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1.  Cardiovascular Complications and Mortality After Diabetes Diagnosis for South Asian and Chinese Patients 
Diabetes Care  2013;36(9):2670-2676.
OBJECTIVE
Many non-European ethnic groups have an increased risk for diabetes; however, the published literature demonstrates considerable uncertainty about the rates of diabetes complications among minority populations. The objective of this study was to determine the risks of cardiovascular complications and of mortality after diabetes diagnosis for South Asian and Chinese patients, compared with European patients.
RESEARCH DESIGN AND METHODS
A population-based cohort study identified all 491,243 adults with newly diagnosed diabetes in Ontario, Canada, between April 2002 and March 2009. Subjects were followed until March 2011 for the first occurrence of any cardiovascular complication of diabetes (coronary artery disease, stroke, or lower-extremity amputation) and for all-cause mortality. Median follow-up was 4.7 years.
RESULTS
The crude incidence of cardiovascular complications after diabetes diagnosis was 17.9 per 1,000 patient-years among European patients, 12.0 among South Asian patients, and 7.7 among Chinese patients. After adjusting for baseline characteristics, the cause-specific hazard ratios (HRs) for cardiovascular complications relative to European patients were 0.95 (95% CI 0.90–1.00; P = 0.056) and 0.50 (0.46–0.53; P < 0.001) for South Asian and Chinese patients, respectively. Mortality was lower for both minority groups (adjusted HR for South Asian patients 0.56 [95% CI 0.52–0.60]; P < 0.001; for Chinese patients 0.58 [0.55–0.62]; P < 0.001).
CONCLUSIONS
Chinese patients were at substantially lower risk than European patients for cardiovascular complications after diabetes diagnosis, whereas South Asian patients were at comparable risk. Mortality after diabetes diagnosis was markedly lower for both minority populations.
doi:10.2337/dc12-2105
PMCID: PMC3747942  PMID: 23637350
2.  Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema 
Pharmacogenetics and genomics  2013;23(9):470-478.
Objective
The objective of this study was to identify genetic variants associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema.
Participants and methods
We carried out a genome-wide association study in 175 individuals with ACE inhibitor-associated angioedema and 489 ACE inhibitor-exposed controls from Nashville (Tennessee) and Marshfield (Wisconsin). We tested for replication in 19 cases and 57 controls who participated in Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET).
Results
There were no genome-wide significant associations of any single-nucleotide polymorphism (SNP) with angioedema. Sixteen SNPs in African Americans and 41 SNPs in European Americans were associated moderately with angioedema (P<10−4) and evaluated for association in ONTARGET. The T allele of rs500766 in PRKCQ was associated with a reduced risk, whereas the G allele of rs2724635 in ETV6 was associated with an increased risk of ACE inhibitor-associated angioedema in the Nashville/Marshfield sample and ONTARGET. In a candidate gene analysis, rs989692 in the gene encoding neprilysin (MME), an enzyme that degrades bradykinin and substance P, was significantly associated with angioedema in ONTARGET and Nashville/Marshfield African Americans.
Conclusion
Unlike other serious adverse drug effects, ACE inhibitor-associated angioedema is not associated with a variant with a large effect size. Variants in MME and genes involved in immune regulation may be associated with ACE inhibitor-associated angioedema.
doi:10.1097/FPC.0b013e328363c137
PMCID: PMC3904664  PMID: 23838604
adverse drug event; angioedema; angiotensin-converting enzyme; neprilysin
3.  Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multiethnic Population 
Diabetes Care  2013;36(9):2836-2842.
OBJECTIVE
To determine if 16 single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2DM) in Europeans are also associated with T2DM in South Asians and Latinos and if they can add to the prediction of incident T2DM in a high-risk population.
RESEARCH DESIGN AND METHODS
In the EpiDREAM prospective cohort study, physical measures, questionnaires, and blood samples were collected from 25,063 individuals at risk for dysglycemia. Sixteen SNPs that have been robustly associated with T2DM in Europeans were genotyped. Among 15,466 European, South Asian, and Latino subjects, we examined the association of these 16 SNPs alone and combined in a gene score with incident cases of T2DM (n = 1,016) that developed during 3.3 years of follow-up.
