Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.
We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.
An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).
Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
Although COPD is a major cause of disability worldwide, its determinants remain poorly defined.
We hypothesized that both pulmonary and extra-pulmonary factors would predict prospective disablement across a hierarchy of activities in persons with COPD.
609 participants were studied at baseline (T0) and 2.5 years later (T1). The Valued Life Activities (VLA) scale quantified disability (10-point scale; 0=no difficulty, 10=unable to perform), defining disability as any activity newly rated “unable to perform” at T1. Predictors included pulmonary (lung function, six-minute walk distance, and COPD severity score) and extra-pulmonary (quadriceps strength, lower extremity function) factors. Prospective disability risk was tested by separate logistic regression models for each predictor (baseline value and its change, T0 to T2; odds ratios were scaled at 1 standard deviation per factor. Incident disability across a hierarchy of obligatory, committed, and discretionary VLA subscales was compared.
Subjects manifested a 40% or greater increased odds of developing disability for each predictor (baseline and change over time). Disability in discretionary activities developed at a rate 2.2-times higher than observed in committed activities, which was in turn, 2.5-times higher than the rate observed in obligatory activities (p<0.05 for each level).
Disability is common in COPD. Both pulmonary and extra-pulmonary factors are important in predicting its development.
Chronic obstructive pulmonary disease; disability; exercise capacity; functional limitation; peripheral muscle weakness
There has been reduced active smoking, decreased societal acceptance for smoking indoors, and changing smoking policy since the mid-1980s. We quantified passive smoke exposure trends and their relationship with workplace policy.
We studied 2,504 CARDIA participants (blacks and whites, 18–30 years old when recruited in 1985–86 from four US cities, reexamination 2, 5, 7, 10, and 15 years later) who never reported smoking and attended exams at 10 or 15 years.
In non-smokers with a college degree (n = 1,581), total passive smoke exposure declined from 16.3 hr/wk in 1985/86 to 2.3 hr/wk in 2000/01. Less education tended to be associated with more exposure at all timepoints for example, in high school or less (n = 349) 22.2 hours/wk in 1985/86 to 8.5 hr/wk in 2000/01. Those who experienced an increase in the restrictiveness of self-reported workplace smoking policy from 1995/96 to 2000/01 were exposed to almost 3 hours per week less passive smoke than those whose workplace policies became less restrictive in this time period.
The increasing presence of restrictive workplace policies seemed to be a component of the substantial decline in self-reported passive smoke exposure since 1985.
Environmental Tobacco Smoke Pollution; Occupational Health; Passive Smoking; Socioeconomic factors
A prolonged QT interval is a marker for an increased risk of ventricular tachyarrhythmias. Both endogenous and exogenous sex hormones have been shown to affect the QT interval. Endogenous testosterone and progesterone shorten the action potential, and estrogen lengthens the QT interval. During a single menstrual cycle, progesterone levels, but not estrogen levels, have the dominant effect on ventricular repolarization in women. Studies of menopausal hormone therapy (MHT) in the form of estrogen-alone therapy (ET) and estrogen plus progesterone therapy (EPT) have suggested a counterbalancing effect of exogenous estrogen and progesterone on the QT. Specifically, ET lengthens the QT, whereas EPT has no effect. To date, there are no studies on oral contraception (OC) and the QT interval, and future research is needed. This review outlines the current literature on sex hormones and QT interval, including the endogenous effects of estrogen, progesterone, and testosterone and the exogenous effects of estrogen and progesterone therapy in the forms of MHT and hormone contraception. Further, we review the potential mechanisms and pathophysiology of sex hormones on the QT interval.
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10−8), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
There is evidence across several species for genetic control of phenotypic variation of complex traits1–4, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)5–7, is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation9,10. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
Few studies to date have described the prevalence of electrocardiographic (ECG) abnormalities in a biracial middle-aged cohort.
Methods and Results
Participants underwent measurement of traditional risk factors and 12-lead ECGs coded using both Minnesota Code (MC) and Novacode (NC) criteria. Among 2585 participants, of whom 57% were women and 44% were black (mean age 45 years), the prevalence of major and minor abnormalities were significantly higher (all P<0.001) among black men and women compared to whites. These differences were primarily due to higher QRS voltage and ST/T wave abnormalities among blacks. There was also a higher prevalence of Q waves (MC 1-1, 1-2, 1-3) than described by previous studies. These racial differences remained after multivariate adjustment for traditional cardiovascular (CV) risk factors.
