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1.  Prevalence of and Risk Factors for Subclinical Cardiovascular Disease in Selected US Hispanic Ethnic Groups 
American journal of epidemiology  2008;167(8):962-969.
In this study, the authors determined the prevalence and extent of cardiovascular disease (CVD) risk factors and subclinical CVD in four US Hispanic subgroups, as well as associations between the CVD risk factors and subclinical CVD in these groups. Participants were 1,437 Hispanic men and women enrolled in the Multi-Ethnic Study of Atherosclerosis in 2000–2002. Fifty-six percent were Mexican-American, 12% were Dominican-American, 14% were Puerto Rican-American, and 18% were Other Hispanic-American. All participants underwent clinical examinations for coronary artery calcium, thoracic aortic calcium, carotid intimal-medial thickness, ankle-brachial index, left ventricular mass, and left ventricular size. Mexican Americans had the highest levels of coronary artery calcium, thoracic aortic calcium, and carotid intimal-medial thickness, while Puerto Rican Americans had the highest prevalence of an ankle-brachial index less than 1.0 and levels of left ventricular mass. The magnitudes of the associations between coronary artery calcium and age, sex, and body mass index were similar across all Hispanic subgroups. However, there were differences in the magnitude and significance of the associations between coronary artery calcium and hypertension, hypercholesterolemia, and cigarette smoking among the different Hispanic subgroups. This finding was also present for the other subclinical CVD measures. These results suggest a differential relationship between risk factors and either prevalence or extent of subclinical disease by Hispanic subgroup.
doi:10.1093/aje/kwm402
PMCID: PMC4107279  PMID: 18283034
atherosclerosis; cardiovascular diseases; ethnic groups; Hispanic Americans; risk factors
2.  Heart Disease and Stroke Statistics—2011 Update 
Circulation  2010;123(4):e18-e209.
Summary
Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 1999, the Statistical Update has been cited more than 8700 times in the literature (including citations of all annual versions). In 2009 alone, the various Statistical Updates were cited ≈1600 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas. For this year’s edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year and added a new chapter detailing how family history and genetics play a role in cardiovascular disease (CVD) risk. Also, the 2011 Statistical Update is a major source for monitoring both cardiovascular health and disease in the population, with a focus on progress toward achievement of the AHA’s 2020 Impact Goals. Below are a few highlights from this year’s Update.
Death Rates From CVD Have Declined, Yet the Burden of Disease Remains High
The 2007 overall death rate from CVD (International Classification of Diseases 10, I00–I99) was 251.2 per 100 000. The rates were 294.0 per 100 000 for white males, 405.9 per 100 000 for black males, 205.7 per 100 000 for white females, and 286.1 per 100 000 for black females. From 1997 to 2007, the death rate from CVD declined 27.8%. Mortality data for 2007 show that CVD (I00–I99; Q20–Q28) accounted for 33.6% (813 804) of all 2 243 712 deaths in 2007, or 1 of every 2.9 deaths in the United States.
On the basis of 2007 mortality rate data, more than 2200 Americans die of CVD each day, an average of 1 death every 39 seconds. More than 150 000 Americans killed by CVD (I00–I99) in 2007 were <65 years of age. In 2007, nearly 33% of deaths due to CVD occurred before the age of 75 years, which is well before the average life expectancy of 77.9 years.
Coronary heart disease caused ≈1 of every 6 deaths in the United States in 2007. Coronary heart disease mortality in 2007 was 406 351. Each year, an estimated 785 000 Americans will have a new coronary attack, and ≈470 000 will have a recurrent attack. It is estimated that an additional 195 000 silent first myocardial infarctions occur each year. Approximately every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one.
Each year, ≈795 000 people experience a new or recurrent stroke. Approximately 610 000 of these are first attacks, and 185 000 are recurrent attacks. Mortality data from 2007 indicate that stroke accounted for ≈1 of every 18 deaths in the United States. On average, every 40 seconds, someone in the United States has a stroke. From 1997 to 2007, the stroke death rate fell 44.8%, and the actual number of stroke deaths declined 14.7%.
In 2007, 1 in 9 death certificates (277 193 deaths) in the United States mentioned heart failure.
Prevalence and Control of Traditional Risk Factors Remains an Issue for Many Americans
Data from the National Health and Nutrition Examination Survey (NHANES) 2005–2008 indicate that 33.5% of US adults ≥20 years of age have hypertension (Table 7-1). This amounts to an estimated 76 400 000 US adults with hypertension. The prevalence of hypertension is nearly equal between men and women. African American adults have among the highest rates of hypertension in the world, at 44%. Among hypertensive adults, ≈80% are aware of their condition, 71% are using antihypertensive medication, and only 48% of those aware that they have hypertension have their condition controlled.
Despite 4 decades of progress, in 2008, among Americans ≥18 years of age, 23.1% of men and 18.3% of women continued to be cigarette smokers. In 2009, 19.5% of students in grades 9 through 12 reported current tobacco use. The percentage of the nonsmoking population with detectable serum cotinine (indicating exposure to secondhand smoke) was 46.4% in 1999 to 2004, with declines occurring, and was highest for those 4 to 11 years of age (60.5%) and those 12 to 19 years of age (55.4%).
An estimated 33 600 000 adults ≥20 years of age have total serum cholesterol levels ≥240 mg/dL, with a prevalence of 15.0% (Table 13-1).
In 2008, an estimated 18 300 000 Americans had diagnosed diabetes mellitus, representing 8.0% of the adult population. An additional 7 100 000 had undiagnosed diabetes mellitus, and 36.8% had prediabetes, with abnormal fasting glucose levels. African Americans, Mexican Americans, Hispanic/Latino individuals, and other ethnic minorities bear a strikingly disproportionate burden of diabetes mellitus in the United States (Table 16-1).
The 2011 Update Expands Data Coverage of the Obesity Epidemic and Its Antecedents and Consequences
The estimated prevalence of overweight and obesity in US adults (≥20 years of age) is 149 300 000, which represents 67.3% of this group in 2008. Fully 33.7% of US adults are obese (body mass index ≥30 kg/m2). Men and women of all race/ethnic groups in the population are affected by the epidemic of overweight and obesity (Table 15-1).
Among children 2 to 19 years of age, 31.9% are overweight and obese (which represents 23 500 000 children), and 16.3% are obese (12 000 000 children). Mexican American boys and girls and African American girls are disproportionately affected. Over the past 3 decades, the prevalence of obesity in children 6 to 11 years of age has increased from ≈4% to more than 20%.
Obesity (body mass index ≥30 kg/m2) is associated with marked excess mortality in the US population. Even more notable is the excess morbidity associated with overweight and obesity in terms of risk factor development and incidence of diabetes mellitus, CVD end points (including coronary heart disease, stroke, and heart failure), and numerous other health conditions, including asthma, cancer, degenerative joint disease, and many others.
The prevalence of diabetes mellitus is increasing dramatically over time, in parallel with the increases in prevalence of overweight and obesity.
On the basis of NHANES 2003–2006 data, the age-adjusted prevalence of metabolic syndrome, a cluster of major cardiovascular risk factors related to overweight/obesity and insulin resistance, is 34% (35.1% among men and 32.6% among women).
The proportion of youth (≤18 years of age) who report engaging in no regular physical activity is high, and the proportion increases with age. In 2007, among adolescents in grades 9 through 12, 29.9% of girls and 17.0% of boys reported that they had not engaged in 60 minutes of moderate-to-vigorous physical activity, defined as any activity that increased heart rate or breathing rate, even once in the previous 7 days, despite recommendations that children engage in such activity ≥5 days per week.
Thirty-six percent of adults reported engaging in no vigorous activity (activity that causes heavy sweating and a large increase in breathing or heart rate).
Data from NHANES indicate that between 1971 and 2004, average total energy consumption among US adults increased by 22% in women (from 1542 to 1886 kcal/d) and by 10% in men (from 2450 to 2693 kcal/d; see Chart 19-1).
The increases in calories consumed during this time period are attributable primarily to greater average carbohydrate intake, in particular, of starches, refined grains, and sugars. Other specific changes related to increased caloric intake in the United States include larger portion sizes, greater food quantity and calories per meal, and increased consumption of sugar-sweetened beverages, snacks, commercially prepared (especially fast food) meals, and higher energy-density foods.
The 2011 Update Provides Critical Data Regarding Cardiovascular Quality of Care, Procedure Utilization, and Costs
In light of the current national focus on healthcare utilization, costs, and quality, it is critical to monitor and understand the magnitude of healthcare delivery and costs, as well as the quality of healthcare delivery, related to CVDs. The Update provides these critical data in several sections.