RESULTS
Nine of the 16 SNPs were significantly associated with T2DM, and their direction of effect was consistent across the three ethnic groups. The gene score was significantly higher among subjects who developed incident T2DM (cases vs. noncases: 16.47 [2.50] vs. 15.99 [2.56]; P = 0.00001). The gene score remained an independent predictor of incident T2DM, with an odds ratio of 1.08 (95% CI 1.05–1.11) per additional risk allele after adjustment for T2DM risk factors. The gene score in those with no family history of T2DM was 16.02, whereas it was 16.19 in those with one parent with T2DM and it was 16.32 in those with two parents with T2DM (P trend = 0.0004). The C statistic of T2DM risk factors was 0.708 (0.691–0.725) and increased only marginally to 0.714 (0.698–0.731) with the addition of the gene score (P for C statistic change = 0.0052).
CONCLUSIONS
T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
doi:10.2337/dc12-2553
PMCID: PMC3747911  PMID: 23603917
4.  Does genetic heterogeneity account for the divergent risk of type 2 diabetes in South Asian and white European populations? 
Diabetologia  2014;57(11):2270-2281.
Aims/hypothesis
South Asians are up to four times more likely to develop type 2 diabetes than white Europeans. It is postulated that the higher prevalence results from greater genetic risk. To evaluate this hypothesis, we: (1) systematically reviewed the literature for single nucleotide polymorphisms (SNPs) predisposing to type 2 diabetes in South Asians; (2) compared risk estimates, risk alleles and risk allele frequencies of predisposing SNPs between South Asians and white Europeans; and (3) tested the association of novel SNPs discovered from South Asians in white Europeans.
Methods
MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the Cochrane registry were searched for studies of genetic variants associated with type 2 diabetes in South Asians. Meta-analysis estimates for common and novel bi-allelic SNPs in South Asians were compared with white Europeans from the DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) consortium. The population burden from predisposing SNPs was assessed using a genotype score.
Results
Twenty-four SNPs from 21 loci were associated with type 2 diabetes in South Asians after meta-analysis. The majority of SNPs increase odds of the disorder by 15–35% per risk allele. No substantial differences appear to exist in risk estimates between South Asians and white Europeans from SNPs common to both groups, and the population burden also does not differ. Eight of the 24 are novel SNPs discovered from South Asian genome-wide association studies, some of which show nominal associations with type 2 diabetes in white Europeans.
Conclusions/interpretation
Based on current literature there is no strong evidence to indicate that South Asians possess a greater genetic risk of type 2 diabetes than white Europeans.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3354-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-014-3354-1
PMCID: PMC4180911  PMID: 25145545
Epidemiology; Ethnicity; Genetic risk; Meta-analysis; South Asian; Type 2 diabetes; White Europeans
5.  Cardiovascular risk among South Asians living in Canada: a systematic review and meta-analysis 
CMAJ Open  2014;2(3):E183-E191.
Background
South Asians represent about 3% of the Canadian population and have a higher burden of certain cardiovascular risk factors and cardiovascular disease (CVD) compared with white people. The objective of this study was to review the literature to compare cardiovascular risk factors and disease management practices among adult South Asian and white Canadians.
Methods
We searched MEDLINE, Embase, Cochrane and Cumulative Index to Nursing and Allied Health Literature databases from their inception through Feb. 17, 2014 and the reference lists of the selected articles. English-language studies of interventions and observational studies of biological mechanisms underlying CVD risk in South Asians conducted in Canada were eligible for inclusion. Where appropriate, we used random-effects meta-analyses to integrate results comparing the CVD risk profiles of South Asian and white Canadians.
Results
We included 50 articles (n = 5 805 313 individuals) in this review. Compared with white Canadians, South Asian Canadians had a higher prevalence and incidence of CVD, an increased prevalence of diabetes (odds ratio [OR] 2.25, 95% confidence interval [CI] 1.81 to 2.80, p < 0.001) and hypertension (OR 1.11, 95% CI 1.02 to 1.22, p = 0.02), lower high-density lipoprotein cholesterol levels (mean difference –0.19 mmol/L, 95% CI –0.25 to –0.13 mmol/L, p < 0.001) and a higher percentage of body fat (men: absolute mean difference 3.23%, 95% CI 0.83% to 5.62%, p = 0.008; women: absolute mean difference 4.09%, 95% CI 3.46% to 4.72%, p < 0.001). South Asian people are also more sedentary, consume higher levels of carbohydrates and are less likely to smoke tobacco (OR 0.38, 95% CI 0.24 to 0.60, p < 0.001]) than white Canadians. No differences in access to diagnostic tests, outcomes following cardiovascular surgery or use of cardiac rehabilitation programs were apparent.
