2.2. Centenarian case-control study of Ashkenazi Jews

In order to validate significant results identified in the CHS population, we utilized previously collected DNA and phenotypic data from a study of 388 Ashkenazi Jewish cases with exceptional longevity [289 females and 99 males, average age 97.7 (0.2) years (mean SE), age range 95-108 years; 20% over the age of 100] and Ashkenazi Jewish control subjects [n = 364, mean age 79.5 (0.4) years (mean SE), 58% female] without a family. For the Ashkenazi Jewish validation study, genotyping was performed at the Albert Einstein College of Medicine using Sequenom MASSarray System (Sequenom Inc., San Diego, CA) according to the manufacturer's instructions. SOF validation genotyping was performed using the SNPstream 48plex genotyping platform (Beckman Coulter, Fullerton CA) according to the manufacturer's instructions.

3. Results

2.5. Statistical analysis

CHS participant baseline characteristics by race are summarized in Table 1. In univariate and multivariable-adjusted regression analyses, older age, male sex, current smoking, higher BMI, alcohol consumption, and prevalent CVD were significantly associated with higher IL-6 (all p < 0.001). When analyzed by quartiles and adjusted for other risk factors, baseline IL-6 levels were strongly and independently associated with a linear increase in all-cause mortality, as well as mortality due to cardiovascular and non-cardiovascular causes (Table 2).

To assess the association of baseline plasma IL-6 concentration with mortality during follow-up, we used Cox proportional hazards to model quartiles of IL-6 level. Results were reported as hazard ratios with 95% confidence intervals (95%CI). Hazard ratios were adjusted for baseline age, sex, race, body mass index, total cholesterol, diabetes, systolic blood pressure, smoking, race, clinic site, and clinical CVD at baseline.

Each SNP and logarithmically transformed IL-6 concentration levels were analyzed using multiple linear regression that included covariate terms for age, sex, clinic, body mass index, and smoking. Analyses were performed separately in CHS EA and AA participants. SNP genotype was coded 0/1/2 for the number of copies of the minor allele assuming an additive genetic model. Logistic regression was used to assess associations between each SNP genotype and longevity case/control status. Cox regression was used to model associations between SNP genotype and total mortality or cause-specific mortality (cardiovascular or non-cardiovascular). Covariates for the initial case-control longevity analysis included sex and recruitment site. The Cox models were also adjusted for baseline age. We also performed more fully adjusted multivariable models that included baseline hypertension, diabetes, smoking status, clinical CVD, and diagnosis of cancer. Clinical CVD, used for adjusting multivariable models, was defined as self-reported myocardial infarction, stroke, angina, transient ischemic attack, claudication, or revascularization procedure.