Tanika N. Kelly

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in East Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10−8) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10−31 and P = 1.3 × 10−35 for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.

Systematic review: glucose control and cardiovascular disease in type 2 diabetes.

Context The relative benefits and harms of intensive versus conventional glucose control for type 2 diabetes are controversial. Contribution This review of 5 large trials found that, compared with conventional control, intensive glucose control reduced the risk for cardiovascular disease (mostly nonfatal myocardial infarction) but not for cardiovascular death or all-cause mortality, and increased risk for severe hypoglycemia. Trial design, achieved control, and findings were heterogeneous: Early trials suggested possible decreased risk for death with intensive control, whereas some more recent trials suggested possible increased risk for death with more stringent control. Caution The investigators did not evaluate costs. They pooled summary findings from trials rather than individual data from patients. The Editors The prevalence of type 2 diabetes is increasing globally (13). Epidemiologic evidence indicates that diabetes is a major risk factor for cardiovascular disease (CVD), and recent data suggest that the CVD burden attributable to diabetes is on the rise (47). Clinical trials have shown that intensive glucose control reduces the risk for microvascular complications among patients with type 2 diabetes, but its effect on CVD, including coronary heart disease (CHD), stroke, and peripheral arterial disease, is uncertain (810). Early data from the UKPDS (United Kingdom Prospective Diabetes Study) 34 suggested a protective effect of improved glucose control on CVD, CVD deaths, and all-cause mortality (11). However, within the past year, 3 large randomized, controlled trials have reported conflicting results (1214). Although ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) and VADT (Veterans Affairs Diabetes Trial) found no effect of intensive glucose control on major cardiovascular events (13, 14), ACCORD (Action to Control Cardiovascular Disease in Diabetes) identified an increased risk for death from cardiovascular causes and total mortality associated with intensive glucose control (12). On the basis of these results, a recent article by Montori and colleagues suggested that additional research is needed to confirm or refute the importance of tight glucose control (15). Thus, recommendations for health care providers regarding optimal hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes remain unclear. Because of the early termination of ACCORD and fewer events than anticipated in ADVANCE and VADT, there is real concern that these studies were underpowered to capture the true effects of intensive glucose control on CVD risk (1214). Therefore, we conducted a meta-analysis of randomized, controlled trials to examine the effects of intensive glucose control on CVD among patients with type 2 diabetes. Furthermore, we examined the separate effects of intensive glucose control on all-cause mortality, CVD mortality, CHD, congestive heart failure (CHF), stroke, and peripheral artery disease. In an effort to explain incongruities among trial results, we conducted subgroup analyses and examined the occurrence of severe hypoglycemia. Methods Data Sources and Searches We developed and followed a standard protocol for all steps of the review. Investigators searched the MEDLINE database (January 1950 through April 2009) using the Medical Subject Headings cardiovascular diseases; coronary disease; stroke; peripheral vascular diseases; hypoglycemic agents; and diabetes mellitus, type 2, as well as the keywords coronary heart disease, glucose control, and glycemic control. We restricted the search to randomized, controlled trials conducted among human adults (age 19 years), with no language restrictions. We also manually searched references cited in the published original reports and contacted experts in the field. Study Selection Two investigators independently reviewed the contents of 341 abstracts or full-text manuscripts identified through the literature search to determine whether they met the eligibility criteria. Studies were eligible for inclusion if 1) the study was a randomized, controlled trial; 2) the study compared intensive glucose control with conventional treatment, with a priori specification of glycemic goals for the intensive and conventional glucose control groups; 3) clinical CVD was the primary end point; 4) the study sample size was 500 patients or more; and 5) the study participants had type 2 diabetes mellitus. Reviewers resolved disagreements about study inclusion or exclusion by consensus and by referring to the original reports. Data Extraction and Quality Assessment Study investigators independently abstracted data in duplicate using a standardized data collection form. Reviewers did not contact authors to request additional