Black men and women have a significantly higher prevalence of ECG abnormalities, independent of traditional CV risk factors, than whites in a contemporary cohort middle-aged participants.
Mammographically-detected breast arterial calcifications (BAC) are considered to be an incidental finding without clinical importance since they are not associated with increased risk of breast cancer. The goal of this article is to review existing evidence that the presence of BAC on mammography correlates with several (but not all) traditional cardiovascular disease (CVD) risk factors and with prevalent and incident CVD. Thus, BAC detected during routine mammography is a noteworthy finding that could be valuable in identifying asymptomatic women at increased future CVD risk that may be candidates for more aggressive management. In addition, there are notable differences in measures of subclinical atherosclerosis burden in women (ie, coronary artery calcification) by race/ethnic background, and the same appears to be true for BAC, although data are very limited. Another noteworthy limitation of prior research on BAC is the reliance on absence vs presence of BAC; no study to date has determined gradation of BAC. Further research is thus required to elucidate the role of BAC gradation in the prediction of CVD outcomes and to determine whether adding BAC gradation to prediction models based on traditional risk factors improves classification of CVD risk.
Breast arterial calcification; Cardiovascular disease risk; Cardiovascular risk factors; Risk stratification; Mammography
To delineate the relationship of obesity to airflow obstruction (AO) and respiratory symptoms in adults without a previous diagnosis of chronic obstructive pulmonary disease (COPD).
We analyzed data for potential referents recruited to be healthy controls for an ongoing study of COPD. The potential referents had no prior diagnosis of COPD or healthcare utilization attributed to COPD in the 12 months prior to recruitment. Subjects completed a structured interview and a clinical assessment including body mass index, spirometry, Six Minute Walk Test (SMWT) and the Short Performance Physical Battery (SPPB). We used multiple regression analyses to test the associations of obesity (BMI≥30kg/m2) and smoking with AO (FEV1/FVC ratio<0.7). We also tested the association of obesity with respiratory symptoms and impaired functional capacity (SPPB, SMWT), adjusting for AO.
Of 371 subjects (aged 40–65), 69 (19%) manifested AO. In multivariate analysis, smoking was positively associated with AO (per 10 pack-years, OR 1.24; 95% CI: 1.04 – 1.49), while obesity was negatively associated with AO (OR 0.54; 95% CI: 0.30 – 0.98). Obesity was associated with increased odds of reporting dyspnea on exertion (OR 3.6; 95% CI: 2.0 – 6.4), productive cough (OR 2.5; 95% CI: 1.1 – 6.0), and with decrements in SMWT distance (−67 ± 9meters; 95% CI: −84 to −50m) and SPPB score (OR 1.9; 95% CI: 1.1 – 3.5). None of these outcomes were associated with AO.
Although AO and obesity are both common among adults without an established COPD diagnosis, obesity, but not AO, is linked to a higher risk of reporting dyspnea on exertion, productive cough, and poorer functional capacity.
airflow obstruction; obesity; functional status; health status; dyspnea
Four custom Axiom genotyping arrays were designed for a genome-wide association (GWA) study of 100,000 participants from the Kaiser Permanente Research Program on Genes, Environment and Health. The array optimized for individuals of European race/ethnicity was previously described. Here we detail the development of three additional microarrays optimized for individuals of East Asian, African American, and Latino race/ethnicity. For these arrays, we decreased redundancy of high-performing SNPs to increase SNP capacity. The East Asian array was designed using greedy pairwise SNP selection. However, removing SNPs from the target set based on imputation coverage is more efficient than pairwise tagging. Therefore, we developed a novel hybrid SNP selection method for the African American and Latino arrays utilizing rounds of greedy pairwise SNP selection, followed by removal from the target set of SNPs covered by imputation. The arrays provide excellent genome-wide coverage and are valuable additions for large-scale GWA studies.
Microarray; Genome-wide association study; Coverage; Imputation; Single nucleotide polymorphism; Throughput
To examine whether kidney dysfunction is associated with the type of clinical presentation of coronary heart disease (CHD).
Reduced kidney function increases risk of developing CHD, but it is not known whether it also influences the acuity of clinical presentation, which has important prognostic implications.