Quality-of-Care Metrics for CVDs
Chapter 20 reviews many metrics related to the quality of care delivered to patients with CVDs, as well as healthcare disparities. In particular, quality data are available from the AHA’s “Get With The Guidelines” programs for coronary artery disease and heart failure and the American Stroke Association/ AHA’s “Get With the Guidelines” program for acute stroke. Similar data from the Veterans Healthcare Administration, national Medicare and Medicaid data and National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network - “Get With The Guidelines” Registry data are also reviewed. These data show impressive adherence with guideline recommendations for many, but not all, metrics of quality of care for these hospitalized patients. Data are also reviewed on screening for cardiovascular risk factor levels and control.
Cardiovascular Procedure Utilization and Costs
Chapter 21 provides data on trends and current usage of cardiovascular surgical and invasive procedures. For example, the total number of inpatient cardiovascular operations and procedures increased 27%, from 5 382 000 in 1997 to 6 846 000 in 2007 (National Heart, Lung, and Blood Institute computation based on National Center for Health Statistics annual data).
Chapter 22 reviews current estimates of direct and indirect healthcare costs related to CVDs, stroke, and related conditions using Medical Expenditure Panel Survey data. The total direct and indirect cost of CVD and stroke in the United States for 2007 is estimated to be $286 billion. This figure includes health expenditures (direct costs, which include the cost of physicians and other professionals, hospital services, prescribed medications, home health care, and other medical durables) and lost productivity resulting from mortality (indirect costs). By comparison, in 2008, the estimated cost of all cancer and benign neoplasms was $228 billion ($93 billion in direct costs, $19 billion in morbidity indirect costs, and $116 billion in mortality indirect costs). CVD costs more than any other diagnostic group.
The AHA, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current data available in the Statistics Update. The 2007 mortality data have been released. More information can be found at the National Center for Health Statistics Web site, http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_01.pdf.
Finally, it must be noted that this annual Statistical Update is the product of an entire year’s worth of effort by dedicated professionals, volunteer physicians and scientists, and outstanding AHA staff members, without whom publication of this valuable resource would be impossible. Their contributions are gratefully acknowledged. Véronique L. Roger, MD, MPH, FAHAMelanie B. Turner, MPHOn behalf of the American Heart Association Heart Disease and Stroke Statistics Writing Group
Note: Population data used in the compilation of NHANES prevalence estimates is for the latest year of the NHANES survey being used. Extrapolations for NHANES prevalence estimates are based on the census resident population for 2008 because this is the most recent year of NHANES data used in the Statistical Update.
doi:10.1161/CIR.0b013e3182009701
PMCID: PMC4418670  PMID: 21160056
AHA Statistical Update; cardiovascular diseases; epidemiology; risk factors; statistics; stroke
3.  Pediatric nonalcoholic fatty liver disease, metabolic syndrome and cardiovascular risk 
Nonalcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis, includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. NAFLD has become the most common cause of chronic liver disease in children and adolescents. The recent rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome (MetS), a highly atherogenic condition, and this has stimulated interest in the possible role of NAFLD in the development of atherosclerosis. Accumulating evidence suggests that NAFLD is associated with a significantly greater overall mortality than in the general population, as well as with increased prevalence of cardiovascular disease (CVD), independently of classical atherosclerotic risk factors. Yet, several studies including the pediatric population have reported independent associations between NAFLD and impaired flow-mediated vasodilatation and increased carotid artery intimal medial thickness-two reliable markers of subclinical atherosclerosis-after adjusting for cardiovascular risk factors and MetS. Therefore, the rising prevalence of obesity-related MetS and NAFLD in childhood may lead to a parallel increase in adverse cardiovascular outcomes. In children, the cardiovascular system remains plastic and damage-reversible if early and appropriate interventions are established effectively. Therapeutic goals for NAFLD should address nutrition, physical activity, and avoidance of smoking to prevent not only end-stage liver disease but also CVD.
doi:10.3748/wjg.v17.i26.3082
PMCID: PMC3158407  PMID: 21912450
Nonalcoholic fatty liver disease; Metabolic syndrome; Cardiovascular risk; Children
4.  The Ankle-Brachial Index and Incident Cardiovascular Events in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Objectives
The purpose of this study was to examine the association of both a low and a high ankle-brachial index (ABI) with incident cardiovascular events in a multi-ethnic cohort.
Background
Abnormal ankle-brachial indices (ABIs), both low and high, are associated with elevated cardiovascular disease (CVD) risk. However, it is unknown whether this association is consistent across different ethnic groups, and whether it is independent of both newer biomarkers and other measures of subclinical atherosclerotic CVD.
Methods
6647 non-Hispanic white, African-American, Hispanic, and Chinese men and women aged 45–84 years from free-living populations in six United States field centers and free of clinical CVD at baseline had extensive measures of traditional and newer biomarker risk factors, and measures of subclinical CVD, including the ABI. Incident CVD, defined as coronary disease, stroke, or other atherosclerotic CVD death, was determined over a mean follow-up of 5.3 years.
Results
Both a low (<1.00) and a high (≥ 1.40) ABI were associated with incident CVD events. Gender- specific and ethnic-specific analyses showed consistent results. Hazard ratios were 1.77 (p<.001) for a low and 1.85 (p=.050) for a high ABI after adjustment for both traditional and newer biomarker CVD risk factors, and the ABI significantly improved risk discrimination. Further adjustment for coronary artery calcium score, common and internal carotid intimal medial thickness, and major ECG abnormalities only modestly attenuated these hazard ratios.
Conclusions
In this study both a low and a high ABI were associated with elevated CVD risk in persons free of known CVD, independent of standard and novel risk factors, and independent of other measures of subclinical CVD. Further research should address the cost-effectiveness of measuring the ABI in targeted population groups.
doi:10.1016/j.jacc.2010.04.060
PMCID: PMC2962558  PMID: 20951328
peripheral arterial disease; ankle-brachial index; cardiovascular events; risk factors; subclinical atherosclerosis
5.  Associations of Pentraxin 3 with Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis 
Objective
Pentraxin 3 (PTX3) is likely a specific marker of vascular inflammation. However, associations of PTX3 with cardiovascular disease (CVD) risk have not been well studied in healthy adults or multi-ethnic populations. We examined associations of PTX3 with CVD risk factors, measures of subclinical CVD, coronary artery calcification (CAC) and CVD events in the Multi-Ethnic Study of Atherosclerosis (MESA).
Approach and Results
2838 participants free of prevalent CVD with measurements of PTX3 were included in the present study. Adjusting for age, sex and ethnicity, PTX3 was positively associated with age, obesity, insulin, systolic blood pressure, C-reactive protein (CRP) and carotid intima media thickness (all p<0.045). A one standard deviation increase in PTX3 (1.62 ng/ml) was associated with the presence of CAC in fully adjusted models including multiple CVD risk factors (relative risk; 95% confidence interval 1.05; 1-01-1.08). In fully adjusted models, a standard deviation higher level of PTX3 was associated with an increased risk of myocardial infarction (hazard ratio; 95% confidence interval 1.51; 1.16-1.97), combined CVD events (1.23; 1.05-1.45) and combined CHD events (1.33; 1.10-1.60) but not stroke, CVD-related mortality or all cause death.
Conclusions
In these apparently healthy adults, PTX3 was associated with CVD risk factors, subclinical CVD, CAC and incident coronary heart disease events independent of CRP and CVD risk factors. These results support the hypothesis that PTX3 reflects different aspects of inflammation than CRP and may provide additional insight into the development and progression of atherosclerosis.
doi:10.1111/jth.12557
PMCID: PMC4055511  PMID: 24628740
Atherosclerosis; Cardiovascular Diseases; Epidemiology; Inflammation; Pentraxin 3
6.  Relationship between Common Carotid Intima-Media Thickness and Thoracic Aortic Calcification: the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2009;209(1):142-146.
Background
Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score.
Methods
In the Multi-Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT.
Results
The prevalence of TAC was 28% (n=1846) and the mean maximum (±SD) CIMT was 0.87±0.19 mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, P<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups.
Conclusions
Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies.
doi:10.1016/j.atherosclerosis.2009.09.013
PMCID: PMC2830343  PMID: 19782983
Atherosclerosis; carotid IMT; aortic calcification; ethnic; cardiac CT
7.  EFFECT OF LOWER TARGETS FOR BLOOD PRESSURE AND LDL CHOLESTEROL ON ATHEROSCLEROSIS IN DIABETES 
JAMA  2008;299(14):1678-1689.
Context
Individuals with diabetes are at greatly increased risk for developing cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested.
