The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding. INTERPRETATION: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. FUNDING: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Investigating causality between liability to ADHD and substance use, and liability to substance use and ADHD risk, using Mendelian randomization.

Attention-deficit hyperactivity disorder (ADHD) has consistently been associated with substance use, but the nature of this association is not fully understood. To inform intervention development and public health messages, a vital question is whether there are causal pathways from ADHD to substance use and/or vice versa. We applied bidirectional Mendelian randomization, using summary-level data from the largest available genome-wide association studies (GWAS) on ADHD, smoking (initiation, cigarettes per day, cessation, and a compound measure of lifetime smoking), alcohol use (drinks per week, alcohol problems, and alcohol dependence), cannabis use (initiation), and coffee consumption (cups per day). Genetic variants robustly associated with the "exposure" were selected as instruments and identified in the "outcome" GWAS. Effect estimates from individual genetic variants were combined with inverse-variance weighted regression and five sensitivity analyses (weighted median, weighted mode, MR-Egger, generalized summary data-based MR, and Steiger filtering). We found evidence that liability to ADHD increases likelihood of smoking initiation and heaviness of smoking among smokers, decreases likelihood of smoking cessation, and increases likelihood of cannabis initiation. There was weak evidence that liability to ADHD increases alcohol dependence risk but not drinks per week or alcohol problems. In the other direction, there was weak evidence that smoking initiation increases ADHD risk, but follow-up analyses suggested a high probability of horizontal pleiotropy. There was no clear evidence of causal pathways between ADHD and coffee consumption. Our findings corroborate epidemiological evidence, suggesting causal pathways from liability to ADHD to smoking, cannabis use, and, tentatively, alcohol dependence. Further work is needed to explore the exact mechanisms mediating these causal effects.

The Parkinson's Disease Mendelian Randomization Research Portal.

BACKGROUND: Mendelian randomization is a method for exploring observational associations to find evidence of causality. OBJECTIVE: To apply Mendelian randomization between risk factors/phenotypic traits (exposures) and PD in a large, unbiased manner, and to create a public resource for research. METHODS: We used two-sample Mendelian randomization in which the summary statistics relating to single-nucleotide polymorphisms from 5,839 genome-wide association studies of exposures were used to assess causal relationships with PD. We selected the highest-quality exposure genome-wide association studies for this report (n = 401). For the disease outcome, summary statistics from the largest published PD genome-wide association studies were used. For each exposure, the causal effect on PD was assessed using the inverse variance weighted method, followed by a range of sensitivity analyses. We used a false discovery rate of 5% from the inverse variance weighted analysis to prioritize exposures of interest. RESULTS: We observed evidence for causal associations between 12 exposures and risk of PD. Of these, nine were effects related to increasing adiposity and decreasing risk of PD. The remaining top three exposures that affected PD risk were tea drinking, time spent watching television, and forced vital capacity, but these may have been biased and were less convincing. Other exposures at nominal statistical significance included inverse effects of smoking and alcohol. CONCLUSIONS: We present a new platform which offers Mendelian randomization analyses for a total of 5,839 genome-wide association studies versus the largest PD genome-wide association studies available (https://pdgenetics.shinyapps.io/MRportal/). Alongside, we report further evidence to support a causal role for adiposity on lowering the risk of PD. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Investigating the effects of lycopene and green tea on the metabolome of men at risk of prostate cancer: The ProDiet randomised controlled trial.

Lycopene and green tea consumption have been observationally associated with reduced prostate cancer risk, but the underlying mechanisms have not been fully elucidated. We investigated the effect of factorial randomisation to a 6-month lycopene and green tea dietary advice or supplementation intervention on 159 serum metabolite measures in 128 men with raised PSA levels (but prostate cancer-free), analysed by intention-to-treat. The causal effects of metabolites modified by the intervention on prostate cancer risk were then assessed by Mendelian randomisation, using summary statistics from 44,825 prostate cancer cases and 27,904 controls. The systemic effects of lycopene and green tea supplementation on serum metabolic profile were comparable to the effects of the respective dietary advice interventions (R2 = 0.65 and 0.76 for lycopene and green tea respectively). Metabolites which were altered in response to lycopene supplementation were acetate [ß (standard deviation difference vs. placebo): 0.69; 95% CI = 0.24, 1.15; p = 0.003], valine (ß: -0.62; -1.03, -0.02; p = 0.004), pyruvate (ß: -0.56; -0.95, -0.16; p = 0.006) and docosahexaenoic acid (ß: -0.50; -085, -0.14; p = 0.006). Valine and diacylglycerol were lower in the lycopene dietary advice group (ß: -0.65; -1.04, -0.26; p = 0.001 and ß: -0.59; -1.01, -0.18; p = 0.006). A genetically instrumented SD increase in pyruvate increased the odds of prostate cancer by 1.29 (1.03, 1.62; p = 0.027). An intervention to increase lycopene intake altered the serum metabolome of men at risk of prostate cancer. Lycopene lowered levels of pyruvate, which our Mendelian randomisation analysis suggests may be causally related to reduced prostate cancer risk.

