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1.  The Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort study: assessment of environmental exposures 
The Canadian Healthy Infant Longitudinal Development birth cohort was designed to elucidate interactions between environment and genetics underlying development of asthma and allergy. Over 3600 pregnant mothers were recruited from the general population in four provinces with diverse environments. The child is followed to age 5 years, with prospective characterization of diverse exposures during this critical period. Key exposure domains include indoor and outdoor air pollutants, inhalation, ingestion and dermal uptake of chemicals, mold, dampness, biological allergens, pets and pests, housing structure, and living behavior, together with infections, nutrition, psychosocial environment, and medications. Assessments of early life exposures are focused on those linked to inflammatory responses driven by the acquired and innate immune systems. Mothers complete extensive environmental questionnaires including time-activity behavior at recruitment and when the child is 3, 6, 12, 24, 30, 36, 48, and 60 months old. House dust collected during a thorough home assessment at 3–4 months, and biological specimens obtained for multiple exposure-related measurements, are archived for analyses. Geo-locations of homes and daycares and land-use regression for estimating traffic-related air pollution complement time-activity-behavior data to provide comprehensive individual exposure profiles. Several analytical frameworks are proposed to address the many interacting exposure variables and potential issues of co-linearity in this complex data set.
PMCID: PMC4611361  PMID: 25805254
environmental exposure assessment; longitudinal birth cohort; indoor air quality; etiology of asthma; biomarkers; CHILD study
2.  Effect of Referral Strategies on Access to Cardiac Rehabilitation Among Women 
Despite its proven benefits and need, women’s access to cardiac rehabilitation (CR) is suboptimal. Referral strategies, such as systematic referral, have been advocated to improve access to CR. This study examined sex differences in CR referral and enrollment by referral strategies; and the impact of referral strategies for referral and enrollment concordance among women.
Prospective cohort study.
This prospective study included 2635 coronary artery disease inpatients from 11 Ontario hospitals that utilized 1 of 4 referral strategies. Participants completed a sociodemographic survey, and clinical data were extracted from charts. One year later, 1809 participants (452 [25%] women) completed a mailed survey that assessed CR utilization. Referral strategies were compared among women using generalized estimating equations to control for effect of hospital.
Overall, significantly more men than women were referred (67.2% and 57.8% respectively, p<.001), and enrolled in CR (58.6% and 49.3% respectively, p=.001). Of the retained women, combined systematic and liaison-facilitated referral resulted in significantly greater CR referral (Odds Ratio [OR]=10.3, 95% Confidence Interval [CI] = 4.11–25.58) and enrollment (OR=6.6, 95% CI = 4.34–9.92) among women when compared to usual referral. Conversely, concordance between referral and enrollment was greatest following usual referral (K=.85), and decreased with referral intensity.
While a lower proportion of referred patients enroll, systematic and liaison-facilitated inpatient referral strategies result in the greatest CR enrolment rates among women. Such strategies have the potential to improve access among women, and reduce “cherry picking” of patients for referral.
PMCID: PMC4522313  PMID: 23471593 CAMSID: cams4480
cardiac rehabilitation; cardiovascular diseases; health services accessibility; patient participation; referral; utilization
3.  Access to cardiac rehabilitation among South Asian patients by referral method: A qualitative study 
South Asians (SA) suffer an increased prevalence of coronary artery disease. Although cardiac rehabilitation (CR) is effective, SA are among the least likely to participate. ‘Automatic’ referral increases CR utilization and may reduce access inequalities.
This study qualitatively explored whether CR referral knowledge/access varied by referral method among SA patients. Participants were SA cardiac patients from Ontario hospitals. Each hospital refers to CR through one of four methods: automatically through paper or electronically; through discussion with allied health professionals (liaison referral); or through usual referral at physician discretion. Data was collected via interviews and analyzed using Interpretive-descriptive analysis.
Four themes emerged: 1) importance of pre-discharge CR discussions with health care providers; 2) limited knowledge of CR; 3) ease of referral process as facilitator of CR attendance; 4) participants’ need for personal autonomy over decision to attend CR.
Liaison referral was perceived to be the most suitable method of referral for participants. It facilitated communication between patients and providers, ensuring improved CR understanding. Automatic referral may be less suited for this population, due to reduced patient-provider communication.
