Obstructive Sleep Apnea Increases Sudden Cardiac Death in Incident Hemodialysis Patients.

BACKGROUND: Mortality in end-stage renal disease (ESRD) occurs predominantly from cardiovascular disease (CVD) and sudden cardiac death (SCD). Obstructive sleep apnea (OSA) is characterized by periodic airflow limitation associated with sleep arousal and oxygen desaturation and is prevalent in patients with ESRD. Whether OSA increases the risk for SCD, cardiovascular and all-cause mortality among hemodialysis patients remains unknown. METHODS: In a prospective cohort of 558 incident hemodialysis patients, we examined the association of OSA with all-cause mortality, cardiovascular mortality, and SCD using Cox proportional hazards models controlling for traditional CVD risk factors. RESULTS: Sixty-six incident hemodialysis patients (12%) had OSA. Mean age (56 years) and percentage of males (56%) were identical in OSA and no-OSA groups. Fewer African Americans had OSA than non-African Americans (9 vs. 18%, respectively). Participants with OSA had higher body-mass index, Charlson comorbidity score, and left ventricular mass index and greater prevalence of diabetes and coronary artery disease. During 1,080 person-years of follow-up, 104 deaths occurred, 29% of which were cardiovascular. OSA was associated with a higher risk of all-cause mortality (HR 1.90 [95% CI 1.04-3.46]) and cardiovascular mortality (HR 3.62 [95% CI 1.36-9.66]) after adjusting for demographics and body-mass index. OSA was associated with a higher risk of SCD after adjusting for demographics (HR 3.28 [95% CI 1.12-9.57]) and multiple cardiovascular risk factors. CONCLUSIONS: Incident hemodialysis patients with OSA are at increased risk of all-cause and cardiovascular mortality and SCD. Future studies should assess the impact of screening for OSA and OSA-targeted interventions on mortality in ESRD.

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.

Association of Arterial Stiffness and Central Pressure With Cognitive Function in Incident Hemodialysis Patients: The PACE Study.

INTRODUCTION: Cognitive impairment commonly occurs in hemodialysis patients, with vascular disease potentially implicated in its pathogenesis. However, the relationship of detailed vascular assessment with cognitive function in patients new to hemodialysis has not been demonstrated. METHODS: In a prospective study of incident hemodialysis participants enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in ESRD (PACE) study, we determined aortic stiffness by pulse-wave velocity (PWV), systemic arterial stiffness by the augmentation index (AIx) and central pulse pressure (cPP), and examined their associations with cognitive processing speed, executive function, and global cognitive impairment measured by the Trail making test A (TMTA), Trail making test B (TMTB), and the modified Mini-Mental State Exam (3MS). RESULTS: Mean baseline age was 55 ± 13 years, 58% were male, 72% were African American, 35% had coronary artery disease, 55% had diabetes, and 10% had cognitive impairment. At baseline, higher PWV and cPP were associated with a longer TMTA, and a higher PWV was associated with a longer TMTB, but the associations were attenuated after multivariable adjustment. At 1 year, PWV was not independently associated with TMTA, TMTB, or 3MS. However, unadjusted and adjusted analyses revealed every 10% increase in AIx and 10 mm Hg increase in cPP were associated with longer TMTB (time differenceAIx: 0.14; 95% confidence interval [CI]: 0.02-0.25 log-seconds; time differencecPP: 0.11; 95% CI: 0.05-0.17 log-seconds) and global cognitive impairment (odds ratio [OR]AIx: 10.23; 95% CI: 1.77-59.00; ORcPP: 2.88; 95% CI: 1.48-5.59). DISCUSSION: Higher AIx and cPP, which are indicative of abnormal wave reflections in distal vessels, are associated with, and might contribute to, declining cognitive function in patients starting hemodialysis.

Cardiovascular risk factors and risk of incident depression throughout adulthood among men: The Johns Hopkins Precursors Study.

