Yiqing Song

Accumulated Evidence on Fish Consumption and Coronary Heart Disease Mortality: A Meta-Analysis of Cohort Studies

Background—Results from observational studies on fish consumption and coronary heart disease (CHD) mortality are inconsistent. Methods and Results—A meta-analysis of cohort studies was conducted to examine the association between fish intake and CHD mortality. Studies were included if they provided a relative risk (RR) and corresponding 95% CI for CHD mortality in relation to fish consumption and the frequency of fish intake. A database was developed on the basis of 11 eligible studies and 13 cohorts, including 222 364 individuals with an average 11.8 years of follow-up. Pooled RR and 95% CI for CHD mortality were calculated by using both fixed-effect and random-effect models. A linear regression analysis of the log RR weighted by the inverse of variance was performed to assess the possible dose-response relation. Compared with those who never consumed fish or ate fish less than once per month, individuals with a higher intake of fish had lower CHD mortality. The pooled multivariate RRs for CHD mortality were 0.89 (95% CI, 0.79 to 1.01) for fish intake 1 to 3 times per month, 0.85 (95% CI, 0.76 to 0.96) for once per week, 0.77 (95% CI, 0.66 to 0.89) for 2 to 4 times per week, and 0.62 (95% CI, 0.46 to 0.82) for 5 or more times per week. Each 20-g/d increase in fish intake was related to a 7% lower risk of CHD mortality (P for trend=0.03). Conclusions—These results indicate that fish consumption is inversely associated with fatal CHD. Mortality from CHD may be reduced by eating fish once per week or more.

Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease.