Objective
To compare the progression of subclinical atherosclerotic disease in diabetic adults treated to aggressive targets of low-density lipoprotein cholesterol (LDL-C) ≤ 70 mg/dL and blood pressure (BP) ≤ 115/75 mm Hg (aggressive) versus treatment to standard targets of LDL-C ≤ 100 mg/dL and BP ≤ 130/85 mm Hg (standard).
Design
Randomized, open label, blinded-to-endpoint 3-year trial in individuals with diabetes conducted April 2003-July 2004.
Setting
Four clinical centers in southwestern Oklahoma; Phoenix, AZ; northeastern Arizona; and South Dakota.
Participants
499 American Indian men and women ≥ age 40 with type 2 diabetes and no prior CVD events.
Interventions
Participants were randomized to aggressive vs. standard treatment. The same treatment algorithms were followed for both groups.
Main Outcome Measures
Primary endpoint was a composite of progression of atherosclerosis as measured by common carotid artery intimal medial thickness (IMT) and clinical events. Secondary endpoints included other carotid and cardiac ultrasonographic measures.
Results
LDL-C and systolic BP (SBP) goals for both groups were reached within 12 months and maintained to 36 months. LDL-C and SBP in the last 12 months averaged 72 and 104 mg/dL and 116 and 129 mm Hg in the aggressive and standard groups, respectively. Regression of IMT (-0.017 vs. 0.041 mm, p < .0001) and arterial mass (-0.14 vs. 1.14 mm2, p < .0001) and greater decrease in left ventricular mass (-2.4 vs. -1.3 g/m2.7, p = .05) were observed in the aggressive group. Clinical CVD events were lower than expected and did not differ between groups
Conclusions
Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outomes.
doi:10.1001/jama.299.14.1678
PMCID: PMC4243925  PMID: 18398080
8.  How Has the Age-Related Process of Overweight or Obesity Development Changed over Time? Co-ordinated Analyses of Individual Participant Data from Five United Kingdom Birth Cohorts 
PLoS Medicine  2015;12(5):e1001828.
Background
There is a paucity of information on secular trends in the age-related process by which people develop overweight or obesity. Utilizing longitudinal data in the United Kingdom birth cohort studies, we investigated shifts over the past nearly 70 years in the distribution of body mass index (BMI) and development of overweight or obesity across childhood and adulthood.
Methods and Findings
The sample comprised 56,632 participants with 273,843 BMI observations in the 1946 Medical Research Council National Survey of Health and Development (NSHD; ages 2–64 years), 1958 National Child Development Study (NCDS; 7–50), 1970 British Cohort Study (BCS; 10–42), 1991 Avon Longitudinal Study of Parents and Children (ALSPAC; 7–18), or 2001 Millennium Cohort Study (MCS; 3–11). Growth references showed a secular trend toward positive skewing of the BMI distribution at younger ages. During childhood, the 50th centiles for all studies lay in the middle of the International Obesity Task Force normal weight range, but during adulthood, the age when a 50th centile first entered the overweight range (i.e., 25–29.9 kg/m2) decreased across NSHD, NCDS, and BCS from 41 to 33 to 30 years in males and 48 to 44 to 41 years in females. Trajectories of overweight or obesity showed that more recently born cohorts developed greater probabilities of overweight or obesity at younger ages. Overweight or obesity became more probable in NCDS than NSHD in early adulthood, but more probable in BCS than NCDS and NSHD in adolescence, for example. By age 10 years, the estimated probabilities of overweight or obesity in cohorts born after the 1980s were 2–3 times greater than those born before the 1980s (e.g., 0.229 [95% CI 0.219–0.240] in MCS males; 0.071 [0.065–0.078] in NSHD males). It was not possible to (1) model separate trajectories for overweight and obesity, because there were few obesity cases at young ages in the earliest-born cohorts, or (2) consider ethnic minority groups. The end date for analyses was August 2014.
Conclusions
Our results demonstrate how younger generations are likely to accumulate greater exposure to overweight or obesity throughout their lives and, thus, increased risk for chronic health conditions such as coronary heart disease and type 2 diabetes mellitus. In the absence of effective intervention, overweight and obesity will have severe public health consequences in decades to come.
In a longitudinal analysis, William Johnson and colleagues examine how individual lifetime BMI trajectories among white citizens of the UK have changed from 1946 to 2014.
Editors' Summary
Background
Overweight and obesity are major threats to global health. The global prevalence of obesity (the proportion of the world's population that is obese) has more than doubled since 1980; 13% of the adult population, or 0.6 billion people, are now classified as obese, while an additional 1.3 billion adults are overweight. Both classifications are determined by body mass index (BMI), which is calculated by dividing a person's weight in kilograms by the square of their height in meters. Obese individuals have a BMI of 30 kg/m2 or more, while overweight individuals have a BMI of 25–30 kg/m2. BMI values above 25 kg/m2 increase the risk of developing non-communicable diseases (NCDs), including cardiovascular diseases, cancers and diabetes. Each year, NCDs kill 38 million people (including 28 million people in low- and middle-income countries and 9 million people under 60 years of age), thereby accounting for more than 75% of the world's annual deaths.
In the United Kingdom, studies report that roughly one quarter of adults are obese, and a further third or more are overweight. This “obesity epidemic” extends to children; according to the National Child Measurement Programme for England (NCMP), about 9% of 4–5-year-olds and 19% of 10–11-year-olds were obese in 2013. In parallel, the UK has not seen the improvements in child and young adult mortality seen in comparable European states.
Why Was This Study Done?
Cross-sectional surveys in the UK, United States, and elsewhere have documented the obesity epidemic, but longitudinal data—drawn from periodic BMI measurements from individuals over their lifetimes—are needed to clarify the time course, or trajectory, of overweight and obesity. Longitudinal data can answer practical questions important for designing health policy interventions. Is the age at which individuals develop overweight or obesity changing over time? In which individuals are the greatest increases in BMI occurring? The authors leveraged longitudinal data from five birth cohort studies (studies that follow a selected group of individuals born during a short window of time), incepted in 1946, 1958, 1970, 1991, and 2001. These large cohort projects were funded by the UK government for the purpose of providing data for long-term health analyses such as this one; in total, the current study’s included sample comprised 56,632 participants with 273,843 BMI observations from participants aged 2 through 64.
What Did the Researchers Do and Find?
The present study aimed to investigate (1) shifts from the 1940s to the 2000s in the distribution of BMI across age and (2) shifts over the same period in the probability of developing overweight or obesity across age. For each of the five cohorts, subdivided by sex and childhood versus adulthood (thus, a total of 20 datasets), the authors applied statistical models to produce trajectories for each BMI centile (subset that results from dividing the distribution of BMI measurements into 100 groups with equal frequency; here, the 90th centile is the group for which 90% of the relevant population has lower BMI). They then investigated secular trends (long-term, non-periodic variations) at different centiles of the BMI distribution. For example, by comparing the trajectories of the 50th centile for adult males across the five cohorts, the researchers could see how the age at which BMI values reached the obese range varied between eras among this group.
The data revealed that most of the between-cohort, and thus between-era, increases in BMI took place in the highest centiles, indicating that overall gains in BMI mainly comprised very high BMI individuals carrying even more weight. Across the 1946, 1958, and 1970 cohorts, the age at which the 50th centile of adults entered the overweight range decreased from 41 to 33 to 30 years in males and 48 to 44 to 41 years in females. The probabilities of overweight and obesity across adulthood also increased. While children in the 50th BMI centile have remained at normal weight through the decades, the overall childhood probability of developing overweight or obesity has increased 2–3-fold from before to after the 1980s.
What Do These Findings Mean?
