Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD.

The Incremental Validity of Self-Report and Performance-Based Methods for Assessing Hostility to Predict Cardiovascular Disease in Physicians.

We evaluated the utility of an integrative, multimethod approach for assessing hostility-related constructs to predict premature cardiovascular disease (CVD) and premature coronary heart disease (CHD) using participants from the Johns Hopkins Precursors Study, which was designed to identify risk factors for heart disease. Participants were assessed at baseline while in medical school from 1946 to 1962 (M age = 24.6) and have been followed annually since then. Baseline assessment included individually administered Rorschach protocols (N = 416) scored for aggressive imagery (i.e., Aggressive Content, Aggressive Past) and self-reports of 3 possible anger responses to stress. Cox regression analyses predicting morbidity or mortality by age 55 revealed a significant interaction effect; high levels of Aggressive Content with high self-reported hostility predicted an increased rate of premature CVD and CHD, and incrementally predicted the rate of these events after controlling for the significant covariates of smoking (CVD and CHD) and cholesterol (CHD) that were also assessed at baseline. The hostility and anger measures, as well as other baseline covariates, were not predictors of CVD risk factors assessed at midlife during follow-up. Overall, this integrative model of hostility illustrates the potential value of multimethod assessment to areas of health psychology and preventive medicine.

Selecting SNPs informative for African, American Indian and European Ancestry: application to the Family Investigation of Nephropathy and Diabetes (FIND).

BACKGROUND: The presence of population structure in a sample may confound the search for important genetic loci associated with disease. Our four samples in the Family Investigation of Nephropathy and Diabetes (FIND), European Americans, Mexican Americans, African Americans, and American Indians are part of a genome- wide association study in which population structure might be particularly important. We therefore decided to study in detail one component of this, individual genetic ancestry (IGA). From SNPs present on the Affymetrix 6.0 Human SNP array, we identified 3 sets of ancestry informative markers (AIMs), each maximized for the information in one the three contrasts among ancestral populations: Europeans (HAPMAP, CEU), Africans (HAPMAP, YRI and LWK), and Native Americans (full heritage Pima Indians). We estimate IGA and present an algorithm for their standard errors, compare IGA to principal components, emphasize the importance of balancing information in the ancestry informative markers (AIMs), and test the association of IGA with diabetic nephropathy in the combined sample. RESULTS: A fixed parental allele maximum likelihood algorithm was applied to the FIND to estimate IGA in four samples: 869 American Indians; 1385 African Americans; 1451 Mexican Americans; and 826 European Americans. When the information in the AIMs is unbalanced, the estimates are incorrect with large error. Individual genetic admixture is highly correlated with principle components for capturing population structure. It takes ~700 SNPs to reduce the average standard error of individual admixture below 0.01. When the samples are combined, the resulting population structure creates associations between IGA and diabetic nephropathy. CONCLUSIONS: The identified set of AIMs, which include American Indian parental allele frequencies, may be particularly useful for estimating genetic admixture in populations from the Americas. Failure to balance information in maximum likelihood, poly-ancestry models creates biased estimates of individual admixture with large error. This also occurs when estimating IGA using the Bayesian clustering method as implemented in the program STRUCTURE. Odds ratios for the associations of IGA with disease are consistent with what is known about the incidence and prevalence of diabetic nephropathy in these populations.

Effects of low-carbohydrate and low-fat diets: a randomized trial.