Context Many studies investigate relationships between apolipoprotein E (apoE) polymorphisms and coronary heart disease (CHD) risk. What do these studies show? Contribution This comprehensive review of 48 studies found that carriers of the apoE4 allele had a higher risk for CHD than did persons with the 3/3 genotype. The reviewers found no consistent associations between the 2 allele and CHD risk. They also found that the results of studies sometimes varied because of differences in geographic settings, ethnicity of study samples, allele frequency, CHD phenotypes, and potential geneenvironment interactions. Implications The apoE4 allele is probably a risk factor for CHD. The Editors Apolipoprotein E (apoE) plays a key role in the metabolisms of cholesterol and triglyceride by serving as a receptor-binding ligand mediating the clearance of chylomicron and remnants of very-low-density lipoprotein cholesterol from plasma (1-4). A common polymorphism in the apoE gene that codes for the 3 common isoforms E2, E3, and E4 has been studied extensively. Compared with 3 homozygotes, carriers of the 2 allele, which has defective receptor-binding ability, have lower circulating cholesterol levels and higher triglyceride levels, whereas carriers of the 4 allele appear to have higher plasma levels of total and low-density lipoprotein cholesterol (1). It has been estimated that apoE polymorphism may account for 2% to 11% of the total variation in serum or plasma cholesterol levels in apparently healthy white persons (5). Recent evidence also indicates that apoE may play additional roles in the development of coronary heart disease (CHD) through macrophage cholesterol efflux, platelet aggregation, and allele-specific antioxidant and immune activities (2,6,7). Since Utermann and colleagues first described the effects of apoE polymorphism on dysbetalipoproteinemia (known as type III familial hyperlipoproteinemia) in 1977 (8), numerous epidemiologic studies have investigated the relation between apoE genotypes and CHD risk in the general population, especially in Europe (9-69). Apolipoprotein E polymorphism is believed to confer substantial susceptibility to CHD risk; however, the evidence from population studies remains controversial. In 1996, a meta-analysis of 14 published studies reported that compared with carriers of the apoE 3/3 genotype, carriers of the apoE 4 allele were at greater risk for CHD (odds ratio [OR], 1.26 [95% CI, 1.13 to 1.41]) while the 2 allele was not associated with CHD risk (OR, 0.98 [CI, 0.85 to 1.14]) (70). Since the publication of that review, more than 50 other studies have been conducted involving more than 10 000 additional patients with CHD. However, results have conflicted. Some studies have shown highly significant associations (22-47), while others have shown no association (48-69). Of note, differences in study design, end point validation, and sample, coupled with the fact that most individual studies have very limited statistical power, have led to difficulties in estimating the potentially true but modest effects of apoE genotypes on CHD risk in the general population. In an attempt to understand the cumulative evidence on this topic, we qualitatively and quantitatively examined sources of heterogeneity in previous studies regarding the direct relation of apoE genotypes to CHD risk. To reliably assess the hypothesized apoECHD relationship on the basis of these existing data, we also provided pooled estimates using both a classic random-effects model and a Bayesian hierarchical model. Methods Study Selection We conducted a comprehensive literature search of MEDLINE from 1966 through January 2004 using the following index terms: apolipoprotein E, apoE, APOE polymorphism, atherosclerosis, coronary heart disease, ischemic heart disease, coronary artery disease, and myocardial infarction. We also retrieved additional studies by hand searching the bibliographies of original research reports and review articles. All studies were considered potentially eligible if they aimed to investigate the relation between apoE genotypes and CHD risk. Our selection criteria were qualitatively predefined and required each included study to clearly describe study design, control selection, CHD end points, genotype frequency, and genotyping methods (71). Also, the included studies reported the relative risks or ORs and 95% CIs for CHD related to apoE polymorphism or provided raw data that allowed us to estimate these values. Figure 1 describes the study selection process that led to the final 48 studies in this meta-analysis. Figure 1. Literature search for selected studies. Two of the authors independently identified and reviewed each relevant paper. Disagreements were reconciled through group discussion. The final data set for our meta-analyses included 48 published studies comprising 15 492 case-patients and 32 965 controls. Data Extraction Following the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement for reporting meta-analyses of observational studies (72), we used a standardized reporting form to independently abstract data from each included study. We collected information on the first authors name; country; year of publication; study design; sex studied; mean age or age range for case-patients; major CHD end point; selection of controls (population-based or other); allele frequencies of 2, 3, and 4 among controls; genotype distribution in case-patients and controls; confounding factors by matching or adjustment; and the relative risk or ORs for CHD associated with the apoE genotype. As was done in most previous studies, we defined carriers of the 4 allele as those who had the 3/4 and 4/4 genotypes, defined carriers of the 2 allele as those who had the 2/3 and 2/2 genotypes, and used carriers of the 3/3 genotype as a referent group. Definition of CHD end points included myocardial infarction, angina pectoris, percutaneous transluminal coronary angioplasty, coronary artery bypass graft surgery, and severe stenosis on coronary angiography. In most studies that included case-patients with coronary artery disease, diagnosis was based on angiographically documented luminal stenosis ( 50%) in at least 1 of the 3 major coronary arteries. Study design was classified as prospective if information about relevant variables, including blood sample, was collected before the onset of the CHD event and as retrospective if this information was collected after the event. Studies were also classified as population-based if the controls were selected from the same source population as the case-patients, including the community and the general population. Studies using hospital- or clinic-based patients with other illnesses as controls and studies that used an unidentified healthy control group were considered hospital-based. Data Synthesis Qualitative Analysis We first assessed all potential sources of heterogeneity across studies, following the established principles in evaluating the validity of genetic association studies (71, 73). All major features thought to contribute to between-study heterogeneity were examined a priori, including study design (prospective and retrospective studies; population-based controls and hospital-based controls), population origins (Europe, North America, Asia, and other continents), types of CHD end points (nonfatal myocardial infarction, fatal myocardial infarction, CHD death, and angiographically documented CHD), sex (men, women, and both), presence of HardyWeinberg equilibrium for apoE genotype frequencies among controls (yes or no), and genotyping methods (polymerase chain reactionbased methods vs. phenotype methods). Quantitative Analysis We used both the chi-square statistic and stratified analyses to formally examine between-study heterogeneity using features identified in our qualitative analysis. We synthesized the results from individual studies by using the DerSimonian and Laird random-effects model to incorporate both within-study and between-study variability (74). To further adjust for uncertainty due to between-study heterogeneity, we performed a Bayesian hierarchical (random-effects) model to assess the robustness of our pooled estimates (75, 76). Assuming a normal distribution for the natural logarithms of the OR from each study, we completed the Bayesian specification by assigning prior distributions to the overall mean effect () and between-study variation (2). Assuming that and are independent, we used the diffuse prior distribution for and a diffuse but proper (noninformative) prior distribution for . The posterior estimate for each study was determined through an application of Bayes theorem. The posterior mean for the pooled effect was estimated by combining the posterior mean from each study using the relative weights inversely in proportion to between-study variation. To examine the impact of the prespecified factors on the pooled estimates, we included them with the mean age of CHD case-patients and the allele frequency among controls from each study as study-level variables in the hierarchical model. Finally, we calculated the posterior OR and 95% credible interval (CrI), the Bayesian analogue to CI, for the effect of apoE genotypes on CHD risk. Our Bayesian hierarchical meta-analysis models were performed by using S-Plus programs (S-Plus, version 2000 for Windows, Mathsoft, Inc., Seattle, Washington) written by DuMouchel and colleagues (75, 76). For sensitivity analyses, we compared the pooled estimates from the classic random-effects model with those from Bayesian hierarchical models adjusted for study-level covariates. Furthermore, we examined whether excluding studies with substantial deviation from HardyWeinberg equilibrium among controls or different study-level covariates in the hierarchical model affected our pooled estimates of ORs. We also conducted a cumulative meta-analysis to assess the sufficiency of these accumulating data