PMCID: PMC4461376  PMID: 20450019 CAMSID: cams4487
Cardiac Rehabilitation; South Asian; Referral; Qualitative
4.  Assessing the quality of published genetic association studies in meta-analyses: the quality of genetic studies (Q-Genie) tool 
BMC Genetics  2015;16:50.
Advances in genomics technology have led to a dramatic increase in the number of published genetic association studies. Systematic reviews and meta-analyses are a common method of synthesizing findings and providing reliable estimates of the effect of a genetic variant on a trait of interest. However, summary estimates are subject to bias due to the varying methodological quality of individual studies. We embarked on an effort to develop and evaluate a tool that assesses the quality of published genetic association studies. Performance characteristics (i.e. validity, reliability, and item discrimination) were evaluated using a sample of thirty studies randomly selected from a previously conducted systematic review.
The tool demonstrates excellent psychometric properties and generates a quality score for each study with corresponding ratings of ‘low’, ‘moderate’, or ‘high’ quality. We applied our tool to a published systematic review to exclude studies of low quality, and found a decrease in heterogeneity and an increase in precision of summary estimates.
This tool can be used in systematic reviews to inform the selection of studies for inclusion, to conduct sensitivity analyses, and to perform meta-regressions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0211-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4431044  PMID: 25975208
Quality assessment; Genetic association studies; Genetic epidemiology
5.  Gene-centric meta-analyses for central adiposity traits in up to 57 412 individuals of European descent confirm known loci and reveal several novel associations 
Yoneyama, Sachiko | Guo, Yiran | Lanktree, Matthew B. | Barnes, Michael R. | Elbers, Clara C. | Karczewski, Konrad J | Padmanabhan, Sandosh | Bauer, Florianne | Baumert, Jens | Beitelshees, Amber | Berenson, Gerald S. | Boer, Jolanda M.A. | Burke, Gregory | Cade, Brian | Chen, Wei | Cooper-Dehoff, Rhonda M. | Gaunt, Tom R. | Gieger, Christian | Gong, Yan | Gorski, Mathias | Heard-Costa, Nancy | Johnson, Toby | Lamonte, Michael J. | Mcdonough, Caitrin | Monda, Keri L. | Onland-Moret, N. Charlotte | Nelson, Christopher P. | O'Connell, Jeffrey R. | Ordovas, Jose | Peter, Inga | Peters, Annette | Shaffer, Jonathan | Shen, Haiqinq | Smith, Erin | Speilotes, Liz | Thomas, Fridtjof | Thorand, Barbara | Monique Verschuren, W. M. | Anand, Sonia S. | Dominiczak, Anna | Davidson, Karina W. | Hegele, Robert A. | Heid, Iris | Hofker, Marten H. | Huggins, Gordon S. | Illig, Thomas | Johnson, Julie A. | Kirkland, Susan | König, Wolfgang | Langaee, Taimour Y. | Mccaffery, Jeanne | Melander, Olle | Mitchell, Braxton D. | Munroe, Patricia | Murray, Sarah S. | Papanicolaou, George | Redline, Susan | Reilly, Muredach | Samani, Nilesh J. | Schork, Nicholas J. | Van Der Schouw, Yvonne T. | Shimbo, Daichi | Shuldiner, Alan R. | Tobin, Martin D. | Wijmenga, Cisca | Yusuf, Salim | Hakonarson, Hakon | Lange, Leslie A. | Demerath, Ellen W | Fox, Caroline S. | North, Kari E | Reiner, Alex P. | Keating, Brendan | Taylor, Kira C.
Human Molecular Genetics  2013;23(9):2498-2510.