Interpretation
Compared with white people, South Asian people living in Canada have a higher prevalence and incidence of CVD and possess a unique cardiovascular risk profile.
doi:10.9778/cmajo.20130064
PMCID: PMC4183167  PMID: 25295238
6.  The association between ownership of common household devices and obesity and diabetes in high, middle and low income countries 
Background:
Household devices (e.g., television, car, computer) are common in high income countries, and their use has been linked to obesity and type 2 diabetes mellitus. We hypothesized that device ownership is associated with obesity and diabetes and that these effects are explained through reduced physical activity, increased sitting time and increased energy intake.
Methods:
We performed a cross-sectional analysis using data from the Prospective Urban Rural Epidemiology study involving 153 996 adults from high, upper-middle, lower-middle and low income countries. We used multilevel regression models to account for clustering at the community and country levels.
Results:
Ownership of a household device increased from low to high income countries (4% to 83% for all 3 devices) and was associated with decreased physical activity and increased sitting, dietary energy intake, body mass index and waist circumference. There was an increased odds of obesity and diabetes with the ownership of any 1 household device compared to no device ownership (obesity: odds ratio [OR] 1.43, 95% confidence interval [CI] 1.32–1.55; diabetes: OR 1.38, 95% CI 1.28–1.50). Ownership of a second device increased the odds further but ownership of a third device did not. Subsequent adjustment for lifestyle factors modestly attenuated these associations. Of the 3 devices, ownership of a television had the strongest association with obesity (OR 1.39, 95% CI 1.29–1.49) and diabetes (OR 1.33, 95% CI 1.23–1.44). When stratified by country income level, the odds of obesity and diabetes when owning all 3 devices was greatest in low income countries (obesity: OR 3.15, 95% CI 2.33–4.25; diabetes: OR 1.97, 95% CI 1.53–2.53) and decreased through country income levels such that we did not detect an association in high income countries.
Interpretation:
The ownership of household devices increased the likelihood of obesity and diabetes, and this was mediated in part by effects on physical activity, sitting time and dietary energy intake. With increasing ownership of household devices in developing countries, societal interventions are needed to mitigate their effects on poor health.
doi:10.1503/cmaj.131090
PMCID: PMC3940572  PMID: 24516093
7.  Meta-analysis of genetic association studies under heterogeneity 
European Journal of Human Genetics  2012;20(11):1174-1181.
In multi-cohort genetic association studies or meta-analysis, associations of genetic variants with complex traits across cohorts may be heterogeneous because of genuine genetic diversity or differential biases or errors. To detect the associations of genes with heterogeneous associations across cohorts, new global fixed-effect (FE) and random-effects (RE) meta-analytic methods have been recently proposed. These global methods had improved power over both traditional FE and RE methods under heterogeneity in limited simulation scenarios and data application, but their usefulness in a wide range of practical situations is not clear. We assessed the performance of these methods for both binary and quantitative traits in extensive simulations and applied them to a multi-cohort association study. We found that these new approaches have higher power to detect mostly the very small to small associations of common genetic variants when associations are highly heterogeneous across cohorts. They worked well when both the underlying and assumed genetic models are either multiplicative or dominant. But, they offered no clear advantage for less common variants unless heterogeneity was substantial. In conclusion, these new meta-analytic methods can be used to detect the association of genetic variants with high heterogeneity, which can then be subjected to further exploration, in multi-cohort association studies and meta-analyses.
doi:10.1038/ejhg.2012.75
PMCID: PMC3476718  PMID: 22643179
genome-wide and genetic association studies; single-nucleotide polymorphism; meta-analysis; study heterogeneity; statistical power; type I error rates
8.  Race/Ethnicity, Obesity, and Related Cardio-Metabolic Risk Factors: A Life-Course Perspective 
The adoption of health behaviors characterized by minimal energy expenditure and overconsumption of energy has led to cardiometabolic risk factors in pregnancy, childhood, and youth, all of which increase the prevalence of cardiovascular disease in adulthood. The propensity to develop abdominal obesity and cardiometabolic risk factors appears to disproportionally affect non-white ethnic groups. While the majority of observational research has been conducted in populations of European origin, studies in non-white ethnic groups across the life-course are underway and there is evidence that unique ethnic-specific differences exist. This review will focus on the life-course determinants of obesity and its related cardio-metabolic risk factors among diverse ethnic groups including people of Afro-Caribbean origin, South Asian, East Asian, and indigenous ancestry.
doi:10.1007/s12170-013-0329-6
PMCID: PMC3962848  PMID: 24672590
Obesity; Ethnicity; Cardiometabolic risk factors
9.  South Asian Heart Risk Assessment (SAHARA): Randomized Controlled Trial Design and Pilot Study 
JMIR Research Protocols  2013;2(2):e33.