Fish Consumption and Incidence of Stroke A Meta-Analysis of Cohort Studies

Background and Purpose— Results from observational studies on fish consumption and risk of stroke are inconsistent. We quantitatively assessed the relationship between fish intake and incidence of stroke using a meta-analysis of cohort studies. Methods— We searched the Medline and Embase databases (1966 through October 2003) and identified 9 independent cohorts (from 8 studies) that provided a relative risk (RR) and corresponding 95% CI for total or any type of stroke in relation to fish consumption. Pooled RR and 95% CI of stroke were estimated by variance-based meta-analysis. Results— Compared with those who never consumed fish or ate fish less than once per month, the pooled RRs for total stroke were 0.91 (95% CI, 0.79 to 1.06) for individuals with fish intake 1 to 3 times per month, 0.87 (95% CI, 0.77 to 0.98) for once per week, 0.82 (95% CI, 0.72 to 0.94) for 2 to 4 times per week, and 0.69 (95% CI, 0.54 to 0.88) for ≥5 times per week (P for trend= 0.06). In stratified analyses of 3 large cohort studies with data on stroke subtypes, the pooled RRs across 5 categories of fish intake were 1.0, 0.69 (95% CI, 0.48 to 0.99), 0.68 (95% CI, 0.52 to 0.88), 0.66 (95% CI, 0.51 to 0.87), and 0.65 (95% CI, 0.46 to 0.93) for ischemic stroke (P for trend= 0.24); and 1.0, 1.47 (95% CI, 0.81 to 2.69), 1.21 (95% CI, 0.78 to 1.85), 0.89 (95% CI, 0.56 to 1.40), and 0.80 (95% CI, 0.44 to 1.47) for hemorrhagic stroke (P for trend= 0.31). Conclusions— These results suggest that intake of fish is inversely related to risk of stroke, particularly ischemic stroke. Fish consumption as seldom as 1 to 3 times per month may protect against the incidence of ischemic stroke.

Associations of dietary flavonoids with risk of type 2 diabetes, and markers of insulin resistance and systemic inflammation in women: a prospective study and cross-sectional analysis.

Objective: Flavonoids, as antioxidants, may prevent the progressive impairment of pancreatic β-cell function due to oxidative stress and may thus reduce the occurrence of type 2 diabetes. The aim of the present study was to examine the association of dietary flavonol and flavone intake with type 2 diabetes, and biomarkers of insulin resistance and systemic inflammation. Methods: In 38,018 women aged ≥45 y and free of cardiovascular disease, cancer and diabetes with an average 8.8y of follow-up, we calculated relative risks (RRs) of incident type 2 diabetes (1,614 events) according to dietary intake of total or individual flavonols and flavones and flavonoid-rich foods. We also measured and examined plasma concentrations of insulin, HbA1C, CRP, and IL-6 in relation to total flavonol and flavone intake among 344 nondiabetic women. Results: During 332,905 person-years of follow-up, none of total flavonols and flavones, quercetin, kaempferol, myricetin, apigenin, and luteolin was significantly associated with risk of type 2 diabetes. Among flavonoid-rich foods, apple and tea consumption was associated with diabetes risk. Women consuming ≥1 apple/d showed a significant 28% reduced risk of type 2 diabetes compared with those who consumed no apples (the multivariate-adjusted RR = 0.72, 95% CI: 0.56, 0.92; p = 0.006 for trend). Tea consumption was also inversely associated with diabetes risk but with a borderline significant trend (≥4 cups/d vs. none: RR 0.73, 95% CI: 0.52–1.01; p for trend = 0.06). In 344 nondiabetic women, total intake of flavonols and flavones was not significantly related to plasma concentrations of fasting insulin, HbA1C, CRP, or IL-6. Conclusions: These results do not support the hypothesis that high intake of flavonols and flavones reduces the development of type 2 diabetes, although we cannot rule out a modest inverse association with intake of apples and tea.