ProDiet: A Phase II Randomized Placebo-controlled Trial of Green Tea Catechins and Lycopene in Men at Increased Risk of Prostate Cancer.

Epidemiologic studies suggest that diet can alter prostate cancer risk. This study aimed to establish the feasibility and acceptability of dietary modification in men at increased risk of prostate cancer. Men were invited with a PSA level of 2.0-2.95 ng/mL or 3.0-19.95 ng/mL with negative prostate biopsies. Randomization (3 × 3 factorial design) to daily green tea and lycopene: green tea drink (3 cups, unblinded) or capsules [blinded, 600 mg flavan-3-ol ()-epigallocatechin-3-gallate (EGCG) or placebo] and lycopene-rich foods (unblinded) or capsules (blinded, 15 mg lycopene or placebo) for 6 months. Primary endpoints were randomization rates and intervention adherence (blinded assessment of metabolites) at 6 months with secondary endpoints of acceptability (from interviews), safety, weight, blood pressure, and PSA. A total of 133 of 469 (28.4%) men approached agreed to be randomized and 132 were followed-up (99.2%). Mean lycopene was 1.28 [95% confidence intervals (CI), 1.09-1.50, P = 0.003] times higher in the lycopene capsule group and 1.42 (95% CI, 1.21-1.66; P < 0.001) times higher in the lycopene-enriched diet group compared with placebo capsules. Median EGCG was 10.7 nmol/L (95% CI, 7.0-32.0) higher in in the active capsule group and 20.0 nmol/L (95% CI, 0.0-19.0) higher in the green tea drink group compared with placebo capsules (both P < 0.001). All interventions were acceptable and well tolerated although men preferred the capsules. Dietary prevention is acceptable to men at risk of prostate cancer. This intervention trial demonstrates that a chemoprevention clinical trial is feasible. Cancer Prev Res; 11(11); 687-96. ©2018 AACR.

Effects of nutritional supplementation during pregnancy on early adult disease risk: follow up of offspring of participants in a randomised controlled trial investigating effects of supplementation on infant birth weight.

BACKGROUND: Observational evidence suggests that improving fetal growth may improve adult health. Experimental evidence from nutritional supplementation trials undertaken amongst pregnant women in the less developed world does not show strong or consistent effects on adult disease risk and no trials from the more developed world have previously been reported. OBJECTIVE: To test the hypothesis that nutritional supplementation during pregnancy influences offspring disease risk in adulthood. DESIGN: Clinical assessment of a range of established diseases risk markers in young adult offspring of 283 South Asian mothers who participated in two trials of nutritional supplementation during pregnancy (protein/energy/vitamins; energy/vitamins or vitamins only) at Sorrento Maternity Hospital in Birmingham UK either unselected or selected on the basis of nutritional status. RESULTS: 236 (83%) offspring were traced and 118 (50%) of these were assessed in clinic. Protein/energy/vitamins supplementation amongst undernourished mothers was associated with increased infant birthweight. Nutritional supplementation showed no strong association with any one of a comprehensive range of markers of adult disease risk and no consistent pattern of association with risk across markers in offspring of either unselected or undernourished mothers. CONCLUSIONS: We found no evidence that nutritional supplements given to pregnant women are an important influence on adult disease risk however our study lacked power to estimate small effects. Our findings do not provide support for a policy of nutritional supplementation for pregnant women as an effective means to improve adult health in more developed societies.

Analysis of self-selection bias in a population-based cohort study of autism spectrum disorders.