BACKGROUND: Modifiable cardiovascular risk factors elevate risk of subsequent depression in older adults, but the effect of their onset before or after age 65 on incident depression is unclear. METHODS: Participants were 1190 male medical students without a diagnosis of depression, who matriculated in 1948-1964 and followed through 2011. Cox proportional hazards models were used to assess associations of vascular risk-factor burden, diabetes, hypertension, hyperlipidemia, smoking status, and overweight/obese status with onset of incident depression. Adjustment covariates were race, enrollment wave, baseline age, physical activity, and heavy alcohol use. RESULTS: The analysis included 44,175 person-years of follow-up. Among participants depression-free until age 65, vascular risk-factor burden after age 65 (Hazard Ratio, [HR]: 2.13, 95% Confidence Interval, [CI]: 1.17, 3.90) was associated with incident depression risk after age 65. The magnitude of vascular risk-factor burden after age 65 on depression risk after age 65 is comparable to the effect of 8.2 additional years of age. Diabetes (HR: 2.79, 95% CI: 1.25, 6.26), hypertension (HR: 2.72, 95% CI: 1.52, 4.88), and hyperlipidemia (HR: 1.88, 95% CI: 1.05, 3.35) before age 65 were associated with incident depression risk after age 65. Men diagnosed with diabetes after age 65 had 2.87 times the risk of incident depression after age 65 (95% CI: 1.24, 6.62). LIMITATIONS: Our findings are restricted to male former medical students, which may affect study generalizability. CONCLUSIONS: Results support the vascular depression hypothesis. Depression screening in older adults with vascular risk-factor burden may provide an avenue for prevention of late-onset depression.

Electrophysiologic Substrate and Risk of Mortality in Incident Hemodialysis.

The single leading cause of mortality on hemodialysis is sudden cardiac death. Whether measures of electrophysiologic substrate independently associate with mortality is unknown. We examined measures of electrophysiologic substrate in a prospective cohort of 571 patients on incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease Study. A total of 358 participants completed both baseline 5-minute and 12-lead electrocardiogram recordings on a nondialysis day. Measures of electrophysiologic substrate included ventricular late potentials by the signal-averaged electrocardiogram and spatial mean QRS-T angle measured on the averaged beat recorded within a median of 106 days (interquartile range, 78-151 days) from dialysis initiation. The cohort was 59% men, and 73% were black, with a mean±SD age of 55±13 years. Transthoracic echocardiography revealed a mean±SD ejection fraction of 65.5%±12.0% and a mean±SD left ventricular mass index of 66.6±22.3 g/m2.7 During 864.6 person-years of follow-up, 77 patients died; 35 died from cardiovascular causes, of which 15 were sudden cardiac deaths. By Cox regression analysis, QRS-T angle ≥75° significantly associated with increased risk of cardiovascular mortality (hazard ratio, 2.99; 95% confidence interval, 1.31 to 6.82) and sudden cardiac death (hazard ratio, 4.52; 95% confidence interval, 1.17 to 17.40) after multivariable adjustment for demographic, cardiovascular, and dialysis factors. Abnormal signal-averaged electrocardiogram measures did not associate with mortality. In conclusion, spatial QRS-T angle but not abnormal signal-averaged electrocardiogram significantly associates with cardiovascular mortality and sudden cardiac death independent of traditional risk factors in patients starting hemodialysis.

Frailty and Cognitive Function in Incident Hemodialysis Patients.

BACKGROUND AND OBJECTIVES: Patients of all ages undergoing hemodialysis (HD) have a high prevalence of cognitive impairment and worse cognitive function than healthy controls, and those with dementia are at high risk of death. Frailty has been associated with poor cognitive function in older adults without kidney disease. We hypothesized that frailty might also be associated with poor cognitive function in adults of all ages undergoing HD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: At HD initiation, 324 adults enrolled (November 2008 to July 2012) in a longitudinal cohort study (Predictors of Arrhythmic and Cardiovascular Risk in ESRD) were classified into three groups (frail, intermediately frail, and nonfrail) based on the Fried frailty phenotype. Global cognitive function (3MS) and speed/attention (Trail Making Tests A and B [TMTA and TMTB, respectively]) were assessed at cohort entry and 1-year follow-up. Associations between frailty and cognitive function (at cohort entry and 1-year follow-up) were evaluated in adjusted (for sex, age, race, body mass index, education, depression and comorbidity at baseline) linear (3MS, TMTA) and Tobit (TMTB) regression models. RESULTS: At cohort entry, the mean age was 54.8 years (SD 13.3), 56.5% were men, and 72.8% were black. The prevalence of frailty and intermediate frailty were 34.0% and 37.7%, respectively. The mean 3MS was 89.8 (SD 7.6), TMTA was 55.4 (SD 29), and TMTB was 161 (SD 83). Frailty was independently associated with lower cognitive function at cohort entry for all three measures (3MS: -2.4 points; 95% confidence interval [95% CI], -4.2 to -0.5; P=0.01; TMTA: 12.1 seconds; 95% CI, 4.7 to 19.4; P<0.001; and TMTB: 33.2 seconds; 95% CI, 9.9 to 56.4; P=0.01; all tests for trend, P<0.001) and with worse 3MS at 1-year follow-up (-2.8 points; 95% CI, -5.4 to -0.2; P=0.03). CONCLUSIONS: In adult incident HD patients, frailty is associated with worse cognitive function, particularly global cognitive function (3MS).