Insulin Sensitivity and Insulin Secretion Determined by Homeostasis Model Assessment and Risk of Diabetes in a Multiethnic Cohort of Women: The Women's Health Initiative Observational Study

OBJECTIVE— The homeostasis model assessment (HOMA), based on plasma levels of fasting glucose and insulin, has been widely validated and applied for quantifying insulin resistance and β-cell function. However, prospective data regarding its relation to diabetes risk in ethnically diverse populations are limited. RESEARCH DESIGN AND METHODS— Among 82,069 women who were aged 50–79 years, free of cardiovascular disease or diabetes, and participating in the Womens Health Initiative Observational Study, we conducted a nested case-control study to prospectively examine the relations of HOMA of insulin resistance (HOMA-IR) and β-cell function (HOMA-B) with diabetes risk. During a median follow-up period of 5.9 years, 1,584 diabetic patients were matched with 2,198 control subjects by age, ethnicity, clinical center, time of blood draw, and follow-up time. RESULTS— Baseline levels of fasting glucose, insulin, and HOMA-IR were each significantly higher among case compared with control subjects, while HOMA-B was lower (all P values <0.0001). After adjustment for matching factors and diabetes risk factors, all four markers were significantly associated with diabetes risk; the estimated relative risks per SD increment were 3.54 (95% CI 3.02–4.13) for fasting glucose, 2.25 (1.99–2.54) for fasting insulin, 3.40 (2.95–3.92) for HOMA-IR, and 0.57(0.51–0.63) for HOMA-B. While no statistically significant multiplicative interactions were observed between these markers and ethnicity, the associations of both HOMA-IR and HOMA-B with diabetes risk remained significant and robust in each ethnic group, including whites, blacks, Hispanics, and Asians/Pacific Islanders. When evaluated jointly, the relations of HOMA-IR and HOMA-B with diabetes risk appeared to be independent and additive. HOMA-IR was more strongly associated with an increased risk than were other markers after we excluded those with fasting glucose ≥126 mg/dl at baseline. CONCLUSIONS— High HOMA-IR and low HOMA-B were independently and consistently associated with an increased diabetes risk in a multiethnic cohort of U.S. postmenopausal women. These data suggest the value of HOMA indexes for diabetes risk in epidemiologic studies.

Effects of oral magnesium supplementation on glycaemic control in type 2 diabetes: a meta-analysis of randomized double-blind controlled trials

Aimsu2003 The aim of this study was to assess the evidence on the effect of oral magnesium supplementation on glycaemic control in patients with Type 2 diabetes.

Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study

Aims/hypothesisProspective data directly investigating the role of endogenous sex hormones in diabetes risk have been scant, particularly in women. We aimed to examine comprehensively plasma sex hormones in connection with risk of developing type 2 diabetes in postmenopausal women.MethodsWe conducted a prospective, nested case–control study of plasma oestradiol, testosterone and dehydroepiandrosterone sulfate and risk of type 2 diabetes in a cohort of women health professionals with a mean age of 60.3 and 12.2xa0years since menopause. Among women not using hormone therapy and free of baseline cardiovascular disease, cancer and diabetes, 359 incident cases of type 2 diabetes were matched with 359 controls during an average follow-up of 10xa0years.ResultsOestradiol and testosterone were each strongly and positively associated with risk of type 2 diabetes. After adjustment for BMI, family history, lifestyle and reproductive variables, the multivariable relative risks (95% CI) comparing the highest vs lowest quintile were 12.6 (2.83–56.3) for total oestradiol (pu2009=u20090.002 for trend), 13.1 (4.18–40.8) for free oestradiol (pu2009<u20090.001 for trend), 4.15 (1.21–14.2) for total testosterone (pu2009=u20090.019 for trend) and 14.8 (4.44–49.2) for free testosterone (pu2009<u20090.001 for trend). These associations remained robust after adjusting and accounting for other metabolic syndrome components and baseline HbA1c levels.Conclusions/interpretationIn postmenopausal women, higher plasma levels of oestradiol and testosterone were strongly and prospectively related to increased risk of developing type 2 diabetes. These prospective data indicate that endogenous levels of sex hormones may play important roles in the pathogenesis of type 2 diabetes.ClinicalTrials.gov ID no.: NCT00000479.

Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians

Aims/hypothesisFTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.MethodsAll studies published on the association between FTO-rs9939609 (or proxy [r2u2009>u20090.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.ResultsThe FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (pu2009=u20099.0u2009×u200910−19), overweight by 1.13-fold/allele (pu2009=u20091.0u2009×u200910−11) and type 2 diabetes by 1.15-fold/allele (pu2009=u20095.5u2009×u200910−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, pu2009=u20096.6u2009×u200910−5). The FTO-rs9939609 minor allele increased BMI by 0.26xa0kg/m2 per allele (pu2009=u20092.8u2009×u200910−17), WHR by 0.003/allele (pu2009=u20091.2u2009×u200910−6), and body fat percentage by 0.31%/allele (pu2009=u20090.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.Conclusions/interpretationFTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.