BACKGROUND: This study examined potential self-selection bias in a large pregnancy cohort by comparing exposure-outcome associations from the cohort to similar associations obtained from nationwide registry data. The outcome under study was specialist-confirmed diagnosis of autism spectrum disorders (ASDs). METHODS: The cohort sample (n = 89 836) was derived from the population-based prospective Norwegian Mother and Child Cohort Study and its substudy of ASDs, the Autism Birth Cohort (ABC) study. The nationwide registry data were derived from the Medical Birth Registry of Norway (n = 507 856). The children were born in 1999­2007, and seven prenatal and perinatal exposures were selected for analyses. RESULTS: ASDs were reported for 234 (0.26%) children in the cohort and 2072 (0.41%) in the nationwide population. Compared with the nationwide population, the cohort had an under-representation of the youngest women (<25 years), those who had single status, mothers who smoked during pregnancy, and non-users of prenatal folic acid supplements. The ratios of the adjusted odds ratios (ORs) in the cohort over the adjusted ORs in the nationwide population were as follows; primipara pregnancy: 1.39/1.22, prenatal folic acid use: 0.85/0.86, prenatal smoking: 1.20/1.17, preterm birth (<37 weeks): 1.48/1.42, low birthweight (<2500 g): 1.60/1.58, male sex: 4.39/4.59 (unadjusted only); and caesarean section history: 1.03/1.04. CONCLUSIONS: Associations estimated between ASDs and perinatal and prenatal exposures in the cohort are close to those estimated in the nationwide population. Self-selection does not appear to compromise validity of exposure-outcome associations in the ABC study.

Genome-wide association study identifies loci affecting blood copper, selenium and zinc.

Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and > 2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10(-10), and rs2769264, P = 2.63 × 10(-20)); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10(-28) at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10(-12); rs2120019, P = 1.55 × 10(-18); and rs4826508, P = 1.40 × 10(-12), respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).

Vitamin B-12 status during pregnancy and child's IQ at age 8: a Mendelian randomization study in the Avon longitudinal study of parents and children.

Vitamin B-12 is essential for the development and maintenance of a healthy nervous system. Brain development occurs primarily in utero and early infancy, but the role of maternal vitamin B-12 status during pregnancy on offspring cognitive function is unclear. In this study we assessed the effect of vitamin B-12 status in well-nourished pregnant women on the cognitive ability of their offspring in a UK birth cohort (ALSPAC). We then examined the association of SNPs in maternal genes FUT2 (rs492602) and TCN2 (rs1801198, rs9606756) that are related to plasma vitamin B-12, with offspring IQ. Observationally, there was a positive association between maternal vitamin B-12 intake and child's IQ that was markedly attenuated after adjustment for potential confounders (mean difference in offspring IQ score per doubling of maternal B-12 intake, before adjustment: 2.0 (95% CI 1.3, 2.8); after adjustment: 0.7 (95% CI -0.04, 1.4)). Maternal FUT2 was weakly associated with offspring IQ: mean difference in IQ per allele was 0.9 (95% CI 0.1, 1.6). The expected effect of maternal vitamin B-12 on offspring IQ, given the relationships between SNPs and vitamin B-12, and SNPs and IQ was consistent with the observational result. Our findings suggest that maternal vitamin B-12 may not have an important effect on offspring cognitive ability. However, further examination of this issue is warranted.

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).

Is relative leg length a biomarker of childhood nutrition? Long-term follow-up of the Hyderabad Nutrition Trial.

BACKGROUND: Relative leg length is frequently used as a biomarker of childhood nutrition in epidemiological studies, but evidence is lacking. We examined the association between supplemental nutrition in pregnancy and childhood and relative proportions of components of height in adolescence. METHODS: In a community trial of nutritional supplementation, villages from adjacent administrative areas were selected to serve as intervention (n = 15) and control (n = 14) arms. In the intervention villages, balanced protein-calorie supplementation (2.51 MJ, 20 g protein) was offered daily to pregnant women and their offspring until the age of 6 years. Children born in the trial were re-examined 15 years later to assess components of height. RESULTS: A total of 1165 adolescents (intervention: 654, 49% of trial participants; control: 511, 41% of trial participants) aged 13-18 years were examined. Supplemented children were 10 mm taller [95% confidence interval (CI): 1.4 to 18.7 mm], but almost all of the increase was in trunk length (9 mm, 95% CI: 2.6 to 15.4 mm). The age- and gender-adjusted ß-coefficients for the association of nutritional supplementation with relative trunk, leg and lower leg lengths (expressed as standard deviation scores) were 0.26 (95% CI: 0.11 to 0.42), 0.08 (95% CI: -0.03 to 0.19) and 0.03 (95% CI: -0.08 to 0.15) respectively, thereby unsupportive of cephalocaudal gradient in growth. CONCLUSIONS: In this nutritional supplementation trial in an undernourished population, we were unable to confirm relative leg length as a biomarker of childhood nutrition. Alternative explanations may underlie the reported associations between childhood conditions and relative leg length.