These findings describe the changing pattern of age-related progression of overweight and obesity from early childhood in white citizens of the UK. The findings may not be generalizable because other populations have distinct genetic predispositions, environmental exposures, and access to health care. In addition, the accuracy of the findings may be affected by differences between cohorts in how weight and height (and thus BMI) were measured. Nevertheless, these findings—in particular, the increased risk of overweight and obesity at younger ages—suggest that compared to previous generations, current and future generations will accumulate greater overweight or obesity exposure across their lives, likely resulting in increased risk for NCDs. Further research is now needed to determine whether lifestyle factors in the UK have affected the trajectory of BMI and to discover the extent to which these shifting weight trajectories have contributed to morbidity and mortality.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001828. The World Health Organization provides information on obesity and non-communicable diseases around the world (in several languages)The UK National Health Service Choices website also provides detailed information about obesity and a link to a personal story about losing weightThe International Obesity Taskforce provides information about the global obesity epidemicThe US Centers for Disease Control and Prevention provides information on non-communicable diseases around the world and on overweight and obesity and diabetes (including some information in Spanish)The US Department of Agriculture's ChooseMyPlate.gov website provides a personal healthy eating planThe Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)MedlinePlus has links to further information about obesity (in English and Spanish)
doi:10.1371/journal.pmed.1001828
PMCID: PMC4437909  PMID: 25993005
9.  The Role of Adiposity in Cardiometabolic Traits: A Mendelian Randomization Analysis 
Fall, Tove | Hägg, Sara | Mägi, Reedik | Ploner, Alexander | Fischer, Krista | Horikoshi, Momoko | Sarin, Antti-Pekka | Thorleifsson, Gudmar | Ladenvall, Claes | Kals, Mart | Kuningas, Maris | Draisma, Harmen H. M. | Ried, Janina S. | van Zuydam, Natalie R. | Huikari, Ville | Mangino, Massimo | Sonestedt, Emily | Benyamin, Beben | Nelson, Christopher P. | Rivera, Natalia V. | Kristiansson, Kati | Shen, Huei-yi | Havulinna, Aki S. | Dehghan, Abbas | Donnelly, Louise A. | Kaakinen, Marika | Nuotio, Marja-Liisa | Robertson, Neil | de Bruijn, Renée F. A. G. | Ikram, M. Arfan | Amin, Najaf | Balmforth, Anthony J. | Braund, Peter S. | Doney, Alexander S. F. | Döring, Angela | Elliott, Paul | Esko, Tõnu | Franco, Oscar H. | Gretarsdottir, Solveig | Hartikainen, Anna-Liisa | Heikkilä, Kauko | Herzig, Karl-Heinz | Holm, Hilma | Hottenga, Jouke Jan | Hyppönen, Elina | Illig, Thomas | Isaacs, Aaron | Isomaa, Bo | Karssen, Lennart C. | Kettunen, Johannes | Koenig, Wolfgang | Kuulasmaa, Kari | Laatikainen, Tiina | Laitinen, Jaana | Lindgren, Cecilia | Lyssenko, Valeriya | Läärä, Esa | Rayner, Nigel W. | Männistö, Satu | Pouta, Anneli | Rathmann, Wolfgang | Rivadeneira, Fernando | Ruokonen, Aimo | Savolainen, Markku J. | Sijbrands, Eric J. G. | Small, Kerrin S. | Smit, Jan H. | Steinthorsdottir, Valgerdur | Syvänen, Ann-Christine | Taanila, Anja | Tobin, Martin D. | Uitterlinden, Andre G. | Willems, Sara M. | Willemsen, Gonneke | Witteman, Jacqueline | Perola, Markus | Evans, Alun | Ferrières, Jean | Virtamo, Jarmo | Kee, Frank | Tregouet, David-Alexandre | Arveiler, Dominique | Amouyel, Philippe | Ferrario, Marco M. | Brambilla, Paolo | Hall, Alistair S. | Heath, Andrew C. | Madden, Pamela A. F. | Martin, Nicholas G. | Montgomery, Grant W. | Whitfield, John B. | Jula, Antti | Knekt, Paul | Oostra, Ben | van Duijn, Cornelia M. | Penninx, Brenda W. J. H. | Davey Smith, George | Kaprio, Jaakko | Samani, Nilesh J. | Gieger, Christian | Peters, Annette | Wichmann, H.-Erich | Boomsma, Dorret I. | de Geus, Eco J. C. | Tuomi, TiinaMaija | Power, Chris | Hammond, Christopher J. | Spector, Tim D. | Lind, Lars | Orho-Melander, Marju | Palmer, Colin Neil Alexander | Morris, Andrew D. | Groop, Leif | Järvelin, Marjo-Riitta | Salomaa, Veikko | Vartiainen, Erkki | Hofman, Albert | Ripatti, Samuli | Metspalu, Andres | Thorsteinsdottir, Unnur | Stefansson, Kari | Pedersen, Nancy L. | McCarthy, Mark I. | Ingelsson, Erik | Prokopenko, Inga
PLoS Medicine  2013;10(6):e1001474.
In this study, Prokopenko and colleagues provide novel evidence for causal relationship between adiposity and heart failure and increased liver enzymes using a Mendelian randomization study design.
Please see later in the article for the Editors' Summary
Background
The association between adiposity and cardiometabolic traits is well known from epidemiological studies. Whilst the causal relationship is clear for some of these traits, for others it is not. We aimed to determine whether adiposity is causally related to various cardiometabolic traits using the Mendelian randomization approach.
Methods and Findings
We used the adiposity-associated variant rs9939609 at the FTO locus as an instrumental variable (IV) for body mass index (BMI) in a Mendelian randomization design. Thirty-six population-based studies of individuals of European descent contributed to the analyses.
Age- and sex-adjusted regression models were fitted to test for association between (i) rs9939609 and BMI (n = 198,502), (ii) rs9939609 and 24 traits, and (iii) BMI and 24 traits. The causal effect of BMI on the outcome measures was quantified by IV estimators. The estimators were compared to the BMI–trait associations derived from the same individuals. In the IV analysis, we demonstrated novel evidence for a causal relationship between adiposity and incident heart failure (hazard ratio, 1.19 per BMI-unit increase; 95% CI, 1.03–1.39) and replicated earlier reports of a causal association with type 2 diabetes, metabolic syndrome, dyslipidemia, and hypertension (odds ratio for IV estimator, 1.1–1.4; all p<0.05). For quantitative traits, our results provide novel evidence for a causal effect of adiposity on the liver enzymes alanine aminotransferase and gamma-glutamyl transferase and confirm previous reports of a causal effect of adiposity on systolic and diastolic blood pressure, fasting insulin, 2-h post-load glucose from the oral glucose tolerance test, C-reactive protein, triglycerides, and high-density lipoprotein cholesterol levels (all p<0.05). The estimated causal effects were in agreement with traditional observational measures in all instances except for type 2 diabetes, where the causal estimate was larger than the observational estimate (p = 0.001).
Conclusions
We provide novel evidence for a causal relationship between adiposity and heart failure as well as between adiposity and increased liver enzymes.
Please see later in the article for the Editors' Summary
Editors' Summary
Cardiovascular disease (CVD)—disease that affects the heart and/or the blood vessels—is a major cause of illness and death worldwide. In the US, for example, coronary heart disease—a CVD in which narrowing of the heart's blood vessels by fatty deposits slows the blood supply to the heart and may eventually cause a heart attack—is the leading cause of death, and stroke—a CVD in which the brain's blood supply is interrupted—is the fourth leading cause of death. Globally, both the incidence of CVD (the number of new cases in a population every year) and its prevalence (the proportion of the population with CVD) are increasing, particularly in low- and middle-income countries. This increasing burden of CVD is occurring in parallel with a global increase in the incidence and prevalence of obesity—having an unhealthy amount of body fat (adiposity)—and of metabolic diseases—conditions such as diabetes in which metabolism (the processes that the body uses to make energy from food) is disrupted, with resulting high blood sugar and damage to the blood vessels.
Why Was This Study Done?
Epidemiological studies—investigations that record the patterns and causes of disease in populations—have reported an association between adiposity (indicated by an increased body mass index [BMI], which is calculated by dividing body weight in kilograms by height in meters squared) and cardiometabolic traits such as coronary heart disease, stroke, heart failure (a condition in which the heart is incapable of pumping sufficient amounts of blood around the body), diabetes, high blood pressure (hypertension), and high blood cholesterol (dyslipidemia). However, observational studies cannot prove that adiposity causes any particular cardiometabolic trait because overweight individuals may share other characteristics (confounding factors) that are the real causes of both obesity and the cardiometabolic disease. Moreover, it is possible that having CVD or a metabolic disease causes obesity (reverse causation). For example, individuals with heart failure cannot do much exercise, so heart failure may cause obesity rather than vice versa. Here, the researchers use “Mendelian randomization” to examine whether adiposity is causally related to various cardiometabolic traits. Because gene variants are inherited randomly, they are not prone to confounding and are free from reverse causation. It is known that a genetic variant (rs9939609) within the genome region that encodes the fat-mass- and obesity-associated gene (FTO) is associated with increased BMI. Thus, an investigation of the associations between rs9939609 and cardiometabolic traits can indicate whether obesity is causally related to these traits.
What Did the Researchers Do and Find?