Background
People of South Asian origin suffer a high burden of premature myocardial infarction (MI). South Asians form a growing proportion of the Canadian population and preventive strategies to mitigate the risk of MI in this group are needed. Prior studies have shown that multimedia interventions are effective and feasible in inducing health behavior changes among the obese, smokers, and among those who are sedentary.
Objective
Among at-risk South Asians living in Canada, our objectives are to determine: (1) the feasibility of a culturally tailored multimedia intervention to induce positive behavioral changes associated with reduced MI risk factors, and (2) the effectiveness and acceptability of information communicated by individualized MI and genetic risk score (GRS) reports.
Methods
The South Asian HeArt Risk Assessment (SAHARA) pilot study enrolled 367 individuals of South Asian origin recruited from places of worship and community centers in Ontario, Canada. MI risk factors including the 9p21 genetic variant status were provided to all participants after the baseline visit. Participants were randomly allocated to receive a multimedia intervention or control. The intervention group selected health goals and received personalized health messages to promote adherence to their selected goals. After 6 months, all participants had their MI risk factors repeated. The methods and results of this study are reported based on the CONSORT-EHEALTH guidelines.
Results
The mean age of participants was 53.8 years (SD 11.4), 52.0% (191/367) were women, and 97.5% (358/367) were immigrants to Canada. The mean INTERHEART risk score was 13.0 (SD 5.8) and 73.3% (269/367) had one or two copies of the risk allele for the 9p21 genetic variant. Both the intervention and control groups made some progress in health behavior changes related to diet and physical activity over 6 months. Participants reported that their risk score reports motivated behavioral changes, although half of the participants could not recall their risk scores at the end of study evaluation. Some components of the multimedia intervention were not widely used such as logging onto the website to set new health goals, and participants requested having more personal interactions with the study team.
Conclusions
Some, but not all, components of the multimedia intervention are feasible and have the potential to induce positive health behavior changes. MI and GRS reports are desired by participants although their impact on inducing sustained health behavior change requires further evaluation. Information generated from this pilot study has directly informed the design of another randomized trial designed to reduce MI risk among South Asians.
Trial Registration
ClinicalTrials.gov NCT01577719; http://clinicaltrials.gov/ct2/show/NCT01577719 (Archived by WebCite at http://www.webcitation.org/6J11uYXgJ).
doi:10.2196/resprot.2621
PMCID: PMC3757993  PMID: 23965279
multimedia; South Asians; health; risk; assessment; randomized; trial
10.  Aboriginal birth cohort (ABC): a prospective cohort study of early life determinants of adiposity and associated risk factors among Aboriginal people in Canada 
BMC Public Health  2013;13:608.
Background
Aboriginal people living in Canada have a high prevalence of obesity, type 2 diabetes, and cardiovascular disease (CVD). To better understand the pre and postnatal influences on the development of adiposity and related cardio-metabolic factors in adult Aboriginal people, we will recruit and follow prospectively Aboriginal pregnant mothers and their children – the Aboriginal Birth Cohort (ABC) study.
Methods/design
We aim to recruit 300 Aboriginal pregnant mothers and their newborns from the Six Nations Reserve, and follow them prospectively to age 3 years. Key details of environment and health including maternal nutrition, glucose tolerance, physical activity, and weight gain will be collected. At birth, cord blood and placenta samples will be collected, as well as newborn anthropometric measurements. Mothers and offspring will be followed annually with serial measurements of diet and physical activity, growth trajectory, and adiposity.