Maternal anemia, iron intake in pregnancy, and offspring blood pressure in the Avon Longitudinal Study of Parents and Children.

BACKGROUND: In animals, maternal iron deficiency during pregnancy results in elevated offspring blood pressure (BP). Studies in pregnant women are limited in number, have had inconsistent results, and have not accounted for maternal iron supplementation. OBJECTIVE: The objective was to assess the association between maternal iron status during pregnancy and offspring BP. DESIGN: Maternal hemoglobin (n = 1255), iron supplementation (n = 7484), food-based iron intake (n = 7130), and offspring BP were assessed in a prospective cohort at 7 y of age. RESULTS: Maternal anemia during pregnancy was associated with lower systolic BP in the offspring at 7 y of age (third trimester, age- and sex-adjusted: beta = -1.09; 95% CI: -2.21, -0.05 mm Hg; P = 0.04). Adjustment for confounders attenuated this association (beta = -0.49; 95% CI: -1.71, 0.72 mm Hg; P = 0.4). In women who did not take iron supplements during pregnancy, the observed association with maternal anemia was even stronger: minimally adjusted models (beta = -2.11; 95% CI: -3.61, -0.61 mm Hg; P = 0.006) and fully adjusted models (beta = -1.48; 95% CI: -3.21, 0.25 mm Hg; P = 0.09). Iron supplementation was not associated with offspring BP after confounding by multivitamin intake was accounted for, and no association with iron intake from food was observed. CONCLUSION: In contrast with animal studies, maternal iron intake during pregnancy is not associated with offspring BP, and some evidence indicates that maternal anemia in contemporary pregnant women is associated with lower offspring BP. It is possible that, in well-nourished populations, low hemoglobin is more likely to reflect greater plasma volume expansion (and thus better maternal and offspring health) than iron deficiency.

Schizophrenia and neural tube defects: comparisons from an epidemiological perspective.

In this review, we examine and compare epidemiological studies of schizophrenia and neural tube defects (NTDs). Although there is no apparent link between these 2 disparate disorders in terms of clinical manifestation or phenotypes, overlapping patterns in the variation of incidence of schizophrenia with that of NTDs indicate the existence of one or more shared etiological risk factors. Evidence in support of such a phenomenon may enhance our understanding of underlying pathological mechanisms and may guide future studies of etiology and prevention. The similarities that occur in a number of epidemiological observations for these disorders are in keeping with a hypothesis of nutritional deficiencies in utero acting as a risk factor for both schizophrenia and NTDs. Programes of periconceptual folate and multivitamin supplementation aimed to reduce the risk of NTDs are already in place in many countries. Nevertheless, evidence of additional effects of specific maternal micronutrient deficiency on risk of schizophrenia may not only increase enthusiasm for expansion of such programes but also enhance understanding of etiology of this disorder and offer the potential for targeted interventions in high-risk groups.

Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk.

BACKGROUND: Evidence from case-control studies suggests that increasing dietary folate intake is associated with a reduced risk of breast cancer. However, large cohort studies have found no such association, and animal studies suggest that folate supplementation may promote tumorigenesis. We conducted a meta-analysis to summarize the available evidence from observational studies on this issue and a meta-analysis of the association between a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, a key enzyme in folate metabolism, and breast cancer risk. METHODS: We searched Medline and ISI Web of Knowledge databases for relevant studies that were published through May 31, 2006. We used random-effects analysis to calculate odds ratios (ORs) for case-control studies or relative risks (RRs) for cohort studies for a 100-microg/d increase in folate intake. Unadjusted odds ratios were calculated for the studies of MTHFR genotype based on published genotype frequencies. RESULTS: A total of 13 case-control studies and nine cohort studies were included in the meta-analysis of folate intake and breast cancer risk. We found a summary OR of 0.91 (95% confidence interval [CI] = 0.87 to 0.96) from the case-control studies and a summary RR of 0.99 (95% CI = 0.98 to 1.01) from the cohort studies for a 100-microg/d increase in folate intake. We found evidence that the case-control studies may have suffered from substantial publication bias. The case-control and cohort studies may have been subject to measurement error, confounding, and possibly spurious associations arising from subgroup analyses; in addition, the case-control studies were potentially subject to recall bias and publication bias. Seventeen studies were included in the meta-analysis of MTHFR C677T genotype and breast cancer risk. We found no difference in breast cancer risk between MTHFR 677 TT homozygotes and CC homozygotes (OR = 1.05, 95% CI = 0.88 to 1.25), and there was no evidence of an interaction between folate intake and MTHFR genotype on breast cancer risk. CONCLUSION: A lack of dietary folate intake is not associated with the risk of breast cancer.