information. Reviewers abstracted characteristics of each trial and its participants. Reviewers critically appraised methodological characteristics of trials, such as randomization procedures, blinded assessment of outcomes, adjudication procedures for outcomes, and follow-up rates, but did not use a scoring system to formally rate study quality of the individual trials (Appendix Table 1). Appendix Table 1. Assessment of Methodological Characteristics Reviewers recorded the following as the main outcomes of interest: number of clinical CVD, CHD, stroke, and CHF events, along with cardiovascular deaths and all-cause mortality, for the intensive and conventional glucose control groups. Reviewers also recorded single end points, including nonfatal myocardial infarction, fatal myocardial infarction, nonfatal stroke, fatal stroke, and peripheral artery disease. In addition, reviewers recorded the number of severe hypoglycemic events for each trial group. Because definitions of certain composite outcomes varied between trials, each outcome is defined for each trial in Appendix Table 2. Appendix Table 2. Definitions of Composite Outcomes for Each Trial Data Synthesis and Analysis We examined the relationship between intensive glucose control and risk for all study outcomes using relative risk and risk difference measures. We calculated the relative risks in each trial on the basis of the number of events in the intensive glucose control and conventional treatment groups and used these estimates for pooling analyses. To estimate the risk difference, we first calculated the annual absolute risk for an event in participants in each trial group by dividing the number of events in each trial group by the corresponding number of person-years (estimated as median treatment time number of participants in the trial group). We then multiplied the annual absolute risk by 5 to estimate the 5-year risk among participants in each trial group. We calculated the risk difference for each trial by subtracting the 5-year risk in the conventional glucose control group from the 5-year risk in the intensive glucose control group. We logarithmically transformed the relative risks and risk differences and their corresponding standard errors to stabilize the variance and normalize their distribution. We pooled relative risks and risk differences using both fixed-effects and DerSimonian and Laird random-effects models (16). We used inverse variance weighting to calculate fixed- and random-effects summary estimates. We assessed heterogeneity formally by using the Dersimonian and Laird Q test, considering any P value less than 0.100 as evidence of heterogeneity, and by examining the I 2 quantity. Although fixed- and random-effects models yielded similar findings, we detected between-study heterogeneity for several study outcomes (severe hypoglycemia, cardiovascular deaths, all-cause mortality, and fatal myocardial infarction). Because of this heterogeneity and trial differences in median diabetes duration of participants, achieved HbA1c levels, and therapeutic regimens, we present results from the random-effects models. We conducted a prestated subgroup analysis to examine the effects of intensive glucose control on all study outcomes. We then compared the relative risks for CVD, CHD, CHF, stroke, cardiovascular deaths, all-cause mortality, and severe hypoglycemia, as well as fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and peripheral artery disease between the early UKPDS trials (8, 11) and the 3 more recent ACCORD, ADVANCE, and VADT trials (1214). We conducted all analyses by using Stata software, version 9.2 (Stata Corp, College Station, Texas). Role of the Funding Source This study was funded in part by a career development award from the National Heart, Lung, and Blood Institute and by an award from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The funding sources played no role in the study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the paper for publication. Results Figure 1 depicts the study selection process. We excluded 2 trials, the Kumamoto Study (n = 110) and the Veterans Affairs (VA) Diabetes Feasibility Trial (n = 153), because of small sample sizes (9, 17). The VA Diabetes Feasibility Trial was a pilot study that examined whether intensive glucose control could be effectively sustained in patients with type 2 diabetes and was a precursor to the subsequent VADT. The Kumamoto Study examined the effects of intensive glucose control on microvascular complications of diabetes. The current meta-analysis included a total of 5 trials conducted among 27 802 participants (8, 1114). Table 1 presents the characteristics of the 5 randomized, controlled trials and trial participants. The number of trial participants ranged from 753 to 11 140, while intervention duration ranged from 3.4 to 10.7 years. The UKPDS 33 and 34 recruited participants with newly diagnosed diabetes. Those inclusion criteria differed from those of ADVANCE, ACCORD and VADT, whose participants had an average duration of diabetes ranging

