Jenny, Nancy S.

Background: Levels of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 and the anti-inflammatory cytokine IL-10 are altered in acute stroke patients compared to controls. However, results for IL-10 are inconsistent (higher in stroke patients compared to controls in some studies and decreased in others) and very few studies have examined associations of these biomarkers with risk of incident stroke. Methods: We examined associations of baseline levels of IL-6, IL-8 and IL-10 with stroke risk factors and risk of incident stroke in 1,572 white and black men and women from the REGARDS Study; an observational cohort of 30,239 adults followed for 5 years. Among those without prebaseline stroke, stroke cases (n=592, 53% men, 59% white, mean age 70 years) were compared to a cohort random sample (n=980, 44% men, 58% white, mean age 65 years). We used Cox proportional hazards models to examine associations of biomarkers with incident stroke. Hazard ratios (HR; 95% confidence intervals) for highest compared to lowest quartile for each biomarker are presented. Results: Baseline IL-6 was significantly higher in incident stroke cases compared to the cohort sample (p<0.001) while IL-8 and IL-10 levels did not vary significantly (p>0.05 for both). Adjusting for age, sex and race, IL-6 was higher in blacks compared to whites and higher in current smokers compared to never/former smokers (all p≤0.01). IL-6 was inversely associated with physical activity, alcohol use and education (all p≤0.01). IL-8 and IL-10 did not vary significantly with the risk factors examined. Adjusting for age, sex and race, the HR for risk of incident stroke in those in the highest compared to lowest quartile of IL-6 was 2.4 (1.6-3.4). HRs for IL-8 and IL-10 were 1.5 (1.0-2.1) and 1.4 (1.0-1.9), respectively. Adjusting for Framingham stroke risk factors and history of coronary heart disease, only IL-6 remained significantly associated with stroke risk (HR 2.0; 1.3-3.2). HRs for IL-8 and IL-10 were 1.1 (0.7-1.6) and 1.2 (0.8-1.8), respectively. IL-6 remained significantly associated with stroke risk when C-reactive protein was added to the model (HR 1.7; 1.1-2.7). Associations did not differ by race. Conclusions: In this population-based sample of US black and white adults, IL-6, but not IL-8 or IL-10, was associated with stroke risk factors and risk of incident stroke. Further study is needed on the clinical utility of IL-6 measurement in stroke risk assessment.

Several loci have been discovered and replicated for urine albumin-creatinine ratio (ACR), a measure of kidney function, in European populations; however, other ethnic populations such as African-Americans have been less studied for this trait. We examined the association of genetic variants on the Metabochip with natural log transformed ACR (ln(ACR)) in 4,629 African-Americans from the Population Architecture using Genomics and Epidemiology (PAGE) Study which includes participants from the Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health Study (CHS), Coronary Artery Risk Development in Young Adults (CARDIA), and Epidemiologic Architecture for Genes Linked to the Environment (EAGLE-BioVU) studies. We then replicated our findings in 1,533 African-American participants from the Multi-Ethnic Study of Atherosclerosis (MESA). Linear regression models were used to examine associations, assuming additive effects of the SNPs. Within each study, models were adjusted for age, field center (where applicable), and principal components of ancestry, and stratified by sex. Fixed effects inverse variance weighted meta-analysis was used to combine results from contributing studies. Array-wide statistical significance was concluded for SNP associations of p-value less than 2.8 x 10-7. Mean ln(ACR) ranged from 1.4 to 2.9 mg/g, average age ranged from 44 to 77 years, and percent female participants ranged from 59-65% in the contributing studies. Four SNPs were significantly associated array-wide with ACR in the discovery sample: rs17399841 in GRHL2 (β=-0.67, MAF=0.01, p=2.7x10-9), rs153914 near SPATA9/RHOBTB3 (β=-0.59, MAF=0.01, p=1.0x10-7), rs17439845 in LEF1 (β=-0.49, MAF=0.02, p=1.3x10-7), and rs11836243 near ZNF641/ANP32D (β=0.23, MAF=0.12, p=1.8x10-7). Of these four loci, only the association of rs17439845 with ACR replicated in MESA (β=-0.36, p=0.038), with a combined discovery-replication beta of -0.46 and p value of 1.8x10-8. Combined discovery-replication for rs17399841, rs153914, and rs11836243 no longer achieved array-wide significance (p-values 9.84x10-7, 1.98x10-5, and 1.32x10-4, respectively). LEF1 is a mediator in the Wnt signaling pathway, and has been previously implicated in systemic lupus erythematosus and osteoporosis, as well as previously associated with waist circumference, echocardiographic traits, bone mineral density, and blood count traits. Continuing studies in diverse populations are warranted to identify a set of loci important in contributing to the variation in ACR.