Different risk factor profiles between subtypes of ischemic stroke. A case-control study in Korean men.

Ischemic stroke is composed of subtypes with variable underlying pathogenesis and studies on ischemic stroke as a whole may inadequately evaluate risk factors, being influenced by subtype distribution among studied population. This study aimed to evaluate risk factors associated with individual ischemic stroke subtypes defined by the Trial of ORG10172 in Acute Stroke Treatment. In a case-control study (290 first-ever ischemic stroke cases and 1160 individually matched controls without stroke) nested within Korean male public servants cohort, a range of potential risk factors measured at periodic health surveys prior to the onset of stroke event were examined using conditional logistic regression analysis. Increased risk for large-artery atherosclerosis was associated with hypercholesterolemia (> or = 6.2 mmol/L), hypertension, and smoking. Increased risk for small-artery occlusion was associated with hypertension, hyperglycemia (> or = 7.0 mmol/L), and frequent alcohol intake. No specific risk factor was identified for cardioembolism. For combined ischemic stroke, hypercholesterolemia, hyperglycemia, hypertension, and smoking were associated with the increased risk, but the relative odds were much smaller than those estimated from subtype analysis. Significance of risk factors evaluated for subtypes, rather than ischemic stroke as a whole, should be reflected in preventive efforts against the burden of ischemic stroke.

Folic acid supplements in pregnancy and birth outcome: re-analysis of a large randomised controlled trial and update of Cochrane review.

Periconceptual folic acid prevents neural tube defects. The effect of folic acid taken throughout pregnancy is unclear, however. We re-analysed data from a large randomised controlled trial performed between 1966 and 1967 and combined the results with those from trials included in a Cochrane review. A total of 2928 women were randomised: 1977 were allocated to placebo, 466 to folic acid 200 microg/day and 485 to folic acid 5 mg/day. Folic acid supplementation was not associated with any difference in mean birthweight, placental weight or gestational age. When combined with trials in the Cochrane review folic acid at high doses was associated with reduced risk of low birthweight (pooled relative risk 0.73 [95% CI 0.53, 0.99]). We found no conclusive evidence of benefit for folic acid supplementation in pregnant women given from time of booking onwards.

Infant nutrition and blood pressure in early adulthood: the Barry Caerphilly Growth study.

BACKGROUND: Evidence suggests that environmental factors acting early in life may affect blood pressure in adulthood. OBJECTIVE: The objective was to test the hypothesis that dried formula milk (derived from cow milk) intake in infancy is positively associated with blood pressure in early adulthood. DESIGN: We conducted a long-term follow-up (1997-1999) of the Barry Caerphilly Growth study cohort (1972-1974) into which mothers and their offspring had originally been randomly assigned to receive a milk supplement or usual care. Participants were the offspring, who were aged 23-27 y at follow-up. The main outcome measures were systolic and diastolic blood pressure. RESULTS: The social and demographic characteristics of the subjects who were (n = 679) and were not (n = 272) followed up were similar. For each increase in quartile of dried milk consumption (in oz) at 3 mo of age, there was a 1.28-mm Hg (95% CI: 0.46, 2.10 mm Hg) increase in systolic and a 0.63-mm Hg (95% CI: 0.04, 1.22 mm Hg) increase in diastolic blood pressure after adjustment for sex, intervention group, birth weight z scores, social class in childhood, age at follow-up, alcohol consumption, and pack-years of smoking. These coefficients were attenuated when adult body mass index and height were included in the models, but the association of dried milk consumption at 3 mo of age with systolic pressure remained significant (1.07 mm Hg; 95% CI: 0.27, 1.87 mm Hg). CONCLUSIONS: Our findings are consistent with the hypothesis that high blood pressure in later life is influenced by early postnatal nutrition. Thus, interventions to optimize infant nutrition may have important long-term health benefits.