Cross-sectional association of volume, blood pressures, and aortic stiffness with left ventricular mass in incident hemodialysis patients: the Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study.

BACKGROUND: Higher left ventricular mass (LV) strongly predicts cardiovascular mortality in hemodialysis patients. Although several parameters of preload and afterload have been associated with higher LV mass, whether these parameters independently predict LV mass, remains unclear. METHODS: This study examined a cohort of 391 adults with incident hemodialysis enrolled in the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study. The main exposures were systolic and diastolic blood pressure (BP), pulse pressure, arterial stiffness by pulse wave velocity (PWV), volume status estimated by pulmonary pressures using echocardiogram and intradialytic weight gain. The primary outcome was baseline left ventricular mass index (LVMI). RESULTS: Each systolic, diastolic blood, and pulse pressure measurement was significantly associated with LVMI by linear regression regardless of dialysis unit BP or non-dialysis day BP measurements. Adjusting for cardiovascular confounders, every 10 mmHg increase in systolic or diastolic BP was significantly associated with higher LVMI (SBP ß = 7.26, 95 % CI: 4.30, 10.23; DBP ß = 10.05, 95 % CI: 5.06, 15.04), and increased pulse pressure was also associated with higher LVMI (ß = 0.71, 95 % CI: 0.29, 1.13). Intradialytic weight gain was also associated with higher LVMI but attenuated effects after adjustment (ß = 3.25, 95 % CI: 0.67, 5.83). PWV and pulmonary pressures were not associated with LVMI after multivariable adjustment (ß = 0.19, 95 % CI: -1.14, 1.79; and ß = 0.10, 95 % CI: -0.51, 0.70, respectively). Simultaneously adjusting for all main exposures demonstrated that higher BP was independently associated with higher LVMI (SBP ß = 5.64, 95 % CI: 2.78, 8.49; DBP ß = 7.29, 95 % CI: 2.26, 12.31, for every 10 mmHg increase in BP). CONCLUSIONS: Among a younger and incident hemodialysis population, higher systolic, diastolic, or pulse pressure, regardless of timing with dialysis, is most associated with higher LV mass. Future studies should consider the use of various BP measures in examining the impact of BP on LVM and cardiovascular disease. Findings from such studies could suggest that high BP should be more aggressively treated to promote LVH regression in incident hemodialysis patients.

Rationale and design for the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study.

BACKGROUND: Sudden cardiac death occurs commonly in the end-stage renal disease population receiving dialysis, with 25% dying of sudden cardiac death over 5 years. Despite this high risk, surprisingly few prospective studies have studied clinical- and dialysis-related risk factors for sudden cardiac death and arrhythmic precursors of sudden cardiac death in end-stage renal disease. METHODS/DESIGN: We present a brief summary of the risk factors for arrhythmias and sudden cardiac death in persons with end-stage renal disease as the rationale for the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, a prospective cohort study of patients recently initiated on chronic hemodialysis, with the overall goal to understand arrhythmic and sudden cardiac death risk. Participants were screened for eligibility and excluded if they already had a pacemaker or an automatic implantable cardioverter defibrillator. We describe the study aims, design, and data collection of 574 incident hemodialysis participants from the Baltimore region in Maryland, U.S.A.. Participants were recruited from 27 hemodialysis units and underwent detailed clinical, dialysis and cardiovascular evaluation at baseline and follow-up. Cardiovascular phenotyping was conducted on nondialysis days with signal averaged electrocardiogram, echocardiogram, pulse wave velocity, ankle, brachial index, and cardiac computed tomography and angiography conducted at baseline. Participants were followed annually with study visits including electrocardiogram, pulse wave velocity, and ankle brachial index up to 4 years. A biorepository of serum, plasma, DNA, RNA, and nails were collected to study genetic and serologic factors associated with disease. DISCUSSION: Studies of modifiable risk factors for sudden cardiac death will help set the stage for clinical trials to test therapies to prevent sudden cardiac death in this high-risk population.

Health-related and psychosocial concerns about transplantation among patients initiating dialysis.