The researchers analyzed the association between rs9939609 (the “instrumental variable,” or IV) and BMI, between rs9939609 and 24 cardiometabolic traits, and between BMI and the same traits using genetic and health data collected in 36 population-based studies of nearly 200,000 individuals of European descent. They then quantified the strength of the causal association between BMI and the cardiometabolic traits by calculating “IV estimators.” Higher BMI showed a causal relationship with heart failure, metabolic syndrome (a combination of medical disorders that increases the risk of developing CVD), type 2 diabetes, dyslipidemia, hypertension, increased blood levels of liver enzymes (an indicator of liver damage; some metabolic disorders involve liver damage), and several other cardiometabolic traits. All the IV estimators were similar to the BMI–cardiovascular trait associations (observational estimates) derived from the same individuals, with the exception of diabetes, where the causal estimate was higher than the observational estimate, probably because the observational estimate is based on a single BMI measurement, whereas the causal estimate considers lifetime changes in BMI.
What Do These Findings Mean?
Like all Mendelian randomization studies, the reliability of the causal associations reported here depends on several assumptions made by the researchers. Nevertheless, these findings provide support for many previously suspected and biologically plausible causal relationships, such as that between adiposity and hypertension. They also provide new insights into the causal effect of obesity on liver enzyme levels and on heart failure. In the latter case, these findings suggest that a one-unit increase in BMI might increase the incidence of heart failure by 17%. In the US, this corresponds to 113,000 additional cases of heart failure for every unit increase in BMI at the population level. Although additional studies are needed to confirm and extend these findings, these results suggest that global efforts to reduce the burden of obesity will likely also reduce the occurrence of CVD and metabolic disorders.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001474.
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy, including weight management (in several languages); its website includes personal stories about stroke and heart attacks
The US Centers for Disease Control and Prevention has information on heart disease, stroke, and all aspects of overweight and obesity (in English and Spanish)
The UK National Health Service Choices website provides information about cardiovascular disease and obesity, including a personal story about losing weight
The World Health Organization provides information on obesity (in several languages)
The International Obesity Taskforce provides information about the global obesity epidemic
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
MedlinePlus provides links to other sources of information on heart disease, on vascular disease, on obesity, and on metabolic disorders (in English and Spanish)
The International Association for the Study of Obesity provides maps and information about obesity worldwide
The International Diabetes Federation has a web page that describes types, complications, and risk factors of diabetes
doi:10.1371/journal.pmed.1001474
PMCID: PMC3692470  PMID: 23824655
10.  Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey 
A recent explosion in the amount of cardiovascular risk and incipient, undetected subclinical cardiovascular pathology has swept across the globe. Nearly 70% of adult Americans are overweight or obese; the prevalence of visceral obesity stands at 53% and continues to rise. At any one time, 55% of the population is on a weight-loss diet, and almost all fail. Fewer than 15% of adults or children exercise sufficiently, and over 60% engage in no vigorous activity. Among adults, 11%–13% have diabetes, 34% have hypertension, 36% have prehypertension, 36% have prediabetes, 12% have both prediabetes and prehypertension, and 15% of the population with either diabetes, hypertension, or dyslipidemia are undiagnosed. About one-third of the adult population, and 80% of the obese, have fatty livers. With 34% of children overweight or obese, prevalence having doubled in just a few years, type 2 diabetes, hypertension, dyslipidemia, and fatty livers in children are at their highest levels ever. Half of adults have at least one cardiovascular risk factor. Not even 1% of the population attains ideal cardiovascular health. Despite falling coronary death rates for decades, coronary heart disease (CHD) death rates in US women 35 to 54 years of age may now be increasing because of the obesity epidemic. Up to 65% of patients do not have their conventional risk biomarkers under control. Only 30% of high risk patients with CHD achieve aggressive low density lipoprotein (LDL) targets. Of those patients with multiple risk factors, fewer than 10% have all of them adequately controlled. Even when patients are titrated to evidence-based targets, about 70% of cardiac events remain unaddressed. Undertreatment is also common. About two-thirds of high risk primary care patients are not taking needed medications for dyslipidemia. Poor patient adherence, typically below 50%, adds further difficulty. Hence, after all such fractional reductions are multiplied, only a modest portion of total cardiovascular risk burden is actually being eliminated, and the full potential of risk reduction remains unrealized. Worldwide the situation is similar, with the prevalence of metabolic syndrome approaching 50%. Primordial prevention, resulting from healthful lifestyle habits that do not permit the appearance of risk factors, is the preferred method to lower cardiovascular risk. Lowering the prevalence of obesity is the most urgent matter, and is pleiotropic since it affects blood pressure, lipid profiles, glucose metabolism, inflammation, and atherothrombotic disease progression. Physical activity also improves several risk factors, with the additional potential to lower heart rate. Given the current obstacles, success of primordial prevention remains uncertain. At the same time, the consequences of delay and inaction will inevitably be disastrous, and the sense of urgency mounts. Since most CHD events arise in a large subpopulation of low- to moderate-risk individuals, identifying a high proportion of those who will go on to develop events with accuracy remains unlikely. Without a refinement in risk prediction, the current model of targeting high-risk individuals for aggressive therapy may not succeed alone, especially given the rising burden of risk. Estimating cardiovascular risk over a period of 10 years, using scoring systems such as Framingham or SCORE, continues to enjoy widespread use and is recommended for all adults. Limitations in the former have been of concern, including the under- or over-estimation of risk in specific populations, a relatively short 10-year risk horizon, focus on myocardial infarction and CHD death, and exclusion of family history. Classification errors may occur in up to 37% of individuals, particularly women and the young. Several different scoring systems are discussed in this review. The use of lifetime risk is an important conceptual advance, since ≥90% of young adults with a low 10-year risk have a lifetime risk of ≥39%; over half of all American adults have a low 10-year risk but a high lifetime risk. At age 50 the absence of traditional risk factors is associated with extremely low lifetime risk and significantly greater longevity. Pathological and epidemiological data confirm that atherosclerosis begins in early childhood, and advances seamlessly and inexorably throughout life. Risk factors in childhood are similar to those in adults, and track between stages of life. When indicated, aggressive treatment should begin at the earliest indication, and be continued for years. For those patients at intermediate risk according to global risk scores, C-reactive protein (CRP), coronary artery calcium (CAC), and carotid intima-media thickness (CIMT) are available for further stratification. Using statins for primary prevention is recommended by guidelines, is prevalent, but remains underprescribed. Statin drugs are unrivaled, evidence-based, major weapons to lower cardiovascular risk. Even when low density lipoprotein cholesterol (LDL-C) targets are attained, over half of patients continue to have disease progression and clinical events. This residual risk is of great concern, and multiple sources of remaining risk exist. Though clinical evidence is incomplete, altering or raising the blood high density lipoprotein cholesterol (HDL-C) level continues to be pursued. Of all agents available, rosuvastatin produces the greatest reduction in LDL-C, LDL-P, and improvement in apoA-I/apoB, together with a favorable safety profile. Several recent proposals and methods to lower cardiovascular risk are reviewed. A combination of approaches, such as the addition of lifetime risk, refinement of risk prediction, guideline compliance, novel treatments, improvement in adherence, and primordial prevention, including environmental and social intervention, will be necessary to lower the present high risk burden.
doi:10.2147/DDDT.S14934
PMCID: PMC3140289  PMID: 21792295
primary prevention; cardiovascular risk; coronary heart disease; primordial prevention; rosuvastatin; JUPITER study; statin drugs; C-reactive protein; inflammation; low-density lipoprotein; high-density lipoprotein; diabetes; metabolic syndrome; Framingham risk score; Reynolds risk score; SCORE; coronary artery calcification; carotid intima-media thickness; hypertension; obesity; non-HDL-cholesterol; LDL-P; dysfunctional HDL; lifetime risk; advanced lipid testing; Bogalusa Heart Study
11.  Burden of Subclinical Cardiovascular Disease in “Metabolically Benign” and “At-Risk” Overweight and Obese Women: The Study of Women's Health Across the Nation (SWAN) 
Atherosclerosis  2011;217(1):179-186.
Background
Metabolically benign obese individuals have a 10-year cardiovascular disease (CVD) risk comparable to healthy normal weight individuals. However, the burden of subclinical CVD among metabolically benign obese is not well known.
Methods
In cross-sectional analyses of 475 mid-life women, we compared common carotid artery intima media thickness (CCA-IMT), aortic pulse wave velocity (aPWV) and coronary (CAC) and aortic calcification (AC) among three groups: healthy normal weight, metabolically benign overweight/obese (<3 metabolic syndrome components/elevated CRP), and at-risk overweight/obese (≥3 metabolic syndrome components/elevated CRP).