Discussion
There is an urgent need to understand maternal and child factors that underlie the early development of adiposity and type 2 diabetes in Aboriginal people. The information generated from this cohort will assist the Six Nations community in developing interventions to prevent early adiposity in Aboriginal children.
doi:10.1186/1471-2458-13-608
PMCID: PMC3702421  PMID: 23800270
Aboriginal; Birth cohort; Early origins; Adiposity
11.  Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population 
PLoS ONE  2013;8(6):e66808.
Background
Adiponectin, a secretagogue exclusively produced by adipocytes, has been associated with metabolic features, but its role in the development of the metabolic syndrome remains unclear.
Objectives
We investigated the association between serum adiponectin level and metabolic traits, using both observational and genetic epidemiologic approaches in a multiethnic population assembled in Canada.
Methods
Clinical data and serum adiponectin level were collected in 1,157 participants of the SHARE/SHARE-AP studies. Participants were genotyped for the functional rs266729 and rs1260326 SNPs in ADIPOQ and GCKR genes.
Results
Adiponectin level was positively associated with HDL cholesterol and negatively associated with body mass index, waist-to-hip ratio, triglycerides, fasting glucose, fasting insulin, systolic and diastolic pressure (all P<0.002). The rs266729 minor G allele was associated with lower adiponectin and higher HOMA-IR (P = 0.004 and 0.003, respectively). The association between rs266729 SNP and HOMA-IR was no longer significant after adjustment for adiponectin concentration (P = 0.10). The rs266729 SNP was associated with HOMA-IR to an extent that exceeded its effect on adiponectin level (0.15 SD 95% C.I. [0.06, 0.24], P<0.001). There was no significant interaction between rs266729 SNP and ethnicity on adiponectin or HOMA-IR. In contrast, the SNP rs1260326 in GCKR was associated with HOMA-IR (P<0.001), but not with adiponectin level (P = 0.67).
Conclusion
The association of the functional promoter polymorphism rs266729 with lower serum adiponectin and increased insulin resistance in diverse ethnic groups may suggest a causal relationship between adiponectin level and insulin resistance.
doi:10.1371/journal.pone.0066808
PMCID: PMC3691277  PMID: 23826141
12.  Absence of Disparities in the Quality of Primary Diabetes Care for South Asians and Chinese in an Urban Canadian Setting 
Diabetes Care  2012;35(4):794-796.
OBJECTIVE
To examine whether quality of diabetes care is equitable for South Asian and Chinese patients in an urban Canadian setting.
RESEARCH DESIGN AND METHODS
Process and intermediate measures of quality of care were compared between 246 South Asians, 170 Chinese, and 431 patients from the general population with type 2 diabetes selected from 45 family physicians’ practices.
RESULTS
A total of 61% of Chinese achieved A1C ≤7.0% versus 45% of South Asians and 49% of the general population (P < 0.05). They were also more likely to achieve LDL cholesterol ≤2.0 mmol/L, while South Asians were more likely to achieve blood pressure ≤130/80. There was only one significant process of care deficiency: fewer foot examinations among South Asians (34 vs. 49% for the general population, P < 0.01).
CONCLUSIONS
Quality of diabetes care in a Canadian urban setting was equitable, with ethnic minorities somewhat more likely to achieve recommended targets than the general population.
doi:10.2337/dc11-1845
PMCID: PMC3308276  PMID: 22323411
13.  Maternal and Pregnancy Related Predictors of Cardiometabolic Traits in Newborns 
PLoS ONE  2013;8(2):e55815.
Background
The influence of multiple maternal and pregnancy characteristics on offspring cardiometabolic traits at birth is not well understood and was evaluated in this study.
Methods and Findings
The Family Atherosclerosis Monitoring In earLY life (FAMILY) Study prospectively evaluated 11 cardiometabolic traits in 901 babies born to 857 mothers. The influence of maternal age, health (pre-pregnancy weight, blood pressure, glycemic status, lipids), health behaviors (diet, activity, smoking) and pregnancy characteristics (gestational age at birth, gestational weight gain and placental-fetal ratio) were examined. Greater gestational age influenced multiple newborn cardiometabolic traits including cord blood lipids, glucose and insulin, body fat and blood pressure. In a subset of 442 singleton mother/infant pairs, principal component analysis grouped 11 newborn cardiometabolic traits into 5 components (anthropometry/insulin, 2 lipid components, blood pressure and glycemia), accounting for 74% of the variance of the 11 outcome variables. Determinants of these components, corrected for sex and gestational age, were examined. Baby anthropometry/insulin was independently predicted by higher maternal pre-pregnancy weight (standardized estimate 0.30) and gestational weight gain (0.30; both p<0.0001) and was inversely related to smoking during pregnancy (−0.144; p = 0.01) and maternal polyunsaturated to saturated fat intake (−0.135;p = 0.01). Component 2 (HDL-C/Apo Apolipoprotein1) was inversely associated with maternal age. Component 3 (blood pressure) was not clustered with any other newborn cardiometabolic trait and no associations with maternal pregnancy characteristics were identified. Component 4 (triglycerides) was positively associated with maternal hypertension and triglycerides, and inversely associated with maternal HDL and age. Component 5 (glycemia) was inversely associated with placental/fetal ratio (−0.141; p = 0.005). LDL-C was a bridging variable between the lipid factors and glycemia.