BACKGROUND AND OBJECTIVES: Disparities in kidney transplantation remain; one mechanism for disparities in access to transplantation (ATT) may be patient-perceived concerns about pursuing transplantation. This study sought to characterize prevalence of patient-perceived concerns, explore interrelationships between concerns, determine patient characteristics associated with concerns, and assess the effect of concerns on ATT. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prevalences of 12 patient-perceived concerns about pursuing transplantation were determined among 348 adults who recently initiated dialysis, recruited from 26 free-standing dialysis centers around Baltimore, Maryland (January 2009-March 2012). Using variable reduction techniques, concerns were clustered into two categories (health-related and psychosocial) and quantified with scale scores. Associations between patient characteristics and concerns were estimated using modified Poisson regression. Associations between concerns and ATT were estimated using Cox models. RESULTS: The most frequently cited patient-perceived concerns were that participants felt they were doing fine on dialysis (68.4%) and felt uncomfortable asking someone to donate a kidney (29.9%). Older age was independently associated with having high health-related (adjusted relative risk, 1.35 [95% confidence interval, 1.20 to 1.51], for every 5 years older for those ≥ 60 years) or psychosocial (1.15 [1.00 to 1.31], for every 5 years older for those aged ≥ 60 years) concerns, as was being a woman (1.72 [1.21 to 2.43] and 1.55 [1.09 to 2.20]), having less education (1.59 [1.08 to 2.35] and 1.77 [1.17 to 2.68], comparing postsecondary education to grade school or less), and having more comorbidities (1.18 [1.08 to 1.30] and 1.18 [1.07 to 1.29], per one comorbidity increase). Having never seen a nephrologist before dialysis initiation was associated with high psychosocial concerns (1.48 [1.01 to 2.18]). Those with high health-related (0.37 [0.16 to 0.87]) or psychosocial (0.47 [0.23 to 0.95]) concerns were less likely to achieve ATT (median follow-up time 2.2 years; interquartile range, 1.6-3.2). CONCLUSIONS: Patient-perceived concerns about pursuing kidney transplantation are highly prevalent, particularly among older adults and women. Reducing these concerns may help decrease disparities in ATT.

Patient- and provider-reported information about transplantation and subsequent waitlisting.

Because informed consent requires discussion of alternative treatments, proper consent for dialysis should incorporate discussion about other renal replacement options including kidney transplantation (KT). Accordingly, dialysis providers are required to indicate KT provision of information (KTPI) on CMS Form-2728; however, provider-reported KTPI does not necessarily imply adequate provision of information. Furthermore, the effect of KTPI on pursuit of KT remains unclear. We compared provider-reported KTPI (Form-2728) with patient-reported KTPI (in-person survey of whether a nephrologist or dialysis staff had discussed KT) in a prospective ancillary study of 388 hemodialysis initiates. KTPI was reported by both patient and provider for 56.2% of participants, by provider only for 27.8%, by patient only for 8.3%, and by neither for 7.7%. Among participants with provider-reported KTPI, older age was associated with lack of patient-reported KTPI. Linkage with the Scientific Registry for Transplant Recipients showed that 20.9% of participants were subsequently listed for KT. Patient-reported KTPI was independently associated with a 2.95-fold (95% confidence interval [95% CI], 1.54 to 5.66; P=0.001) higher likelihood of KT listing, whereas provider-reported KTPI was not associated with listing (hazard ratio, 1.18; 95% CI, 0.60 to 2.32; P=0.62). Our findings suggest that patient perception of KTPI is more important for KT listing than provider-reported KTPI. Patient-reported and provider-reported KTPI should be collected for quality assessment in dialysis centers because factors associated with discordance between these metrics might inform interventions to improve this process.

Incidental findings on cardiac computed tomography in incident hemodialysis patients: the predictors of arrhythmic and cardiovascular events in end-stage renal disease (PACE) study.