BACKGROUND: Low-carbohydrate diets are popular for weight loss, but their cardiovascular effects have not been well-studied, particularly in diverse populations. OBJECTIVE: To examine the effects of a low-carbohydrate diet compared with a low-fat diet on body weight and cardiovascular risk factors. DESIGN: A randomized, parallel-group trial. (ClinicalTrials.gov: NCT00609271). SETTING: A large academic medical center. PARTICIPANTS: 148 men and women without clinical cardiovascular disease and diabetes. INTERVENTION: A low-carbohydrate (<40 g/d) or low-fat (<30% of daily energy intake from total fat [<7% saturated fat]) diet. Both groups received dietary counseling at regular intervals throughout the trial. MEASUREMENTS: Data on weight, cardiovascular risk factors, and dietary composition were collected at 0, 3, 6, and 12 months. RESULTS: Sixty participants (82%) in the low-fat group and 59 (79%) in the low-carbohydrate group completed the intervention. At 12 months, participants on the low-carbohydrate diet had greater decreases in weight (mean difference in change, -3.5 kg [95% CI, -5.6 to -1.4 kg]; P = 0.002), fat mass (mean difference in change, -1.5% [CI, -2.6% to -0.4%]; P = 0.011), ratio of total-high-density lipoprotein (HDL) cholesterol (mean difference in change, -0.44 [CI, -0.71 to -0.16]; P = 0.002), and triglyceride level (mean difference in change, -0.16 mmol/L [-14.1 mg/dL] [CI, -0.31 to -0.01 mmol/L {-27.4 to -0.8 mg/dL}]; P = 0.038) and greater increases in HDL cholesterol level (mean difference in change, 0.18 mmol/L [7.0 mg/dL] [CI, 0.08 to 0.28 mmol/L {3.0 to 11.0 mg/dL}]; P < 0.001) than those on the low-fat diet. LIMITATION: Lack of clinical cardiovascular disease end points. CONCLUSION: The low-carbohydrate diet was more effective for weight loss and cardiovascular risk factor reduction than the low-fat diet. Restricting carbohydrate may be an option for persons seeking to lose weight and reduce cardiovascular risk factors. PRIMARY FUNDING SOURCE: National Institutes of Health.

Body mass index and risk of incident hypertension over the life course: the Johns Hopkins Precursors Study.

BACKGROUND: The obesity-hypertension link over the life course has not been well characterized, although the prevalence of obesity and hypertension is increasing in the United States. METHODS AND RESULTS: We studied the association of body mass index (BMI) in young adulthood, into middle age, and through late life with risk of developing hypertension in 1132 white men of The Johns Hopkins Precursors Study, a prospective cohort study. Over a median follow-up period of 46 years, 508 men developed hypertension. Obesity (BMI ≥30 kg/m(2)) in young adulthood was strongly associated with incident hypertension (hazard ratio, 4.17; 95% confidence interval, 2.34-7.42). Overweight (BMI 25 to <30 kg/m(2)) also signaled increased risk (hazard ratio, 1.58; 95% confidence interval, 1.28-1.96). Men of normal weight at age 25 years who became overweight or obese at age 45 years were at increased risk compared with men of normal weight at both times (hazard ratio, 1.57; 95% confidence interval, 1.20-2.07), but not men who were overweight or obese at age 25 years who returned to normal weight at age 45 years (hazard ratio, 0.91; 95% confidence interval, 0.43-1.92). After adjustment for time-dependent number of cigarettes smoked, cups of coffee taken, alcohol intake, physical activity, parental premature hypertension, and baseline BMI, the rate of change in BMI over the life course increased the risk of incident hypertension in a dose-response fashion, with the highest risk among men with the greatest increase in BMI (hazard ratio, 2.52; 95% confidence interval, 1.82-3.49). CONCLUSIONS: Our findings underscore the importance of higher weight and weight gain in increasing the risk of hypertension from young adulthood through middle age and into late life.

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.

Genetic association and gene-gene interaction analyses in African American dialysis patients with nondiabetic nephropathy.

BACKGROUND: African Americans have increased susceptibility to nondiabetic nephropathy relative to European Americans. STUDY DESIGN: Follow-up of a pooled genome-wide association study (GWAS) in African American dialysis patients with nondiabetic nephropathy; novel gene-gene interaction analyses. SETTING & PARTICIPANTS: Wake Forest sample: 962 African American nondiabetic nephropathy cases, 931 non-nephropathy controls. Replication sample: 668 Family Investigation of Nephropathy and Diabetes (FIND) African American nondiabetic nephropathy cases, 804 non-nephropathy controls. PREDICTORS: Individual genotyping of top 1,420 pooled GWAS-associated single-nucleotide polymorphisms (SNPs) and 54 SNPs in 6 nephropathy susceptibility genes. OUTCOMES: APOL1 genetic association and additional candidate susceptibility loci interacting with or independently from APOL1. RESULTS: The strongest GWAS associations included 2 noncoding APOL1 SNPs, rs2239785 (OR, 0.33; dominant; P = 5.9 × 10(-24)) and rs136148 (OR, 0.54; additive; P = 1.1 × 10(-7)) with replication in FIND (P = 5.0 × 10(-21) and 1.9 × 10(-05), respectively). rs2239785 remained associated significantly after controlling for the APOL1 G1 and G2 coding variants. Additional top hits included a CFH SNP (OR from meta-analysis in the 3,367 African American cases and controls, 0.81; additive; P = 6.8 × 10(-4)). The 1,420 SNPs were tested for interaction with APOL1 G1 and G2 variants. Several interactive SNPs were detected; the most significant was rs16854341 in the podocin gene (NPHS2; P = 0.0001). LIMITATIONS: Nonpooled GWASs have not been performed in African American patients with nondiabetic nephropathy. CONCLUSIONS: This follow-up of a pooled GWAS provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans and identified additional associated and interactive nondiabetic nephropathy susceptibility genes.