Mortality Attributable to Smoking in China

BACKGROUND Smoking is a risk factor for many diseases and has been increasingly prevalent in economically developing regions of the world. We aimed to estimate the number of deaths attributable to smoking in China. METHODS We conducted a large, prospective cohort study in a nationally representative sample of 169,871 Chinese adults who were 40 years of age or older. Investigators for the China National Hypertension Survey collected data on smoking and other risk factors at a baseline examination in 1991 using a standard protocol. Follow-up evaluation was conducted in 1999 and 2000, with a response rate of 93.4%. We used multivariable-adjusted relative risk, prevalence of smoking, mortality, and population size in each age group, stratified according to sex, to calculate the number of deaths attributable to smoking in 2005. RESULTS There was a significant, dose-response association between pack-years smoked and death from any cause in both men and women after adjustment for multiple risk factors (P<0.001 for trend). We estimated that in 2005, a total of 673,000 deaths (95% confidence interval [CI], 564,700 to 781,400) were attributable to smoking in China: 538,200 (95% CI, 455,800 to 620,600) among men and 134,800 (95% CI, 108,900 to 160,800) among women. The leading causes of smoking-related deaths were as follows: cancer, 268,200 (95% CI, 214,500 to 321,900); cardiovascular disease, 146,200 (95% CI, 79,200 to 213,100); and respiratory disease, 66,800 (95% CI, 20,300 to 113,300). CONCLUSIONS Our study documents that smoking is a major risk factor for mortality in China. Continued strengthening of national programs and initiatives for smoking prevention and cessation is needed to reduce smoking-related deaths in China.

Effects of Low-Carbohydrate Diets Versus Low-Fat Diets on Metabolic Risk Factors: A Meta-Analysis of Randomized Controlled Clinical Trials

The effects of low-carbohydrate diets (≤45% of energy from carbohydrates) versus low-fat diets (≤30% of energy from fat) on metabolic risk factors were compared in a meta-analysis of randomized controlled trials. Twenty-three trials from multiple countries with a total of 2,788 participants met the predetermined eligibility criteria (from January 1, 1966 to June 20, 2011) and were included in the analyses. Data abstraction was conducted in duplicate by independent investigators. Both low-carbohydrate and low-fat diets lowered weight and improved metabolic risk factors. Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol (2.7 mg/dL; 95% confidence interval: 0.8, 4.6), and low density lipoprotein cholesterol (3.7 mg/dL; 95% confidence interval: 1.0, 6.4), but a greater increase in high density lipoprotein cholesterol (3.3 mg/dL; 95% confidence interval: 1.9, 4.7) and a greater decrease in triglycerides (-14.0 mg/dL; 95% confidence interval: -19.4, -8.7). Reductions in body weight, waist circumference and other metabolic risk factors were not significantly different between the 2 diets. These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors. Low-carbohydrate diets could be recommended to obese persons with abnormal metabolic risk factors for the purpose of weight loss. Studies demonstrating long-term effects of low-carbohydrate diets on cardiovascular events were warranted.

Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study.

BACKGROUND Since insulin resistance is thought to be the underlying mechanism for metabolic syndrome, affected individuals might be sensitive to a dietary sodium intervention. We aimed to examine the association between metabolic syndrome and salt sensitivity of blood pressure. METHODS 1906 Chinese participants without diabetes, aged 16 years or more, were selected to receive a low-sodium diet (51.3 mmol per day) for 7 days followed by a high-sodium diet (307.8 mmol per day) for an additional 7 days. Participants were excluded from the analysis if metabolic risk factor information was missing or if they did not complete their dietary interventions. Blood pressure was measured at baseline and on days 2, 5, 6, and 7 of each intervention. Metabolic syndrome was defined as the presence of three or more of: abdominal obesity, raised blood pressure, high triglyceride concentration, low HDL cholesterol, or high glucose. High salt sensitivity was defined as a decrease in mean arterial blood pressure of more than 5 mm Hg during low-sodium or an increase of more than 5 mm Hg during high-sodium intervention. This study is registered with ClinicalTrials.gov, number NCT00721721. FINDINGS Of the 1881 participants with information regarding metabolic syndrome, 283 had metabolic syndrome. 1853 participants completed the low-sodium diet and 1845 completed the high-sodium diet. Multivariable-adjusted mean changes in blood pressure were significantly greater in participants with metabolic syndrome than in those without on both low-sodium and high-sodium diets (p<0.0001 for all comparisons). Additionally, risk of salt sensitivity rose with increasing numbers of risk factors for metabolic syndrome. Compared with those with no risk factors, participants with four or five had a 3.54-fold increased odds (95% CI 2.05-6.11) of high salt-sensitivity during the low-sodium and a 3.13-fold increased odds (1.80-5.43) of high salt-sensitivity during the high-sodium intervention. INTERPRETATION These results suggest that metabolic syndrome enhances blood pressure response to sodium intake. Reduction in sodium intake could be an especially important component in reducing blood pressure in patients with multiple risk factors for metabolic syndrome.

Global Disparities of Hypertension Prevalence and Control: A Systematic Analysis of Population-Based Studies From 90 Countries.

