End stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans. This led to the hypothesis that susceptibility alleles for ESRD have a higher frequency in West African than European gene pool. We performed a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and demonstrated a highly significant association between excess African ancestry and non-diabetic ESRD (LOD 5.70) but not diabetic ESRD (LOD 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% credible interval 0.39 -0.63) compared to African ancestry. Multiple common SNPs (allele frequency ranging from 0.2 to 0.6) in the gene that encodes non-muscle myosin heavy chain type II isoform A (MYH9) were associated with 2-4 times greater risk of non-diabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.End stage renal disease (ESRD) is the near-total loss of kidney function requiring treatment of 472,000 patients with dialysis or transplantation in the US 1 . Diabetes and hypertension are the two leading reported causes of treated ESRD in the U.S. accounting for 44% and 27% of incident cases respectively 1 . African Americans have consistently had a much higher rate of ESRD than European Americans in the US. In 2005, African-Americans had a 3.7 times higher age adjusted risk of ESRD. The risk ratio by assigned primary cause of ESRD was 3.8 for hypertension, 2.6 for diabetes, 2.3 for glomerulonephritis, 2.1 for the other causes of kidney disease 1 . While lower socioeconomic status and poorer access to health care explains some of this excess risk 2-4 , African Americans appear to have greater risk than European Americans after these factors are taken into account. Family studies show clustering of ESRD independent of hypertension and diabetes 5, 6 with one large study shows stronger aggregation in African Americans 6 . Studies attempting to detect susceptibility genes for ESRD and other complex diseases are challenging due to the late age of onset, causing difficulty in collecting multiply-affected families, and because linkage analysis has suggested that there are no genes of high penetrance (>4-fold increased risk) in populations of European descent, the focus of most published studies 7, 8 . For these reasons, ESRD is an excellent phenotype for whole genome association analysis, an approach with enhanced power to detect common variants of modest penetrance, and with the further advantage that unrelated individuals can be studied.We performed a scan for ESRD genes using a particular type of whole genome association analysis, termed admixture mapping or mapping by admixture linkage disequilibrium (MALD) Linda NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 9-11 . Admixture mapping is particularly suitable for finding genetic risk alleles that differ in frequency between populations which we hypothesized might be the case for ESRD.The...

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.

Background The obesity-hypertension link over the life course has not been well characterized although the prevalence of obesity and hypertension are 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/m2) in young adulthood was strongly associated with incident hypertension (hazard ratio (HR) = 4.17, 95% CI (2.34-7.42)). Overweight (BMI 25 to < 30 kg/m2) also signaled increased risk (HR = 1.58, 95% CI (1.28-1.96)). Men of normal weight at age 25 years who became overweight or obese at age 45 were at increased risk compared to men of normal weight at both times (HR = 1.57, 95% CI (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 (HR = 0.91, 95% CI (0.43-1.92)). After adjusting 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 (HR = 2.52, 95% CI (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.