Waist circumference (WC) and waist-to-hip ratio (WHR) are surrogate measures of central adiposity that are associated with adverse cardiovascular events, type 2 diabetes and cancer independent of body mass index (BMI). WC and WHR are highly heritable with multiple susceptibility loci identified to date. We assessed the association between SNPs and BMI-adjusted WC and WHR and unadjusted WC in up to 57 412 individuals of European descent from 22 cohorts collaborating with the NHLBI's Candidate Gene Association Resource (CARe) project. The study population consisted of women and men aged 20–80 years. Study participants were genotyped using the ITMAT/Broad/CARE array, which includes ∼50 000 cosmopolitan tagged SNPs across ∼2100 cardiovascular-related genes. Each trait was modeled as a function of age, study site and principal components to control for population stratification, and we conducted a fixed-effects meta-analysis. No new loci for WC were observed. For WHR analyses, three novel loci were significantly associated (P < 2.4 × 10−6). Previously unreported rs2811337-G near TMCC1 was associated with increased WHR (β ± SE, 0.048 ± 0.008, P = 7.7 × 10−9) as was rs7302703-G in HOXC10 (β = 0.044 ± 0.008, P = 2.9 × 10−7) and rs936108-C in PEMT (β = 0.035 ± 0.007, P = 1.9 × 10−6). Sex-stratified analyses revealed two additional novel signals among females only, rs12076073-A in SHC1 (β = 0.10 ± 0.02, P = 1.9 × 10−6) and rs1037575-A in ATBDB4 (β = 0.046 ± 0.01, P = 2.2 × 10−6), supporting an already established sexual dimorphism of central adiposity-related genetic variants. Functional analysis using ENCODE and eQTL databases revealed that several of these loci are in regulatory regions or regions with differential expression in adipose tissue.
PMCID: PMC3988452  PMID: 24345515
6.  The burden of asthma among South Asian and Chinese populations residing in Ontario 
Respiratory diseases follow closely behind cardiovascular diseases in terms of global disease burden. Research investigating disparities in respiratory outcomes among specific populations in ethnically diverse countries, such as Canada, has been increasing, with the prevalence of asthma in Canada among the highest in the world. This study examined the prevalence of asthma and health care burden in groups that represent a significant proportion of Ontario’s population.
The South Asian and Chinese populations represent a significant portion of the population of Ontario; however, little is known about the burden of respiratory diseases in these populations.
To investigate the prevalence of asthma and the associated health care burden among South Asian and Chinese populations living in Ontario.
Using administrative health data for Ontario, the authors identified individuals of South Asian and Chinese descent using a validated surname algorithm and compared the prevalence of asthma in these groups with the general population using an established asthma case definition for the period 2002 to 2010. Also compared were the rates of asthma-specific emergency department visits and hospitalizations among the ethnic groups.
In 2010, the prevalence of asthma in South Asians residing in Ontario was similar to that of the general population (12.1% versus 12.4%), and was increasing at a faster rate than in the general population (0.51%/year versus 0.34%/year). Compared with the general population, the South Asian population had fewer emergency department visits for asthma, whereas the asthma-related hospitalization rate was greatest among the South Asian population (0.45 per 100 person-years). The Chinese population had the lowest asthma prevalence and associated health care use.
The burden of asthma among South Asians in Ontario is increasing and warrants further investigation to determine the reasons for this rise.
PMCID: PMC4266153  PMID: 25184509
Asthma; Epidemiology; Ethnicity
7.  Sex differences in skeletal muscle Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) levels: A cross-sectional study 
Scientific Reports  2015;5:9154.
Women have higher adiposity but maintain insulin sensitivity when compared to men. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibits insulin signaling, but it is not known if PTEN regulate insulin resistance in a sex-specific manner. In this cross-sectional study, muscle biopsies from participants in the Molecular Study of Health and Risk in Ethnic Groups (Mol-SHARE) were used to test for sex differences in PTEN expression. Quantitative real-time PCR was performed to determine PTEN gene expression (n = 53), and western blotting detected total and phosphorylated PTEN protein (n = 36). Study participants were comparable in age and body mass index. Women had higher fat mass percentage compared to men (40.25 ± 9.9% in women versus 27.6 ± 8.8% in men; mean difference −0.18, 95%CI (−0.24, −0.11), p-value <0.0001), with similar HOMA-IR (2.46 ± 2.05 in men versus 2.34 ± 3.06 in women; mean difference 0.04; 95% CI (−0.12, 0.21), p-value 0.59). Women had significant downregulation of PTEN gene expression (p-value 0.01) and upregulation of PTEN protein phosphorylation (inactivation) (p-value 0.001) when compared to men after correction for age, ethnicity, HOMA-IR, fat mass and sex. We conclude that the downregulation of muscle PTEN may explain the retention of insulin sensitivity with higher adiposity in women compared to men.