Background: Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010. Methods: We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: In 2010, 31.1% (95% confidence interval, 30.0%–32.2%) of the world’s adults had hypertension; 28.5% (27.3%–29.7%) in high-income countries and 31.5% (30.2%–32.9%) in low- and middle-income countries. An estimated 1.39 (1.34–1.44) billion people had hypertension in 2010: 349 (337–361) million in high-income countries and 1.04 (0.99–1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries. Conclusions: Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries.Background: Hypertension is the leading preventable cause of premature death worldwide. We examined global disparities of hypertension prevalence, awareness, treatment, and control in 2010 and compared secular changes from 2000 to 2010. Methods: We searched MEDLINE from 1995 through 2014 and supplemented with manual searches of retrieved article references. We included 135 population-based studies of 968 419 adults from 90 countries. Sex- and age-specific hypertension prevalences from each country were applied to population data to calculate regional and global numbers of hypertensive adults. Proportions of awareness, treatment, and control from each country were applied to hypertensive populations to obtain regional and global estimates. Results: In 2010, 31.1% (95% confidence interval, 30.0%–32.2%) of the world’s adults had hypertension; 28.5% (27.3%–29.7%) in high-income countries and 31.5% (30.2%–32.9%) in low- and middle-income countries. An estimated 1.39 (1.34–1.44) billion people had hypertension in 2010: 349 (337–361) million in high-income countries and 1.04 (0.99–1.09) billion in low- and middle-income countries. From 2000 to 2010, the age-standardized prevalence of hypertension decreased by 2.6% in high-income countries, but increased by 7.7% in low- and middle-income countries. During the same period, the proportions of awareness (58.2% versus 67.0%), treatment (44.5% versus 55.6%), and control (17.9% versus 28.4%) increased substantially in high-income countries, whereas awareness (32.3% versus 37.9%) and treatment (24.9% versus 29.0%) increased less, and control (8.4% versus 7.7%) even slightly decreased in low- and middle-income countries. Conclusions: Global hypertension disparities are large and increasing. Collaborative efforts are urgently needed to combat the emerging hypertension burden in low- and middle-income countries. # Clinical Perspective {#article-title-35}

Premature deaths attributable to blood pressure in China: a prospective cohort study

BACKGROUND Hypertension is a major global-health challenge because of its high prevalence and concomitant risks of cardiovascular disease. We estimated premature deaths attributable to increased blood pressure in China. METHODS We did a prospective cohort study in a nationally representative sample of 169,871 Chinese adults aged 40 years and older. Blood pressure and other risk factors were measured at a baseline examination in 1991 and follow-up assessment was done in 1999-2000. Premature death was defined as mortality before age 72 years in men and 75 years in women, which were the average life expectancies in China in 2005. We calculated the numbers of total and premature deaths attributable to blood pressure using population-attributable risk, mortality, and the population size of China in 2005. FINDINGS Hypertension and prehypertension were significantly associated with increased all-cause and cardiovascular mortality (p<0.0001). We estimated that in 2005, 2.33 million (95% CI 2.21-2.45) cardiovascular deaths were attributable to increased blood pressure in China: 2.11 million (2.03-2.20) in adults with hypertension and 0.22 million (0.19-0.25) in adults with prehypertension. Additionally, 1.27 million (1.18-1.36) premature cardiovascular deaths were attributable to raised blood pressure in China: 1.15 million (1.08-1.22) in adults with hypertension and 0.12 million (0.10-0.14) in adults with prehypertension. Most blood pressure-related deaths were caused by cerebrovascular diseases: 1.86 million (1.76-1.96) total deaths and 1.08 million (1.00-1.15) premature deaths. INTERPRETATION Increased blood pressure is the leading preventable risk factor for premature mortality in the Chinese general population. Prevention and control of this condition should receive top public-health priority in China. FUNDING American Heart Association (USA); National Heart, Lung, and Blood Institute, National Institutes of Health (USA); Ministry of Health (China); and Ministry of Science and Technology (China).