Conclusions
Maternal health, health behaviours and placenta to fetal weight ratio are associated with newborn cardiometabolic traits over and above gestational age. Future investigations are needed to determine if these factors remain important determinants of cardiometabolic health throughout childhood.
doi:10.1371/journal.pone.0055815
PMCID: PMC3572188  PMID: 23418462
14.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
Objective
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
Conclusion
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
doi:10.1161/ATVBAHA.111.226365
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
15.  Excess of Rare Variants in Non-GWAS Candidate Genes in Patients with Hypertriglyceridemia 
Background
Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus controls. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human Mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG.
Methods and Results
We resequenced protein coding regions of 3 genes with established roles (APOC2, GPIHBP1, LMF1) and 2 genes recently implicated (CREB3L3 and ZHX3) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 controls (OR=2.3; P=0.0050). Post hoc assessment of genetic burden in individual genes using three different tests suggested that the genetic burden was most prominent in the established genes LMF1 and APOC2, and also in the recently identified CREB3L3 gene.
Conclusions
These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies.
doi:10.1161/CIRCGENETICS.111.960864
PMCID: PMC3288444  PMID: 22135386
hyperlipoproteinemia; genetics; apolipoproteins; lipoproteins; cardiovascular diseases
16.  Rationale and design of South Asian Birth Cohort (START): a Canada-India collaborative study 
BMC Public Health  2013;13:79.
Background
People who originate from the Indian subcontinent (South Asians) suffer among the highest rates of type 2 diabetes in the world. Prior evidence suggests that metabolic risk factors develop early in life and are influenced by maternal and paternal behaviors, the intrauterine environment, and genetic factors. The South Asian Birth Cohort Study (START) will investigate the environmental and genetic basis of adiposity among 750 South Asian offspring recruited from highly divergent environments, namely, rural and urban India and urban Canada.
Methods
Detailed information on health behaviors including diet and physical activity, and blood samples for metabolic parameters and DNA are collected from pregnant women of South Asian ancestry who are free of significant chronic disease. They also undergo a provocative test to diagnose impaired glucose tolerance and gestational diabetes. At delivery, cord blood and newborn anthropometric indices (i.e. birth weight, length, head circumference and skin fold thickness) are collected. The mother and growing offspring are followed prospectively and information on the growth trajectory, adiposity and health behaviors will be collected annually up to age 3 years. Our aim is to recruit a minimum of 750 mother-infant pairs equally divided between three divergent environments: rural India, urban India, and Canada.
Summary
The START cohort will increase our understanding of the environmental and genetic determinants of adiposity and related metabolic abnormalities among South Asians living in India and Canada.
doi:10.1186/1471-2458-13-79
PMCID: PMC3585827  PMID: 23356884
Birth cohort; South Asian; Adiposity; Insulin resistance; Early origins; India; Canada
17.  Effectiveness of inpatient and outpatient strategies in increasing referral and utilization of cardiac rehabilitation: a prospective, multi-site study 
Background
Despite the evidence of benefit, cardiac rehabilitation (CR) remains highly underutilized. The present study examined the effect of two inpatient and one outpatient strategy on CR utilization: allied healthcare provider completion of referral (a policy that had been endorsed and approved by the cardiac program leadership in advance; PRE-APPROVED); CR intake appointment booked before hospital discharge (PRE-BOOKED); and early outpatient education provided at the CR program shortly after inpatient discharge (EARLY ED).