PMCID: PMC4366049  PMID: 25777795
8.  Cardiovascular Complications and Mortality After Diabetes Diagnosis for South Asian and Chinese Patients 
Diabetes Care  2013;36(9):2670-2676.
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.
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.
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).
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.
PMCID: PMC3747942  PMID: 23637350
9.  Genetic variants associated with angiotensin-converting enzyme inhibitor-associated angioedema 
Pharmacogenetics and genomics  2013;23(9):470-478.
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).
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.
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.
PMCID: PMC3904664  PMID: 23838604
adverse drug event; angioedema; angiotensin-converting enzyme; neprilysin
10.  Genetic Information and the Prediction of Incident Type 2 Diabetes in a High-Risk Multiethnic Population 
Diabetes Care  2013;36(9):2836-2842.
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.
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.
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).
T2DM genetic associations are generally consistent across ethnic groups, and a gene score only adds marginal information to clinical factors for T2DM prediction.
PMCID: PMC3747911  PMID: 23603917
11.  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.
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.
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.
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.
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.
PMCID: PMC4180911  PMID: 25145545
Epidemiology; Ethnicity; Genetic risk; Meta-analysis; South Asian; Type 2 diabetes; White Europeans
12.  Cardiovascular risk among South Asians living in Canada: a systematic review and meta-analysis 
CMAJ Open  2014;2(3):E183-E191.
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.
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.
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.
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.
PMCID: PMC4183167  PMID: 25295238
13.  The association between ownership of common household devices and obesity and diabetes in high, middle and low income countries 
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.
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.
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.
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.
PMCID: PMC3940572  PMID: 24516093
14.  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.
PMCID: PMC3476718  PMID: 22643179
genome-wide and genetic association studies; single-nucleotide polymorphism; meta-analysis; study heterogeneity; statistical power; type I error rates
15.  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.
PMCID: PMC3962848  PMID: 24672590
Obesity; Ethnicity; Cardiometabolic risk factors
16.  South Asian Heart Risk Assessment (SAHARA): Randomized Controlled Trial Design and Pilot Study 
JMIR Research Protocols  2013;2(2):e33.
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.
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.
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.
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.
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 NCT01577719; (Archived by WebCite at
PMCID: PMC3757993  PMID: 23965279
multimedia; South Asians; health; risk; assessment; randomized; trial
17.  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.
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.
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.
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.
PMCID: PMC3702421  PMID: 23800270
Aboriginal; Birth cohort; Early origins; Adiposity
18.  Causal Relationship between Adiponectin and Metabolic Traits: A Mendelian Randomization Study in a Multiethnic Population 
PLoS ONE  2013;8(6):e66808.
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.
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.
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.
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).
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.
PMCID: PMC3691277  PMID: 23826141
19.  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.
To examine whether quality of diabetes care is equitable for South Asian and Chinese patients in an urban Canadian setting.
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.
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).
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.
PMCID: PMC3308276  PMID: 22323411
20.  Maternal and Pregnancy Related Predictors of Cardiometabolic Traits in Newborns 
PLoS ONE  2013;8(2):e55815.
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.
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.
PMCID: PMC3572188  PMID: 23418462
21.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
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.
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
22.  Excess of Rare Variants in Non-GWAS Candidate Genes in Patients with Hypertriglyceridemia 
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.
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.
PMCID: PMC3288444  PMID: 22135386
hyperlipoproteinemia; genetics; apolipoproteins; lipoproteins; cardiovascular diseases
23.  Rationale and design of South Asian Birth Cohort (START): a Canada-India collaborative study 
BMC Public Health  2013;13:79.
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.
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.
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.
PMCID: PMC3585827  PMID: 23356884
Birth cohort; South Asian; Adiposity; Insulin resistance; Early origins; India; Canada
24.  Effectiveness of inpatient and outpatient strategies in increasing referral and utilization of cardiac rehabilitation: a prospective, multi-site study 
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.
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).
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.
PMCID: PMC3541119  PMID: 23234558
Cardiac rehabilitation; Patient care management; Cardiovascular diseases
25.  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.
PMCID: PMC3517599  PMID: 23236364

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