A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Here we estimated the global prevalence and absolute burden of CKD in 2010 by pooling data from population-based studies. We searched MEDLINE (January 1990 to December 2014), International Society of Nephrology Global Outreach Program funded projects, and bibliographies of retrieved articles and selected 33 studies reporting gender- and age-specific prevalence of CKD in representative population samples. The age standardized global prevalence of CKD stages 1–5 in adults aged 20 and older was 10.4% in men (95% confidence interval 9.3–11.9%) and 11.8% in women (11.2–12.6%). This consisted of 8.6% men (7.3–9.8%) and 9.6% women (7.7–11.1%) in high-income countries, and 10.6% men (9.4–13.1%) and 12.5% women (11.8–14.0%) in low- and middle-income countries. The total number of adults with CKD was 225.7 million (205.7–257.4 million) men and 271.8 million (258.0–293.7 million) women. This consisted of 48.3 million (42.3–53.3 million) men and 61.7 million (50.4–69.9 million) women in high-income countries, and 177.4 million (159.2–215.9 million) men and 210.1 million (200.8–231.7 million) women in low- and middle-income countries. Thus, CKD is an important global-health challenge, especially in low- and middle-income countries. National and international efforts for prevention, detection, and treatment of CKD are needed to reduce its morbidity and mortality worldwide.

Gender Difference in Blood Pressure Responses to Dietary Sodium Intervention in the GenSalt Study

Objective To examine factors related to blood pressure (BP) responses to dietary sodium and potassium interventions. Methods We conducted a dietary feeding study that included a 7-day low-salt intervention (51.3 mmol sodium/day), a 7-day high-salt intervention (307.8 mmol sodium/day), and a 7-day high-salt and potassium-supplementation (60 mmol potassium/day) intervention among 1906 study participants in rural China. The BP was measured nine times during the 3-day baseline observation and during the last 3 days of each intervention phase using a random-zero sphygmomanometer. Results The BP responses to low-sodium intervention were significantly greater in women than in men: −8.1 [95% confidence interval (−8.6 to −7.6)] versus −7.0 (−7.5 to −6.6) mmHg for systolic and −4.5 (−4.9 to −4.1) versus −3.4 (−3.8 to −3.0) mmHg for diastolic. Likewise, BP responses to high-sodium interventions were significantly greater in women than in men: 6.4 (5.9–6.8) versus 5.2 (4.8–5.7) mmHg for systolic and 3.1 (2.7–3.5) versus 1.7 (1.4–2.1) mmHg for diastolic (all P < 0.001). In addition, systolic BP responses to sodium interventions increased with age, and both systolic and diastolic BP responses to sodium interventions increased with baseline BP levels. BP responses to potassium supplementation also increased with baseline BP levels. Conclusion These results suggest that female gender, older age, and hypertension increase the sensitivity to dietary sodium intervention. Furthermore, low dietary sodium intake may be more effective in reducing BP among these subgroups.

Cigarette Smoking and Risk of Stroke in the Chinese Adult Population

Background and Purpose— We studied the relationship between cigarette smoking and stroke incidence and mortality in the Chinese adult population. Methods— We conducted a prospective cohort study in a nationally representative sample of 169 871 Chinese men and women aged 40 years and older. Data on cigarette smoking and other covariables were collected at a baseline examination in 1991 using a standard protocol. Follow-up evaluation was conducted in 1999 to 2000, with a response rate of 93.4%. Results— During an average of 8.3 years follow-up, a total of 6780 stroke events (3979 fatal strokes) were observed. The multivariate-adjusted relative risks (95% confidence interval) of stroke incidence and mortality associated with present cigarette smoking were 1.28 (1.19 to 1.37) and 1.13 (1.03 to 1.25) in men and 1.25 (1.13 to 1.37) and 1.19 (1.04 to 1.36) in women, respectively. The corresponding population attributable risks were 14.2% and 7.1% in men and 3.1% and 2.4% in women. Compared to never-smokers, the multivariate-adjusted relative risks of stroke incidence (95% confidence interval) were 1.21 (1.12 to 1.31), 1.21 (1.11 to 1.32), and 1.36 (1.25 to 1.47) for those who smoked 1 to 9, 10 to 19, and ≥20 cigarettes per day; and 1.18 (1.09 to 1.28), 1.25 (1.15 to 1.35), and 1.34 (1.24 to 1.44) for those who smoked 1 to 11, 12 to 26, and >26 pack-years, respectively (both P<0.0001 for linear trends). Conclusions— Our study identified a positive and dose-response relationship between cigarette smoking and risk of stroke. Smoking prevention and cessation programs should be an important strategy for reducing the burden of stroke in Chinese adults.