Results
The mean (SD) CCA-IMT and aPWV were lowest in the normal weight group (n=145), followed by the benign overweight/obese (n=260) and at-risk overweight/obese (n=70) groups [CCA-IMT: 0.64 (0.08) vs. 0.68 (0.09) vs. 0.73 (0.13) mm, p<0.001; aPWV: 731.0 (176.4) vs. 809.9 (182.3) vs. 875.7 (228.8) cm/s, p<0.001]. Similar results were found for the frequency (%) of women with increased CAC and AC [CAC: 13 (9%) vs. 53(20%) vs. 28(40%), p<0.001; AC: 47(32%) vs. 130 (50%) vs. 55(79%), p<0.001]. These differences remained significant after multivariable adjustment. Further adjustment for BMI attenuated the statistical significance of differences in aPWV and calcification between benign and at-risk overweight/obese women, but had little effect on the magnitude of these differences.
Conclusions
Metabolically benign overweight/obese women have a significantly greater subclinical CVD burden than normal weight women, despite published data finding similar CVD event rates between the two groups. Prospective studies tracking the progression of subclinical atherosclerosis to clinical CVD in these women are needed.
doi:10.1016/j.atherosclerosis.2011.01.007
PMCID: PMC3117052  PMID: 21310415
Obesity phenotypes; subclinical atherosclerosis; carotid intima media thickness; pulse wave velocity; coronary calcification; aortic calcification
12.  Cholesteryl Ester Transfer Protein Genetic Polymorphisms, HDL Cholesterol, and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
Atherosclerosis  2008;200(2):359-367.
The cholesteryl ester transport protein (CETP) plays a key role in high-density lipoprotein (HDL) metabolism. Genetic variants that alter CETP activity and concentration may cause significant alterations in HDL-cholesterol (HDL-C) concentration; however, controversies remain about whether these genetic variants are associated with atherosclerosis. We genotyped the CETP R451Q, A373P, -629C/A, Taq1B, and -2505C/A polymorphisms in a cohort of Caucasian, Chinese, African-American, and Hispanic individuals within the Multi-Ethnic Study of Atherosclerosis. Genotypes were examined in relationship to HDL-C, CETP activity, CETP concentration, and three measures of subclinical cardiovascular disease (CVD): coronary artery calcium (CAC) measured by fast CT scanning, and carotid intimal-medial thickness (IMT) and carotid artery plaque, measured by ultrasonography. Carriers of the 451Q and 373P alleles have significantly higher CETP concentration (22.4% and 19.5%, respectively; p<0.001) and activity (13.1% and 9.4%, respectively; p<0.01) and lower HDL-C (5.6% and 6.0%, respectively; p<0.05). The minor alleles of the R451Q and A373P polymorphisms are associated with the presence of CAC, even after adjusting for CVD risk factors and HDL-C (p=0.006 and p=0.01, respectively). The R451Q polymorphism is also associated with presence of carotid artery plaque (p=0.036). Neither polymorphism is associated with common or internal carotid IMT. We confirmed that the -629A, Taq1B B2, and -2505A alleles are significantly associated with lower CETP concentration (20.8%, 25.0%, and 23.7%, respectively; p<0.001) and activity (14.8%, 19.8%, and 18.4%, respectively; p<0.001) and higher HDL-C concentration (9.7%, 11.5%, and 10.4%, respectively; p<0.01). However, we did not find any associations between these non-coding polymorphisms and subclinical CVD.
doi:10.1016/j.atherosclerosis.2007.12.038
PMCID: PMC3612981  PMID: 18243217
CETP; CVD; HDL; MESA
13.  The Epidemiology of Subclavian Stenosis and its Association with Markers of Subclinical Atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA) 
Atherosclerosis  2010;211(1):266-270.
Background
Recent studies indicate that subclavian stenosis (SS), diagnosed by a large systolic blood pressure difference (SBPD) between the right and left brachial arteries, is associated with cardiovascular disease (CVD) risk factors and outcomes. We sought to describe the epidemiology of SS and determine its association with markers of subclinical CVD in the baseline cohort of the Multi-Ethnic Study of Atherosclerosis.
Methods
We defined SS by an absolute SBPD ≥15 mmHg. Peripheral artery disease (PAD) was defined by an ankle-brachial index ≤0.90. The coronary artery calcium score (CAC) and the common-carotid artery intima-media thickness (CCA-IMT) were measured by computed tomography and B-mode ultrasound, respectively. Odds ratios for the associations of SS with risk factors and subclinical disease were estimated using logistic regression.
Results
Of 6,743 subjects studied, 307 participants (4.6%) had SS, with a higher prevalence in women (5.1%) than men (3.9%), and in African-Americans (7.4%) and non-Hispanic whites (5.1%) than Hispanic (1.9%) or Chinese (1.0%) participants (p<0.01). In a model including age, gender, ethnicity, traditional and novel CVD risk factors, significant associations with SS were observed for C-reactive protein (highest vs. three lower quartiles: OR=1.41; 95%CI: 1.06-1.87) and brachial artery pulse pressure (OR=1.12 /10 mmHg; 95%CI: 1.03-1.21). Adjusted for age, gender, ethnicity, traditional and novel CVD risk factors, SS was significantly associated with PAD (OR=2.35; 1.55-3.56), with CCA-IMT (highest vs. the lower three quartiles: OR=1.32; 1.00-1.75), and high CAC (score >100 vs. score=0; OR=1.43; 1.03-2.01).
Conclusions
The subclavian stenosis is positively associated with other markers of subclinical atherosclerosis.
doi:10.1016/j.atherosclerosis.2010.01.013
PMCID: PMC2925848  PMID: 20138280
subclavian artery; blood pressure; atherosclerosis; epidemiology
14.  Pericardial Fat is Associated with Carotid Stiffness in the Multi-Ethnic Study of Atherosclerosis 
Background and Aims
Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5,770 participants (mean age 62 yrs, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis.
Methods and Results
Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and young’s modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1-standard deviation (41.91 cm3) increment in Pfat was associated with a 0.00007±0.00002 1/mmHg lower DC (p=0.0002) in men and a 48.1±15.1 mmHg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results.
Conclusion
Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.
doi:10.1016/j.numecd.2009.10.010
PMCID: PMC2929306  PMID: 20153618
pericardial fat; arterial stiffness; distensibility; carotid artery
15.  Pulse Pressure and Subclinical Cardiovascular Disease in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Hypertension  2013;26(5):636-642.
BACKGROUND
Brachial pulse pressure (PP) has been found to be associated with markers of subclinical cardiovascular disease, including carotid intima–media thickness and left-ventricular mass index (LVMI), but it is unclear whether these associations are independent of traditional cardiovascular risk factors and of the steady, nonpulsatile component of blood pressure (BP). Moreover, it is unknown whether these associations are modified by gender, age, or race/ethnicity.
METHODS
We used multivariate linear regression models to assess the relationship between brachial PP and three markers of subclinical cardiovascular disease (CVD) (common carotid intima–media thickness (CC-IMT), internal carotid intima–media thickness (IC-IMT), and LVMI) in four race/ethnic groups in the Multi-Ethnic Study of Atherosclerosis. The models were adjusted for traditional Framingham risk factors (age, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, diabetes, smoking status), use of lipid-lowering medication, use of antihypertensive medication, study site, and mean arterial pressure (MAP).
RESULTS
The assessment was done on 6,776 participants (2,612 non-Hispanic white, 1,870 African-American, 1,494 Hispanic, and 800 Chinese persons). The associations between brachial PP and CC-IMT, IC-IMT, and LVMI were significant in fully adjusted models. The three subclinical markers also showed significant interactions with gender (P < 0.0001), with stronger interactions in men. There was an interaction with age for LVMI (P = 0.004) and IC-IMT (P = 0.008). Race/ethnicity modified the association of PP with CC-IMT.
CONCLUSIONS
Brachial PP was independently associated with subclinical CVD after adjustment for cardiovascular risk factors and mean arterial pressure (MAP). The strength of the association differed significantly for strata of gender, age, and race/ethnicity.
doi:10.1093/ajh/hps092
PMCID: PMC3657481  PMID: 23388832
pulse pressare; subclinical cardiovascular disease; carotid intima–media thickness; left ventricular mass index; aging; hypertension; arterial stiffness; blood pressure.
16.  Is Diabetic Retinopathy Related to Subclinical Cardiovascular Disease? 
Ophthalmology  2010;118(5):860-865.
OBJECTIVE
Persons with diabetic retinopathy (DR) have an increased risk of clinical cardiovascular events. Our study aimed to determine whether DR is associated with a range of measures of subclinical cardiovascular disease (CVD) in persons without clinical CVD.
DESIGN
Population-based, cross-sectional epidemiologic study
PARTICIPANTS
Nine hundred and twenty seven persons with diabetes without clinical CVD in the Multi-Ethnic Study of Atherosclerosis.