Admixture mapping of 15,280 African Americans identifies obesity susceptibility loci on chromosomes 5 and X.

The prevalence of obesity (body mass index (BMI) > or =30 kg/m(2)) is higher in African Americans than in European Americans, even after adjustment for socioeconomic factors, suggesting that genetic factors may explain some of the difference. To identify genetic loci influencing BMI, we carried out a pooled analysis of genome-wide admixture mapping scans in 15,280 African Americans from 14 epidemiologic studies. Samples were genotyped at a median of 1,411 ancestry-informative markers. After adjusting for age, sex, and study, BMI was analyzed both as a dichotomized (top 20% versus bottom 20%) and a continuous trait. We found that a higher percentage of European ancestry was significantly correlated with lower BMI (rho = -0.042, P = 1.6x10(-7)). In the dichotomized analysis, we detected two loci on chromosome X as associated with increased African ancestry: the first at Xq25 (locus-specific LOD = 5.94; genome-wide score = 3.22; case-control Z = -3.94); and the second at Xq13.1 (locus-specific LOD = 2.22; case-control Z = -4.62). Quantitative analysis identified a third locus at 5q13.3 where higher BMI was highly significantly associated with greater European ancestry (locus-specific LOD = 6.27; genome-wide score = 3.46). Further mapping studies with dense sets of markers will be necessary to identify the alleles in these regions of chromosomes X and 5 that may be associated with variation in BMI.

Successfully Implementing Digital Health to Ensure Future Global Health Security During Pandemics: A Consensus Statement.

Importance: COVID-19 has highlighted widespread chronic underinvestment in digital health that hampered public health responses to the pandemic. Recognizing this, the Riyadh Declaration on Digital Health, formulated by an international interdisciplinary team of medical, academic, and industry experts at the Riyadh Global Digital Health Summit in August 2020, provided a set of digital health recommendations for the global health community to address the challenges of current and future pandemics. However, guidance is needed on how to implement these recommendations in practice. Objective: To develop guidance for stakeholders on how best to deploy digital health and data and support public health in an integrated manner to overcome the COVID-19 pandemic and future pandemics. Evidence Review: Themes were determined by first reviewing the literature and Riyadh Global Digital Health Summit conference proceedings, with experts independently contributing ideas. Then, 2 rounds of review were conducted until all experts agreed on the themes and main issues arising using a nominal group technique to reach consensus. Prioritization was based on how useful the consensus recommendation might be to a policy maker. Findings: A diverse stakeholder group of 13 leaders in the fields of public health, digital health, and health care were engaged to reach a consensus on how to implement digital health recommendations to address the challenges of current and future pandemics. Participants reached a consensus on high-priority issues identified within 5 themes: team, transparency and trust, technology, techquity (the strategic development and deployment of technology in health care and health to achieve health equity), and transformation. Each theme contains concrete points of consensus to guide the local, national, and international adoption of digital health to address challenges of current and future pandemics. Conclusions and Relevance: The consensus points described for these themes provide a roadmap for the implementation of digital health policy by all stakeholders, including governments. Implementation of these recommendations could have a significant impact by reducing fatalities and uniting countries on current and future battles against pandemics.

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).

Blood pressure change and risk of hypertension associated with parental hypertension: the Johns Hopkins Precursors Study.