BACKGROUND: This is the first study that has examined non-cardiac incidental findings in research cardiac computed tomography (CT) of hemodialysis patients and their relationship with patient characteristics. METHODS: We performed a cross-sectional analysis in the Predictors of Arrhythmic and Cardiovascular Events in End-Stage Renal Disease (PACE) study, a prospective cohort study on incident hemodialysis patients. Non-cardiac structures in the cardiac CT scan were reviewed and evaluated. The type and frequencies of non-cardiac incidental CT findings were summarized. Univariate and multivariate logistic regression were performed to analyze the associations between gender, older age, obesity, history of cardiovascular disease (CVD), smoking status, history of chronic pulmonary disease and history of cancer with presence of any incidental CT findings and, separately, pulmonary nodules. RESULTS: Among the 260 participants, a total of 229 non-cardiac incidental findings were observed in 145 participants (55.8% of all participants). Of these findings, pulmonary nodules were the most common incidental finding (24.2% of all findings), and 41.3% of them requiring further follow-up imaging per radiology recommendation. Vascular and gastrointestinal findings occurred in 11.8% and 15.3% of participants, respectively. Participants 65 years or older had a higher odds of any incidental findings (Odds Ratio (OR) =2.55; 95% Confidence Intervals (CI) 1.30, 4.99) and pulmonary nodules (OR=4.80; 95% CI 2.51, 9.18). Prior history of CVD was independently and significantly associated with any incidental findings (OR=2.00; 95% CI 1.19, 3.40); but not with the presence of pulmonary nodules. CONCLUSIONS: We demonstrate that the prevalence of incidental findings by cardiac CT scanning is extremely high among patients on hemodialysis. Further investigations to follow-up on the high occurrence of incidental findings during our research study and potentially clinical studies raises important practical, ethical and medico-legal issues that need to be carefully considered in research projects using imaging studies.

Age and sex disparities in discussions about kidney transplantation in adults undergoing dialysis.

OBJECTIVES: To explore whether disparities in age and sex in access to kidney transplantation (KT) originate at the time of prereferral discussions about KT. DESIGN: Cross-sectional survey. SETTING: Outpatient dialysis centers in Maryland (n = 26). PARTICIPANTS: Individuals who had recently initiated hemodialysis treatment (N = 416). MEASUREMENTS: Participants reported whether medical professionals (nephrologist, primary medical doctor, dialysis staff) and social group members (significant other, family member, friend) discussed KT with them and, when applicable, rated the tone of discussions. Relative risks were estimated using modified Poisson regression. RESULTS: Participants aged 65 and older were much less likely than those who were younger to have had discussions with medical professionals (44.5% vs 74.8%, P < .001) or social group members (47.3% vs 63.1%, P = .005). Irrespective of sex and independent of race, health-related factors, and dialysis-related characteristics, older adults were more likely not to have had discussions with medical professionals (relative risk (RR) = 1.13, 95% confidence interval (CI) = 1.03-1.24, for each 5-year increase in age through 65; RR = 1.28, 95% CI = 1.14-1.42, for each 5-year increase in age beyond 65). Irrespective of age, women were more likely (RR = 1.45, 95% CI = 1.12-1.89) not to have had discussions with medical professionals. For each 5-year increase in age, men (RR = 1.04, 95% CI = 0.99-1.10) and women (RR = 1.17, 95% CI = 1.10-1.24) were more likely not to have discussions with social group members. Of those who had discussions with medical professionals or social group members, older participants described these discussions as less encouraging (all P < .01). CONCLUSION: Older adults and women undergoing hemodialysis are less likely than younger adults and men to have discussions about KT as a treatment option, supporting a need for better clinical guidelines and education for these individuals, their social network, and their providers.

A genome-wide search for linkage of estimated glomerular filtration rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND).

OBJECTIVE: Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR. METHODS: Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula. RESULTS: The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4 × 10(-5)) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5 × 10(-4)) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5 × 10(-4)) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome. CONCLUSION: The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.

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.

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.

Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study.

BACKGROUND: Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. METHODS: A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. RESULTS: Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10(-5), LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. CONCLUSION: These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.

Alcohol consumption and domain-specific cognitive function in older adults: longitudinal data from the Johns Hopkins Precursors Study.

OBJECTIVES: The association of alcohol consumption with performance in different cognitive domains has not been well studied. METHODS: The Johns Hopkins Precursors Study was used to examine associations between prospectively collected information about alcohol consumption ascertained on multiple occasions starting at age 55 years on average with domain-specific cognition at age 72 years. Cognitive variables measured phonemic and semantic fluency, attention, verbal memory, and global cognition. RESULTS: Controlling for age, hypertension, smoking status, sex, and other cognitive variables, higher average weekly quantity and frequency of alcohol consumed in midlife were associated with lower phonemic fluency. There were no associations with four other measures of cognitive function. With respect to frequency of alcohol intake, phonemic fluency was significantly better among those who drank three to four alcoholic beverages per week as compared with daily or almost daily drinkers. A measure of global cognition was not associated with alcohol intake at any point over the follow-up. DISCUSSION: Results suggest that higher alcohol consumption in midlife may impair some components of executive function in late life.

Propositional density and cognitive function in later life: findings from the Precursors Study.