METHODS
DR was ascertained from retinal photographs according to modification of the Airlie House Classification system. Vision threatening DR (VTDR) was defined as severe non-proliferative DR, proliferative DR or clinically significant macular edema. Subclinical CVD measures were assessed and defined as follows: high coronary artery calcium (CAC) score, defined as CAC score≥400; low ankle-brachial index (ABI), defined as ABI<0.9; high ABI, defined as ABI≥1.4; high carotid intima-media thickness (IMT), defined as highest 25% of IMT; and carotid stenosis, defined as >25% stenosis or presence of carotid plaque.
MAIN OUTCOME MEASURES
Associations between DR and subclinical CVD measures.
RESULTS
The prevalence of DR and VTDR in this sample was 30.0% and 7.2%, respectively. VTDR was associated with a high CAC score (odds ratio [OR] 2.33, 95% condifence interval [CI] 1.15–4.73), low ABI (OR 2.54; 95%CI, 1.08–5.99) and high ABI (OR 12.6, 95% CI, 1.14, 140.6), after adjusting for risk factors including hemoglobin A1c level and duration of diabetes. The association between VTDR and high CAC score remained significant after further adjustment for hypoglycemic, anti-hypertensive and cholesterol-lowering medications. DR was not significantly associated with measures of carotid artery disease.
CONCLUSIONS
In persons with diabetes without a history of clinical CVD, the presence of advanced stage of DR is associated with subclinical coronary artery disease. These findings emphasize the need to be careful about the use of anti-vascular endothelial growth factor for the treatment of DR.
doi:10.1016/j.ophtha.2010.08.040
PMCID: PMC3087839  PMID: 21168222
17.  Associations of SNPs in ADIPOQ and subclinical cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Obesity (Silver Spring, Md.)  2010;19(4):840-847.
Circulating adiponectin has been associated with both clinical and subclinical cardiovascular disease (CVD). Variants of the adiponectin gene (ADIPOQ) are associated with clinical CVD, but little is known about associations with subclinical CVD. We studied the association of 11 ADIPOQ SNPs with common and internal carotid intima media thickness (cIMT), presence of coronary artery calcification (CAC), and CAC scores (in those with CAC) in 2847 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Participants were Caucasian (n=712), African-American (n=712), Chinese (n=718), and Hispanic (n=705). All models were adjusted for age, sex, and field site, and stratified by race/ethnic group. African-Americans with genotypes AG/GG of rs2241767 had 36% greater (95% CI (16%, 59%), p=0.0001) CAC prevalence; they also had a larger common cIMT (p=0.0043). Also in African-Americans, genotypes AG/AA of rs1063537 were associated with a 35% (95% CI (14%, 59%), p=0.0005) greater CAC prevalence. Hispanics with the AA genotype of rs11711353 had a 37% (95% CI (14%, 66%), p=0.0011), greater CAC prevalence compared to those with the GG genotype. Additional adjustment for ancestry in African-American and Hispanic participants did not change the results. No single SNP was associated with subclinical CVD phenotypes in Chinese or Caucasian participants. There appears to be an association between ADIPOQ SNPs and subclinical CVD in African-American and Hispanics. Replication as well as assessment of other ADIPOQ SNPs appears warranted.
doi:10.1038/oby.2010.229
PMCID: PMC3510267  PMID: 20930713
18.  Risk Factor Treatment in Veteran Women at Risk for Cardiovascular Disease 
Objectives
Cardiovascular disease (CVD) is the leading cause of death in women. Aggressive management of atherosclerotic risk factors can prevent or delay the onset of CVD. Treatment of modifiable risk factors provides an important opportunity to reduce the burden of CVD in women and decrease future adverse event rates. The aims of this study were to assess current treatment of atherosclerotic risk factors in women found to be at moderate or high-risk for CVD and to examine levels of CVD knowledge and awareness among women found to be at moderate or high-risk for CVD
Methods
In a cross-sectional study, we screened ambulatory female veterans aged 40 to 85 years for the prevalence of PVD and associated atherosclerotic risk factors, and administered a survey to assess the participants’ knowledge and awareness of CVD, risk factors, and consequences. Medical records, pharmacy data, and clinician encounter notes were reviewed for documented evidence of CVD risk factors, comorbidities, and corresponding treatment. From a total cohort of 162 women, 108 (66.7%) were categorized as having an increased risk of cardiovascular disease based on a modification of the Framingham cardiovascular risk score which took into account the presence of carotid intimal-medial thickness (cIMT) > 1.0 mm or ankle-brachial index ≤ 0.9, as determined by a voluntary, one time, non-invasive screening.
Results
In no category of CVD risk factor were 100% of the women receiving adequate medical or behavioral management. Especially surprising to us were the low levels of treatment for women with heart disease, smoking, and previous history of PAD. Over half of the women who were post-menopausal or who have had hysterectomy at the time of this study, continued to use HRT despite warnings about its role in CAD, stroke, and PAD. One third of moderate- to high-risk women had evidence of increased cIMT, which is a known surrogate marker of subclinical heart disease. Knowledge and awareness scores were low, regardless of risk factor level and respectable levels of education.
Conclusions
Our findings show a high prevalence of CVD risk factors and low knowledge levels among ambulatory veteran women. There is a need for improvement in recognition and aggressive management of CVD risk factors, including the use of non-invasive studies as surrogate markers for early diagnosis. Continued efforts to educate women and providers about CVD risk factors, heart-healthy behaviors, screening, and treatment are vital to improve the current state of women’s health and decrease future adverse cardiac event rates.
doi:10.1016/j.jss.2008.07.014
PMCID: PMC2821709  PMID: 19482299
19.  Abdominal Aortic Diameter and Vascular Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis 
Objectives
To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population.
Design
Cross-sectional cohort
Methods
A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation.
Results
In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized β=0.97), male sex (β=1.88), body surface area (standardized β=0.92), current smoking (β=0.42), D-dimer levels (β=0.19) and hypertension (β=0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (β=-0.70) (P<.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (β's= -0.59, -0.49, and -0.52, respectively, all P<.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (β=0.11 to 0.19), associated with larger AD.
Conclusions
Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease.
doi:10.1016/j.ejvs.2010.12.015
PMCID: PMC3070051  PMID: 21236707
aorta; aneurysm; atherosclerosis; ethnicity; epidemiology
20.  Association between carotid intima-media thickness and index of central fat distribution in middle-aged and elderly Chinese 
Background
Evidence has demonstrated that central fat distribution produces the most profound metabolic abnormalities and is associated with an increased risk of atherosclerotic cardiovascular diseases. We aimed to investigate whether the indexes of central fat distribution, including waist-to-height ratio (WHtR) and visceral fat area (VFA), were stronger risk factors of subclinical atherosclerosis than body mass index (BMI) in Chinese adults.
Methods
A total of 3381 participants aged 40 years or older without history of cardiovascular diseases (CVD) were enrolled in the present cross-sectional study from the Songnan community, Shanghai, China. Height, weight and waist circumference (WC) were measured by experienced physicians. High-resolution B-mode ultrasonography was performed to measure carotid intima-media thickness (CIMT). Regional adiposity was measured by a dual-source computed tomography (CT) scanner.
Results
Normal weight but central obesity group (BMI < 23 kg/m2 and WHtR > 0.5) had higher levels of systolic blood pressure (SBP), fasting plasma glucose (FPG), 2 h post-load glucose (2 h PG), Hemoglobin A1c (HbA1c), and CIMT, as well as an elevated prevalence of hypertension and diabetes compared with overweight/obesity but not central obesity group (BMI ≥ 23 kg/m2 and WHtR ≤ 0.5). In logistic regression analysis, WHtR > 0.5 was significantly and independently associated with elevated CIMT (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.01-1.68, p value = 0.044). Similar association was noted for each standard deviation (SD) increase of WHtR (OR 1.25, 95% CI 1.07-1.47, p value = 0.006). Stepwise multiple linear regression analysis revealed that both WHtR and VFA were important determinants of CIMT, independent of other well-recognized risk factors (both p values < 0.01).
Conclusions
WHtR and VFA were associated with CIMT, independent of BMI and conventional CVD risk factors. Given the relatively high cost and complexness of VFA measurement, WHtR could be a more convenient and appropriate measure of abdominal obesity in clinical practice.
doi:10.1186/s12933-014-0139-2
PMCID: PMC4219037  PMID: 25359238
Waist-to-height ratio; Visceral fat area; Carotid intima-media thickness
21.  Obesity and Overweight Associated With Increased Carotid Diameter and Decreased Arterial Function in Young Otherwise Healthy Men 
American Journal of Hypertension  2013;27(4):628-634.