We conducted a case-control study of subjects whose first clinical presentation of CHD was either acute myocardial infarction or stable exertional angina between October 2001-December 2003. Glomerular filtration rate (eGFR) before the incident event was estimated using calibrated serum creatinine and the abbreviated MDRD equation. Patient characteristics and use of medications were ascertained from self-report and health plan databases. We used multivariable logistic regression to examine the association of reduced eGFR and CHD presentation.
We studied 803 adults with incident acute myocardial infarction and 419 adults with incident stable exertional angina who had a baseline eGFR ≤130 ml/min/1.73 m2. Mean eGFR was lower among subjects with acute myocardial infarction compared with stable angina. Compared with eGFR 90–130 ml/min/1.73 m2, we found a strong, graded independent association between reduced eGFR and presenting with acute myocardial infarction: adjusted odds ratio (OR) 1.36 (95% CI: 0.99 to 1.86) for eGFR 60–89 ml/min/1.73 m2, OR 1.55 (0.92 to 2.62) for eGFR 45–59 ml/min/1.73 m2 and OR 3.82 (1.55 to 9.46) for eGFR <45 ml/min/1.73 m2 (P<0.001 for trend).
eGFR less than 45 ml/min/1.73 m2 is a strong, independent predictor of presenting with acute myocardial infarction versus stable angina as the initial manifestation of CHD.
angina; myocardial infarction; renal failure; chronic kidney disease; risk factor
The success of genome-wide association studies has paralleled the development of efficient genotyping technologies. We describe the development of a next-generation microarray based on the new highly-efficient Affymetrix Axiom genotyping technology that we are using to genotype individuals of European ancestry from the Kaiser Permanente Research Program on Genes, Environment and Health (RPGEH). The array contains 674,517 SNPs, and provides excellent genome-wide as well as gene-based and candidate-SNP coverage. Coverage was calculated using an approach based on imputation and cross validation. Preliminary results for the first 80,301 saliva-derived DNA samples from the RPGEH demonstrate very high quality genotypes, with sample success rates above 94% and over 98% of successful samples having SNP call rates exceeding 98%. At steady state, we have produced 462 million genotypes per week for each Axiom system. The new array provides a valuable addition to the repertoire of tools for large scale genome-wide association studies.
Microarray; Genome-wide association study; Coverage; Throughput; Single nucleotide polymorphism
The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS.
RESEARCH DESIGN AND METHODS
Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected.
Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure.
Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
We sought to quantify the impact of respiratory muscle and lower extremity strength on exercise capacity and lower extremity function in patients with chronic obstructive pulmonary disease (COPD).
In 828 persons with COPD, we assessed the impact of reduced respiratory (maximum inspiratory pressure, MIP) and lower extremity muscle strength (quadriceps, QS) on exercise capacity (6 Minute Walk Distance, 6MWT) and lower extremity function (LEF, Short Physical Performance Battery). Multiple regression analyses taking into account key covariates, including lung function and smoking, tested the associations between muscle strength and exercise and functional capacity.
For each ½ standard deviation (0.5 SD) decrement in QS, men walked 18.3 meters less during 6MWT (95% CI −24.1 to −12.4); women 25.1 meters less (95% CI −31.1 to −12.4). For each 0.5 SD decrement in MIP, men walked 9.4 meters less during 6MWT (95% CI – 15.2 to −3.6); women 8.7 meters less (95% CI −14.1 to −3.4). For each 0.5 SD decrease in QS, men had a 1.32 higher odds (95% CI: 1.11 to 1.15) of poor LEF; women, 1.87 higher odds (95% CI: 1.54 to 2.27). Lower MIP (per 0.5 SD) was associated with increased odds of poor LEF in women (OR 1.18, 95% CI: 1.00 to 1.39), but not in men (OR 1.10, 95% CI: 0.93 to 1.31).
In COPD, reduced respiratory and lower extremity muscle strength are associated with decreased exercise and functional capacity. Muscle weakness is likely an important component of impairment and disability in patients with COPD.