OBJECTIVES: We used longitudinal data from the Johns Hopkins Precursors Study to test the hypothesis that written propositional density measured early in life is lower for people who develop dementia categorized as Alzheimer's disease (AD). This association was reported in 1996 for the Nun Study, and the Precursors Study offered an unprecedented chance to reexamine it among respondents with different gender, education, and occupation profiles. METHODS: Eighteen individuals classified as AD patients (average age at diagnosis: 74) were assigned 2 sex-and-age matched controls, and propositional density in medical school admission essays (average age at writing: 22) was assessed via Computerized Propositional Idea Density Rater 3 linguistic analysis software. Adjusted odds ratios (ORs) for the matched case-control study were calculated using conditional (fixed-effects) logistic regression. RESULTS: Mean propositional density is lower for cases than for controls (4.70 vs. 4.99 propositions per 10 words, 1-sided p = .01). Higher propositional density substantially lowers the odds of AD (OR = 0.16, 95% confidence interval = 0.03-0.90, 1-sided p = .02). DISCUSSION: Propositional density scores in writing samples from early adulthood appear to predict AD in later life for men as well as women. Studies of cognition across the life course might beneficially incorporate propositional density as a potential marker of cognitive reserve.

Reliability of alcohol recall after 15 years and 23 years of follow-up in the Johns Hopkins Precursors Study.

OBJECTIVE: Recall of past alcohol intake is used in many studies of chronic disease, but few studies have been able to examine its long-term reliability. METHOD: We sought to assess the reliability of recalled alcohol intake assessed at an average age of 70 years in 2001, after 15 and 23 years of follow-up, in a prospective study of medical students in classes 1948 to 1964. RESULTS: Average reported alcohol intake 15 years and 23 years prior were 6.3 and 7.4 drinks per week, respectively. Recall of alcohol intake overestimated the concurrently reported intake after 15 years by a mean of 0.47 (95% CI [0.10, 0.85]) drinks per week and underestimated intake after 23 years by a mean of 0.79 (95% CI [-1.27, -0.30]) drinks per week, mostly driven by differences between concurrently reported and recalled distilled spirits consumption. Characteristics associated with underestimation of alcohol recall were age of 71 years or older in 2001, self-report of memory difficulties, and self-report of difficulties in physical functioning. In multivariate regression analyses combining 15- and 23-year recall, subjects who reported consumption of more than 14 alcoholic drinks per week in 2001 marginally overestimated recall by slightly more than 1 drink per week (M = 1.18 drinks/week, 95% CI [-0.03, 2.40]). CONCLUSIONS: Although significant differences were detected, recalled alcohol intake after 15 and 23 years of follow-up is remarkably reliable.

Genome-wide linkage scans for type 2 diabetes mellitus in four ethnically diverse populations-significant evidence for linkage on chromosome 4q in African Americans: the Family Investigation of Nephropathy and Diabetes Research Group.

BACKGROUND: Previous studies have shown that in addition to environmental influences, type 2 diabetes mellitus (T2DM) has a strong genetic component. The goal of the current study is to identify regions of linkage for T2DM in ethnically diverse populations. METHODS: Phenotypic and genotypic data were obtained from African American (AA; total number of individuals [N] = 1004), American Indian (AI; N = 883), European American (EA; N = 537), and Mexican American (MA; N = 1634) individuals from the Family Investigation of Nephropathy and Diabetes. Non-parametric linkage analysis, using an average of 4404 SNPs, was performed in relative pairs affected with T2DM in each ethnic group. In addition, family-based tests were performed to detect association with T2DM. RESULTS: Statistically significant evidence for linkage was observed on chromosome 4q21.1 (LOD = 3.13; genome-wide p = 0.04) in AA. In addition, a total of 11 regions showed suggestive evidence for linkage (estimated at LOD > 1.71), with the highest LOD scores on chromosomes 12q21.31 (LOD = 2.02) and 22q12.3 (LOD = 2.38) in AA, 2p11.1 (LOD = 2.23) in AI, 6p12.3 (LOD = 2.77) in EA, and 13q21.1 (LOD = . 2.24) in MA. While no region overlapped across all ethnic groups, at least five loci showing LOD > 1.71 have been identified in previously published studies. CONCLUSIONS: The results from this study provide evidence for the presence of genes affecting T2DM on chromosomes 4q, 12q, and 22q in AA; 6p in EA; 2p in AI; and 13q in MA. The strong evidence for linkage on chromosome 4q in AA provides important information given the paucity of diabetes genetic studies in this population.