BACKGROUND
Obesity is linked to cardiovascular disease, stroke, increased mortality and vascular remodeling. Although increased arterial diameter is associated with multiple cardiovascular risk factors and obesity, it is unknown whether lumen enlargement is accompanied by unfavorable vascular changes in young and otherwise healthy obese individuals. The purpose of this study was to compare carotid and brachial artery diameter, blood pressure, arterial stiffness, and endothelial function in young, apparently healthy, normal-weight, overweight, and obese male subjects.
METHODS
One hundred sixty-five male subjects (27.39±0.59 years) were divided into 3 groups (normal weight, overweight, and obese) according to body mass index. Subjects underwent cardiovascular measurements to determine arterial diameter, function, and stiffness.
RESULTS
After adjusting for age, the obese group had significantly greater brachial, carotid, and aortic pressures, brachial pulse wave velocity, carotid intima media thickness, and carotid arterial diameter compared with both the overweight and normal-weight groups.
CONCLUSIONS
Obesity is associated with a much worse arterial profile, as an increased carotid lumen size was accompanied by higher blood pressure, greater arterial stiffness, and greater carotid intima media thickness in obese compared with overweight or normal-weight individuals. These data suggest that although obesity may be a factor in arterial remodeling, such remodeling is also accompanied by other hemodynamic and arterial changes consistent with reduced arterial function and increased cardiovascular risk.
doi:10.1093/ajh/hpt152
PMCID: PMC3958602  PMID: 24048148
arterial diameter; arterial remodeling; arterial stiffness; blood pressure; hypertension; obesity.
22.  Abdominal Aortic Calcium and Multi-Site Atherosclerosis: The Multiethnic Study of Atherosclerosis 
Atherosclerosis  2011;214(2):436-441.
Background
Abdominal aortic calcification (AAC) is a measure of subclinical cardiovascular disease (CVD). Data are limited regarding its relation to other measures of atherosclerosis.
Methods
Among 1,812 subjects (49% female, 21% black, 14% Chinese, and 25% Hispanic) within the population-based Multiethnic Study of Atherosclerosis, we examined the cross-sectional relation of AAC with coronary artery calcium (CAC), ankle brachial index (ABI), and carotid intimal medial thickness (CIMT), as well as multiple measures of subclinical CVD.
Results
AAC prevalence ranged from 34% in those aged 45–54 to 94% in those aged 75–84 (p<0.0001), was highest in Caucasians (79%) and lowest in blacks (62%) (p<0.0001). CAC prevalence, mean maximum CIMT ≥ 1 mm, and ABI<0.9 was greater in those with vs. without AAC: CAC 60% vs 16%, CIMT 38% vs 7%, and ABI 5% vs 1% for women and CAC 80% vs 37%, CIMT 43% vs 16%, and ABI 4% vs 2% for men (p<0.01 for all except p<0.05 for ABI in men). The presence of multi-site atherosclerosis (≥ 3 of the above) ranged from 20% in women and 30% in men (p<0.001), was highest in Caucasians (28%) and lowest in Chinese (16%) and ranged from 5% in those aged 45–54 to 53% in those aged 75–84 (p<0.01 to p<0.001). Finally, increased AAC was associated with 2 to 3-fold relative risks for the presence of increased CIMT, low ABI, or CAC.
Conclusions
AAC is associated with an increased likelihood of other vascular atherosclerosis. Its additive prognostic value to these other measures is of further interest.
doi:10.1016/j.atherosclerosis.2010.09.011
PMCID: PMC3040451  PMID: 21035803
atherosclerosis; calcification; cardiovascular disease; epidemiology
23.  Serum 25-hydroxyvitamin D levels are not associated with subclinical vascular disease or C-reactive protein in the Old Order Amish 
Calcified tissue international  2009;84(3):195-202.
Background
The relationship between vitamin D metabolites and subclinical vascular disease is controversial. Because low serum levels of 25-hydroxyvitamin D [25(OH)D] have been associated with many cardiovascular disease (CVD) risk factors, we hypothesized that serum 25(OH)D levels would be inversely associated with inflammation as measured by C-reactive protein (CRP) and with subclinical vascular disease as measured by carotid intimal medial thickness (cIMT) and coronary artery calcification (CAC).
Methods
We measured 25(OH)D levels in 650 Amish participants. CAC was measured by computed tomography, and cIMT by ultrasound. The associations of 25(OH)D levels with natural log(CAC+1), cIMT, and natural log(CRP) levels were estimated following adjustment for age, sex, family structure, and season of examination. Additional analyses were carried out adjusting for body mass index (BMI) and other CVD risk factors.
Results
25(OH)D deficiency (<20 ng/ml) and insufficiency (21-30 ng/ml) were common among the Amish (38.2% and 47.7%, respectively). 25(OH)D levels were associated with season, age, BMI, and parathyroid hormone levels. In neither the minimally or fully adjusted analyses were significant correlations observed between 25(OH)D levels and CAC, cIMT, or CRP (R2 < 0.01 for all).
Conclusion
Contrary to our hypothesis, this study failed to detect a cross-sectional association between serum 25(OH)D levels and CAC, cIMT, or CRP. Either there is no causal relationship between 25(OH)D and CVD risk, or, if there is, it may be mediated through mechanisms other than subclinical vascular disease severity.
doi:10.1007/s00223-008-9209-3
PMCID: PMC2908302  PMID: 19148561
24.  The Association Between A1C and Subclinical Cardiovascular Disease 
Diabetes Care  2009;32(9):1727-1733.
OBJECTIVE
To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI.
RESEARCH DESIGN AND METHODS
This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI.
RESULTS
Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11).
CONCLUSIONS
In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women.
doi:10.2337/dc09-0074
PMCID: PMC2732160  PMID: 19549732
25.  Analysis of common and coding variants with cardiovascular disease in the diabetes heart study 
Background
Type 2 diabetes mellitus (T2DM) is a major cardiovascular disease (CVD) risk factor. Identification of genetic risk factors for CVD is important to understand disease risk. Two recent genome-wide association study (GWAS) meta-analyses in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium detected CVD-associated loci.
Methods
Variants identified in CHARGE were tested for association with CVD phenotypes, including vascular calcification, and conventional CVD risk factors, in the Diabetes Heart Study (DHS) (n = 1208; >80% T2DM affected). This included 36 genotyped or imputed single nucleotide polymorphisms (SNPs) from DHS GWAS data. 28 coding SNPs from 14 top CHARGE genes were also identified from exome sequencing resources and genotyped, along with 209 coding variants from the Illumina HumanExome BeadChip genotype data in the DHS were also tested. Genetic risk scores (GRS) were calculated to evaluate the association of combinations of variants with CVD measures.
Results
After correction for multiple comparisons, none of the CHARGE SNPs were associated with vascular calcification (p < 0.0014). Multiple SNPs showed nominal significance with calcification, including rs599839 (PSRC1, p = 0.008), rs646776 (CELSR2, p = 0.01), and rs17398575 (PIK3CG, p = 0.009). Additional COL4A2 and CXCL12 SNPs were nominally associated with all-cause or CVD-cause mortality. Three SNPs were significantly or nominally associated with serum lipids: rs3135506 (Ser19Trp, APOA5) with triglycerides (TG) (p = 5×10−5), LDL (p = 0.00070), and nominally with high density lipoprotein (HDL) (p = 0.0054); rs651821 (5′UTR, APOA5) with increased TGs (p = 0.0008); rs13832449 (splice donor, APOC3) associated with decreased TGs (p = 0.0015). Rs45456595 (CDKN2A, Gly63Arg), rs5128 (APOC3, 3′UTR), and rs72650673 (SH2B3, Glu400Lys) were nominally associated with history of CVD, subclinical CVD, or CVD risk factors (p < 0.010). From the exome chip, rs3750103 (CHN2, His204Arg/His68Arg) with carotid intima-medial thickness (IMT) (p = 3.9×10−5), and rs61937878 (HAL, Val549Met) with infra-renal abdominal aorta CP (AACP) (p = 7.1×10−5). The unweighted GRS containing coronary artery calcified plaque (CAC) SNPs was nominally associated with history of prior CVD (p = 0.033; OR = 1.09). The weighted GRS containing SNPs was associated with CAC and myocardial infarction (MI) was associated with history of MI (p = 0.026; OR = 1.15).
Conclusions
Genetic risk factors for subclinical CVD in the general population (CHARGE) were modestly associated with T2DM-related risk factors and CVD outcomes in the DHS.
doi:10.1186/1475-2840-13-77
PMCID: PMC4021556  PMID: 24725463
Coronary artery calcified plaque; Type 2 diabetes mellitus; Cardiovascular disease; Genetic risk score

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