In this prospective observational study, 2,635 stable cardiac inpatients from 11 Ontario hospitals completed a sociodemographic survey, and clinical data were extracted from charts. One year later, participants were a mailed survey that assessed CR use. Participating inpatient units and CR programs to which patients were referred were coded to reflect whether each of the strategies was used (yes/no). The effect of each strategy on participants’ CR referral and enrollment was examined using generalized estimating equations.
Results
A total of 1,809 participants completed the post-test survey. Adjusted analyses revealed that the implementation of one of the inpatient strategies was significantly related to greater referral and enrollment (PRE-APPROVED: OR = 1.96, 95%CI = 1.26 to 3.05, and OR = 2.91, 95%CI = 2.20 to 3.85, respectively). EARLY ED also resulted in significantly greater enrollment (OR = 4.85, 95%CI = 2.96 to 7.95).
Conclusions
These readily-implementable strategies could significantly increase access to and enrollment in CR for the cardiac population. The impact of these strategies on wait times warrants exploration.
doi:10.1186/1748-5908-7-120
PMCID: PMC3541119  PMID: 23234558
Cardiac rehabilitation; Patient care management; Cardiovascular diseases
18.  Gene-Centric Meta-Analysis of Lipid Traits in African, East Asian and Hispanic Populations 
PLoS ONE  2012;7(12):e50198.
Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of ∼2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom ∼50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8×10−7 and p = 1.5×10−6 respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5×10−12). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report.
doi:10.1371/journal.pone.0050198
PMCID: PMC3517599  PMID: 23236364
19.  Contextual determinants of health behaviours in an aboriginal community in Canada: pilot project 
BMC Public Health  2012;12:952.
Background
Rapid change in food intake, physical activity, and tobacco use in recent decades have contributed to the soaring rates of obesity, type 2 diabetes and cardiovascular disease (CVD) in Aboriginal populations living in Canada. The nature and influence of contextual factors on Aboriginal health behaviours are not well characterized.
Methods
To describe the contextual determinants of health behaviours associated with cardiovascular risk factors on the Six Nations reserve, including the built environment, access and affordability of healthy foods, and the use of tobacco.
In this cross-sectional study, 63 adults from the Six Nations Reserve completed the modified Neighbourhood Environment Walkability Scale (NEWS), questionnaire assessing food access and availability, tobacco pricing and availability, and the Environmental Profile of Community Health (EPOCH) tool.
Results
The structured environment of Six Nations Reserve scored low for walkability, street connectivity, aesthetics, safety, and access to walking and cycling facilities. All participants purchased groceries off-reserve, although fresh fruits and vegetables were reported to be available and affordable both on and off-reserve. On average $151/week is spent on groceries per family. Ninety percent of individuals report tobacco use is a problem in the community. Tobacco is easily accessible for children and youth, and only three percent of community members would accept increased tobacco taxation as a strategy to reduce tobacco access.
Conclusions
The built environment, access and affordability of healthy food and tobacco on the Six Nations Reserve are not perceived favourably. Modification of these contextual factors described here may reduce adverse health behaviours in the community.
doi:10.1186/1471-2458-12-952
PMCID: PMC3497592  PMID: 23134669
Obesity; Aboriginal health; Health behaviours; Environment design
20.  Smoking Cessation Intervention in a Cardiovascular Hospital Based Clinical Setting 
Introduction. Smoking is a leading cause of morbidity and mortality globally and it is a significant modifiable risk factor for cardiovascular disease (CVD) and other chronic diseases. Efforts to encourage and support smokers to quit are critical to prevent premature smoking-associated morbidity and mortality. Hospital settings are seldom equipped to help patients to quit smoking thus missing out a valuable opportunity to support patients at risk of smoking complications. We report the impact of a smoking cessation clinic we have established in a tertiary care hospital setting to serve patients with CVD. Methods. Patients received behavioural and pharmacological treatments and were followed up for a minimum of 6 months (mean 541 days, SD 197 days). The main study outcome is ≥50% reduction in number of cigarettes smoked at followup. Results. One hundred and eighty-six patients completed ≥6 months followup. More than half of the patients (52.7%) achieved ≥50% smoking reduction at follow up. Establishment of a plan to quit smoking and use of nicotine replacement therapy (NRT) were significantly associated with smoking reduction at followup. Conclusions. A hospital-based smoking cessation clinic is a beneficial intervention to bring about smoking reduction in approximately half of the patients.
doi:10.1155/2012/970108
PMCID: PMC3477663  PMID: 23097692
21.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
Summary
Background
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Interpretation
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
Funding
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
doi:10.1016/S0140-6736(12)60312-2
PMCID: PMC3419820  PMID: 22607825
22.  BRCA2 Variants and cardiovascular disease in a multi-ethnic study 
BMC Medical Genetics  2012;13:56.
