A B C E F G P. Reiner, Paula Diehr, Warren S. Browner, Stephen E. Humphries, H I J K Nancy S. Jenny, Mary Cushman, Russell P. Tracy, Jeremy Walston, C L M L A D E Thomas Lumley, Anne B. Newman, Lewis H. Kuller, Bruce M. Psaty

16 September 2004; received in revised form 6 December 2004; accepted 10 January. Available online 19 February 2005.

Abstract:
Inflammatory response genes may influence lifespan or quality at advanced ages. Using data from the population-based cardiovascular study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes longevity. We ascertained genotypes for interleukin (IL)-6 174 G/C, -fibrinogen 455 G/A, plasminogen activator inhibitor (PAI)-1 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) 438 G/A in 2224 men and women aged 65 years at baseline. During 10 years of follow-up, men with the TAFI 438 A/A genotype had decreased mortality due to all causes and lived on average for 0.9 more years of life or 1.1 more years of healthy life than men with the 438 G allele. The effects of TAFI 438 G/A in women were smaller and not significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men but with greater mortality in women. In exploratory analyses, we observed a possible interaction between anti-inflammatory drugs, interleukin-6 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging and merit further investigation in studies of genetic determinants of human longevity.

Thrombin-activatable fibrinolysis inhibitor; Longevity; Inflammation; Fibrinolysis; Promoter polymorphism.

Genetic factors appear to influence mortality, even at advanced ages [1,2]. Inflammation, an evolutionarily conserved stress response, may reduce the length or quality of life in older adults by affecting adaptation to stressful events, chronic diseases, or the rate of aging. In case-control studies, A.P. Reiner et al. / Atherosclerosis 181 (2005) 175-183 provide complete mortality follow-up. For the current analysis, we used complete 10-year follow-up data on all participants (corresponding to June 2000 for the original CHS cohort and June 2002 for the second CHS cohort).

Of exceptional survival, inflammation and thrombosis gene promoter variants were associated with longevity, often in a sex-specific manner [3-5]. For example, the 174 C allele of interleukin-6 was more common among male but not female centenarians compared to younger sex-matched controls [4]. These retrospective studies of longevity have several limitations. The comparison group is sampled from another birth cohort whose environmental exposures may differ from the long-lived case group. In addition, observed differences in case-control genotype or allele frequency may reflect survival due to association with a single common age-related condition such as coronary heart disease, rather than any influence on the aging process per se.

Primary endpoints for this analysis included years of life as well as years of healthy life defined as the number of years the person reported being in excellent, very good or good health in the 10 years after enrollment [7,8]. This outcome was derived from standard information on self-rated health status (excellent/very good/good/fair/poor) collected at baseline and every 6 months during follow-up. Missing data were imputed by linear interpolation of the available longitudinal data recorded 6 months before and after the missing value [7,8]. For the 3% of subjects whose final 10-year follow-up measurement was still missing, we used the last observation carried forward method of imputation.

Longitudinal cohort studies may allow more accurate assessment of genetic influences on longevity because both cause-specific and overall mortality can be ascertained. We, therefore, performed an analysis of genotype data available for promoter polymorphisms of interleukin-6, -fibrinogen, PAI-1, and TAFI on a subsample of participants from the cardiovascular health study (CHS; for details see Appendix A), a U.S. cohort of white and black men and women aged 65 years and older. After 10 years of follow-up, we assessed sex-specific associations of these gene variants with outcomes that reflect overall longevity (as years of life), life span and quality of life (as years of healthy life), and all-cause and causeProportional hazards models [15]. After 10 years of follow-up, there were 918 deaths, including 451 cardiovascular deaths (303 from coronary heart disease) and 467 non-cardiovascular deaths (156 from cancer). The mean (S.D.) number of years lived per subject during those 10 years was 8.32 ± 2.69; the mean number of healthy years was 6.07 ± 3.43. Age, male sex, black race, baseline fair or poor self-reported health status, smoking, diabetes, obesity, hypertension, and a history of cardiovascular disease were strongly associated with fewer years of life and fewer years of healthy life (all P < 0.001). Subjects having the most common genotype served as the reference group, unless otherwise noted. Covariate-adjusted P-values for genetic main effects were calculated from the composite Wald test for indicator variables corresponding to the two minor genotypes. Because our primary hypotheses required performing multiple independent tests of four unlinked genes, P-values < 0.01 were considered statistically significant. Except for TAFI 438 G/A, the variant promoter alleles were less common among blacks than whites (Table 2). Genotype distributions did not differ significantly according to other baseline health-related variables such as obesity, hypertension, diabetes, cardiovascular disease, cancer, and fair or poor health status (all P > 0.10).