BACKGROUND: Parental hypertension is used to classify hypertension risk in young adults, but the long-term association of parental hypertension with blood pressure (BP) change and risk of hypertension over the adult life span has not been well studied. METHODS: We examined the association of parental hypertension with BP change and hypertension risk from young adulthood through the ninth decade of life in a longitudinal cohort of 1160 male former medical students with 54 years of follow-up. RESULTS: In mixed-effects models using 29 867 BP measurements, mean systolic and diastolic BP readings were significantly higher at baseline among participants with parental hypertension. The rate of annual increase was slightly higher for systolic (0.03 mm Hg, P= .04), but not diastolic, BP in those with parental hypertension. After adjustment for baseline systolic and diastolic BP and time-dependent covariates--body mass index, alcohol consumption, coffee drinking, physical activity, and cigarette smoking--the hazard ratio (95% confidence interval [CI]) of hypertension development was 1.5 (1.2-2.0) for men with maternal hypertension only, 1.8 (1.4-2.4) for men with paternal hypertension only, and 2.4 (1.8-3.2) for men with hypertension in both parents compared with men whose parents never developed hypertension. Early-onset (at age

The association of sudden cardiac death with inflammation and other traditional risk factors.

Despite the frequency of cardiovascular death in dialysis patients, few studies have prospectively measured sudden cardiac death in these individuals. Here, we sought to determine the frequency of sudden cardiac death and its association with inflammation and other risk factors among the CHOICE (Choices for Healthy Outcomes In Caring for ESRD) cohort of 1,041 incident dialysis patients. Sudden cardiac death was defined as that occurring outside of the hospital with an underlying cardiac cause from death certificate data. Over a median 2.5 years of follow-up, 22% of all mortality in this cohort was due to sudden cardiac death. Using Cox proportional hazards, we found that the highest tertiles of high-sensitivity C-reactive protein and of IL-6 were each associated with twice the risk of sudden cardiac death compared to their lowest tertiles when adjusted for demographics, comorbidities and laboratory factors. A decrement in serum albumin was associated with a 1.35 times increased risk for sudden cardiac death in the highest compared to the lowest tertile. These findings were robust and consistent when accounting for competing risks of death from other causes. Hence, we found that sudden cardiac death is common among patients with end stage renal disease and that inflammation and malnutrition significantly increased its occurrence independent of traditional cardiovascular risk factors.

Major causes of death among men and women in China.

BACKGROUND: With China's rapid economic development, the disease burden may have changed in the country. We studied the major causes of death and modifiable risk factors in a nationally representative cohort of 169,871 men and women 40 years of age and older in China. METHODS: Baseline data on the participants' demographic characteristics, medical history, lifestyle-related risk factors, blood pressure, and body weight were obtained in 1991 with the use of a standard protocol. The follow-up evaluation was conducted in 1999 and 2000, with a follow-up rate of 93.4 percent. RESULTS: We documented 20,033 deaths in 1,239,191 person-years of follow-up. The mortality from all causes was 1480.1 per 100,000 person-years among men and 1190.2 per 100,000 person-years among women. The five leading causes of death were malignant neoplasms (mortality, 374.1 per 100,000 person-years), diseases of the heart (319.1), cerebrovascular disease (310.5), accidents (54.0), and infectious diseases (50.5) among men and diseases of the heart (268.5), cerebrovascular disease (242.3), malignant neoplasms (214.1), pneumonia and influenza (45.9), and infectious diseases (35.3) among women. The multivariate-adjusted relative risk of death and the population attributable risk for preventable risk factors were as follows: hypertension, 1.48 (95 percent confidence interval, 1.44 to 1.53) and 11.7 percent, respectively; cigarette smoking, 1.23 (95 percent confidence interval, 1.18 to 1.27) and 7.9 percent; physical inactivity, 1.20 (95 percent confidence interval, 1.16 to 1.24) and 6.8 percent; and underweight (body-mass index [the weight in kilograms divided by the square of the height in meters] below 18.5), 1.47 (95 percent confidence interval, 1.42 to 1.53) and 5.2 percent. CONCLUSIONS: Vascular disease and cancer have become the leading causes of death among Chinese adults. Our findings suggest that control of hypertension, smoking cessation, increased physical activity, and improved nutrition should be important strategies for reducing the burden of premature death among adults in China.