Background
Germline mutations of BRCA1/2 are associated with hereditary breast and ovarian cancer. Recent data suggests excess mortality in mutation carriers beyond that conferred by neoplasia, and recent in vivo and in vitro studies suggest a modulatory role for BRCA proteins in endothelial and cardiomyocyte function. We therefore tested the association of BRCA2 variants with clinical cardiovascular disease (CVD).
Methods
Using data from 1,170 individuals included in two multi-ethnic population-based studies (SHARE and SHARE-AP), the association between BRCA2 variants and CVD was evaluated. 15 SNPs in BRCA2 with minor allele frequencies (MAF) > 0.01 had been previously genotyped using the cardiovascular gene-centric 50 k SNP array. 115 individuals (9.8%) reported a CVD event, defined as myocardial infarction (MI), angina, silent MI, stroke, and angioplasty or coronary artery bypass surgery. Analyses were adjusted for age and sex. The SNPs rs11571836 and rs1799943 were subsequently genotyped using the MassARRAY platform in 1,045 cases of incident MI and 1,135 controls from the South Asian subset of an international case-control study of acute MI (INTERHEART), and rs11571836 was imputed in 4,686 cases and 4500 controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS).
Results
Two BRCA2 SNPs, rs11571836 and rs1799943, both located in untranslated regions, were associated with lower risk of CVD (OR 0.47 p = 0.01 and OR 0.56 p = 0.03 respectively) in the SHARE studies. Analysis by specific ethnicities demonstrated an association with CVD for both SNPs in Aboriginal People, and for rs11571836 only in South Asians. No association was observed in the European and Chinese subgroups. A non-significant trend towards an association between rs11571836 and lower risk of MI was observed in South Asians from INTERHEART [OR = 0.87 (95% CI: 0.75-1.01) p = 0.068], but was not evident in PROMIS [OR = 0.96 (95% CI: 0.90-1.03) p = 0.230]. Meta-analysis of both case-control studies resulted in a combined OR of 0.94 (95% CI: 0.89-1.004, p = 0.06).
Conclusions
Although there was an association between two SNPs in BRCA2 and CVD in a multi-ethnic population, these results were not replicated in two South Asian case-control studies of incident MI. Future studies exploring the association between BRCA variants and cardiovascular disorders are needed to clarify the role, if any, for BRCA variants in CVD pathogenesis.
doi:10.1186/1471-2350-13-56
PMCID: PMC3464815  PMID: 22809218
23.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10-10 versus 3.2×10-7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusions
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
coronary artery disease; myocardial infarction; meta-analysis; genetics
24.  A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex 
Background
Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered.
Methods and Results
We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10−10 versus 3.2×10−7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association.
Conclusion
We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s).
doi:10.1161/CIRCGENETICS.111.961243
PMCID: PMC3335297  PMID: 22319020
Coronary Artery Disease; Myocardial Infarction; Meta-Analysis; Genetics
25.  Promises and challenges of pharmacogenetics: an overview of study design, methodological and statistical issues 
JRSM Cardiovascular Disease  2012;1(1):cvd.2012.012001.
Pharmacogenetics is the study of inherited variation in drug response. The goal of pharmacogenetics is to develop novel ways of maximizing drug efficacy and minimizing toxicity for individual patients. Personalized medicine has the potential to allow for a patient's genetic information to predict optimal dosage for a drug with a narrow therapeutic index, to select the most appropriate pharmacological agent for a given patient and to develop cost-effective treatments. Although there is supporting evidence in favour of pharmacogenetics, its adoption in clinical practice has been slow because of sometimes conflicting findings among studies. This failure to replicate findings may result from a lack of high-quality pharmacogenetic studies, as well as unresolved methodological and statistical issues. The objective of this review is to discuss the benefits of incorporating pharmacogenetics into clinical practice. We will also address outstanding methodological and statistical issues that may lead to heterogeneity among reported pharmacogenetic studies and how they may be addressed.
doi:10.1258/cvd.2012.012001
PMCID: PMC3738322  PMID: 24175062

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