Are Variants in the CAPN10 Gene Related to Risk of Type 2 Diabetes? A Quantitative Assessment of Population and Family-Based Association Studies

The calpain-10 gene (CAPN10) on chromosome 2q37.3 was the first candidate gene for type 2 diabetes (T2D) identified through a genomewide screen and positional cloning. One polymorphism (UCSNP-43: G-->A) and a specific haplotype combination defined by three polymorphisms (UCSNP-43, -19, and -63) were linked to an increased risk of T2D in several populations. To quantitatively assess the collective evidence for the effects of CAPN10 on risk of T2D, we conducted a meta-analysis of both population-based and family-based association studies. We retrieved data from the MEDLINE, PubMed, and Online Mendelian Inheritance in Man databases, as well as from other relevant reports and abstracts published up to July 2003. From a total of 26 studies with primary data (21 population-based studies: 5,013 cases and 5,876 controls; 5 family-based studies: 487 parent-offspring trios), we developed a summary database that contains variables of study design, study population/ethnicity, specific polymorphisms and haplotype combinations in CAPN10, and diabetes-related metabolic phenotypes. For population-based studies, we used both fixed-effects and random-effects models to calculate the pooled odds ratio (OR) and 95% confidence interval (CI) for the associations of CAPN10 genotypes with the risk of T2D. We also calculated weighted mean differences for the associations between CAPN10 and diabetes-related quantitative traits. Under either an additive or a dominant effect model, we found no statistically significant relation between CAPN10 genotypes in the UCSNP-43 locus and T2D risk. However, under a recessive model, individuals homozygous for the common G allele had a statistically significant 19% higher risk of T2D than carriers of the A allele (OR 1.19; 95% CI 1.07-1.33). The association between the 112/121 haplotype combination and T2D risk appeared to be overestimated by several initial small studies with positive findings (OR 1.38; 95% CI 1.04-1.84). After we removed these initial studies, this association became nonsignificant (OR 1.11; 95% CI 0.91-1.35). Moreover, we found no evidence for the associations between the UCSNP-43 G/G genotype and the 112/121 haplotype combination and metabolic phenotypes. Our meta-analysis of family-based studies showed only an overtransmission of the rare allele C in UCSNP-44 from heterozygous parents to their affected offspring with T2D. Our analysis indicates that inadequate statistical power, racial/ethnic differences in frequencies of alleles, haplotypes and haplotype combinations, potential gene-gene or gene-environment interactions, publication bias, and multiple hypothesis testing may contribute to the significant heterogeneity in previous studies of CAPN10 and T2D. Our findings also suggest that both large-scale, well-designed association studies and functional studies are warranted to either reliably confirm or conclusively refute the initial hypothesis regarding the role of CAPN10 in T2D risk.

Effects of vitamins C and E and β-carotene on the risk of type 2 diabetes in women at high risk of cardiovascular disease: a randomized controlled trial

BACKGROUNDnVitamin C, vitamin E, and beta-carotene are major antioxidants and as such may protect against the development of type 2 diabetes via reduction of oxidative stress.nnnOBJECTIVEnThe purpose of this study was to investigate the long-term effects of supplementation with vitamin C, vitamin E, and beta-carotene for primary prevention of type 2 diabetes.nnnDESIGNnIn the Womens Antioxidant Cardiovascular Study, a randomized trial that occurred between 1995 and 2005, 8171 female health professionals aged > or =40 y with either a history of cardiovascular disease (CVD) or > or =3 CVD risk factors were randomly assigned to receive vitamin C (ascorbic acid, 500 mg every day), vitamin E (RRR-alpha-tocopherol acetate, 600 IU every other day), beta-carotene (50 mg every other day), or their respective placebos.nnnRESULTSnDuring a median follow-up of 9.2 y, a total of 895 incident cases occurred among 6574 women who were free of diabetes at baseline. There was a trend toward a modest reduction in diabetes risk in women assigned to receive vitamin C compared with those assigned to receive placebo [relative risk (RR): 0.89; 95% CI: 0.78, 1.02; P = 0.09], whereas a trend for a slight elevation in diabetes risk was observed for vitamin E treatment (RR: 1.13; 95% CI: 0.99, 1.29; P = 0.07). However, neither of these effects reached statistical significance. No significant effect was observed for beta-carotene treatment (RR: 0.97; 95% CI: 0.85, 1.11; P = 0.68).nnnCONCLUSIONnOur randomized trial data showed no significant overall effects of vitamin C, vitamin E, and beta-carotene on risk of developing type 2 diabetes in women at high risk of CVD. This trial was registered at clinicaltrials.gov as NCT00000541.