorphism. All polymorphisms were in Hardy-Weinberg equilibrium in controls, with the exception of M235T, which showed a small excess of heterozygotes (p=0.005; disequilibrium coefficient, D=-0.0264). After adjustment for age, sex, body mass index, race, physical activity, family history of hypertension and cardiovascular disease, and other polymorphisms, subjects with the ACE DD genotype were 1.56 times (95% confidence interval [CI]: 1.05, 2.33) more likely to be hypertensive than carriers of the I allele (p=0.03). Also, adjusted systolic and diastolic blood pressure were 4.58 (95% CI: -0.39, 9.56) and 3.32 (95% CI: 0.78, 5.86) mmHg higher in DD homozygous individuals than in carriers of the I allele, respectively. Approximately 15% of the cases of hypertension in this population could be attributed to carriage of the DD genotype. None of the other polymorphisms was associated with either hypertension or blood pressure level. In conclusion, the ACE DD genotype appears to be an independent risk factor for development of hypertension and may explain a significant fraction of incident cases among Hispanics.

Maternal Zika virus infection and newborn microcephaly-an analysis of the epidemiological evidence.

PURPOSE: To evaluate whether existing data and evidence support a causal link between maternal Zika virus (ZIKV) infection and newborn microcephaly. METHODS: I quantified and compared the prevalence of all and severe microcephaly in Brazil, during and before 2015-2016, to assess whether an outbreak has occurred, used time series analysis to evaluate if the presumed outbreak was linked to a previous outbreak of ZIKV infections, and quantitatively synthesized published data from observational studies testing this association. RESULTS: The prevalences of microcephaly in 2015-2016 were similar or lower than background levels (prevalence ratio [PR] for all microcephaly: 0.19; 95% confidence intervals [CI]: 0.17, 0.20). Changes in the number of cases of ZIKV infections at times matching 11-18 weeks of pregnancy were not followed by changes in the number of microcephaly cases (PR for infection at 12 weeks: 1.02; 95% CI: 0.99, 1.05). In observational studies, the prevalence of microcephaly was not significantly increased in newborns of Zika-infected mothers (average PR: 1.30; 95% CI: 0.84, 2.02). CONCLUSIONS: Existing evidence is insufficient to claim maternal ZIKV infection causes microcephaly. Although a public health response seems sensible, it should be consistent with existing knowledge and consider risks, potential benefits and harm, and competing priorities.

Trends in kidney transplantation rates and disparities.

OBJECTIVE: To examine the likelihood of transplantation and trends over time among persons with end-stage renal disease (ESRD) in Wisconsin. METHODS: We examined the influence of patient- and community-level characteristics on the rate of kidney transplantation in Wisconsin among 22,387 patients diagnosed with ESRD between January 1, 1982 and October 30, 2005. We grouped patients by the year of ESRD onset in order to model the change in transplantation rates over time. RESULTS: After multivariate adjustment, all other racial groups were significantly less likely to be transplanted compared with whites, and the racial disparity increased over calendar time. Older patients were less likely to be transplanted in all periods. Higher community income and education level and a greater distance from patients' residence to the nearest dialysis center significantly increased the likelihood of transplantation. Males also had a significantly higher rate of transplantation than females. CONCLUSION: These results demonstrate a growing disparity in transplantation rates by demographic characteristics and a consistent disparity in transplantation by socioeconomic characteristics. Future studies should focus on identifying specific barriers to transplantation among different subpopulations in order to target effective interventions.

Homocysteine and stroke: evidence on a causal link from mendelian randomisation.

BACKGROUND: Individuals homozygous for the T allele of the MTHFR C677T polymorphism have higher plasma homocysteine concentrations (the phenotype) than those with the CC genotype, which, if pathogenetic, should put them at increased risk of stroke. Since this polymorphism is distributed randomly during gamete formation, its association with stroke should not be biased or confounded. We investigated consistency between the expected odds ratio for stroke among TT homozygotes, extrapolated from genotype-phenotype and phenotype-disease studies, and the observed odds ratio from a meta-analysis of genotype-disease association studies. METHODS: We searched MEDLINE and EMBASE up to June, 2003, for all relevant studies on the association between homocysteine concentration and the MTHFR polymorphism, and until December, 2003, for those on the association between the polymorphism and the risk of stroke. Pooled odds ratios and 95% CI were calculated by random-effects and fixed-effects models. Consistency between expected and observed odds ratios was assessed by interaction test. FINDINGS: 111 studies met the selection criteria. Among 15635 people without cardiovascular disease, the weighted mean difference in homocysteine concentration between TT and CC homozygotes was 1.93 micromol/L (95% CI 1.38 to 2.47). The expected odds ratio for stroke corresponding to this difference based on previous observational studies was 1.20 (1.10 to 1.31). In our genetic meta-analysis (n=13928) the odds ratio for stroke was 1.26 (1.14 to 1.40) for TT versus CC homozygotes, similar to the expected odds ratio (p=0.29). Consistency between the odds ratios was preserved in analyses by age-group, ethnic background, and geographical location. INTERPRETATION: The observed increase in risk of stroke among individuals homozygous for the MTHFR T allele is close to that predicted from the differences in homocysteine concentration conferred by this variant. This concordance is consistent with a causal relation between homocysteine concentration and stroke.