Respiratory and skeletal muscle; chronic obstructive pulmonary disease; exercise capacity; lower extremity function
Whether cardiorespiratory fitness relates to early subclinical atherosclerotic vascular disease remains unknown. We investigated the relation of cardiorespiratory fitness to coronary artery calcification (CAC) in 2373 African-American and White young adults from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. We measured cardiorespiratory fitness in 1985-1986 (baseline) using a symptom-limited exercise test on a treadmill. Coronary calcium scores were measured in 2001-2002 (year 15) using electron-beam or multi-detector computed tomography. CAC was classified as present or absent, while cardiorespiratory fitness was classified as sex-specific low, moderate, and high fitness categories. After adjustment for age, sex, race, clinical center, education, cigarette smoking, waist girth, alcohol intake, physical activity, systolic blood pressure, antihypertensive medication use, diabetes mellitus, and fasting insulin, baseline cardiorespiratory fitness was inversely associated with prevalence of CAC in young adults (P for trend = 0.03). The odds ratios of having CAC for persons in the moderately and highly fit individuals were 0.80 (95% confidence interval (CI), 0.55-1.15) and 0.59 (95% CI, 0.36-0.97), respectively, as compared with the low-fit individuals. High levels of cardiorespiratory fitness were associated with a lower risk of having coronary calcification 15 years later in African-American and White young adults.
Coronary artery calcification; Cardiorespiratory fitness; Physical activity
Few cohort studies have focused on risk factors for end-stage renal disease (ESRD). This investigation evaluated the prognostic value of several potential novel risk factors for ESRD after considering established risk factors.
We studied 177 570 individuals from a large integrated health care delivery system in northern California who volunteered for health checkups between June 1, 1964, and August 31, 1973. Initiation of ESRD treatment was ascertained using US Renal Data System registry data through December 31, 2000.
A total of 842 cases of ESRD were observed during 5 275 957 person-years of follow-up. This comprehensive evaluation confirmed the importance of established risk factors, including the following: male sex, older age, proteinuria, diabetes mellitus, lower educational attainment, and African American race, as well as higher blood pressure, body mass index, and serum creatinine level. The 2 most potent risk factors were proteinuria and excess weight. For proteinuria, the adjusted hazard ratios (HRs) were 7.90 (95% confidence interval [CI], 5.35–11.67) for 3 to 4+ on urine dipstick, 3.59 (2.82–4.57) for 1 to 2+ on urine dipstick, and 2.37 (1.79–3.14) for trace vs negative on urine dipstick. For excess weight, the HRs were 4.39 (95% CI, 3.38–5.70) for class 2 to class 3 obesity, 3.11 (2.51–3.84) for class 1 obesity, and 1.65 (1.39–1.97) for overweight vs normal weight. Furthermore, several independent novel risk factors for ESRD were identified, including lower hemoglobin level (1.33 [1.08–1.63] for lowest vs highest quartile), higher serum uric acid level (2.14 [1.65–2.77] for highest vs lowest quartile), self-reported history of nocturia (1.36 [1.17–1.58]), and family history of kidney disease (HR, 1.40 [95% CI, 1.02–1.90]).
We confirmed the importance of established ESRD risk factors in this large cohort with broad sex and racial/ethnic representation. Lower hemoglobin level, higher serum uric acid level, self-reported history of nocturia, and family history of kidney disease are independent risk factors for ESRD.
Genome-wide SNP analyses reveal the admixed African genetic ancestry of African Americans.
Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.
From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.
These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99
[0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
The contribution of occupational exposures to chronic obstructive pulmonary disease (COPD) and, in particular, their potential interaction with cigarette smoking remains underappreciated.
We used data from the FLOW study of 1,202 subjects with COPD (of which 742 had disease classified as Stage II or above by Global Obstructive Lung Disease [GOLD] criteria) and 302 referent subjects matched by age, sex, and race, recruited from a large managed care organization. Occupational exposures were assessed using two methods: self-reported exposure to vapors, gas, dust, or fumes on the longest held job (VGDF) and a job exposure matrix (JEM) for probability of exposure based on occupation. Multivariate analysis was used to control for age, sex, race, and smoking history. The odds ratio (OR) and the adjusted population attributable fraction (PAF) associated with occupational exposure were calculated.
VGDF exposure was associated with an increased risk of COPD (OR 2.11; 95% CI 1.59-2.82) and a PAF of 31% (95% CI 22-39%). The risk associated with high probability of workplace exposure by JEM was similar (OR 2.27; 95% CI 1.46-3.52), although the PAF was lower (13%; 95% CI 8 to 18%). These estimates were not substantively different when the analysis was limited to COPD GOLD Stage II or above. Joint exposure to both smoking and occupational factors markedly increased the risk of COPD (OR 14.1; 95% CI 9.33-21.2).
Workplace exposures are strongly associated with an increased risk of COPD. On a population level, prevention of both smoking and occupational exposures, and especially both together, is needed to prevent the global burden of disease.
Pulmonary disease; chronic obstructive; occupational exposure