In hypothesis-generating analyses, we explored the interactions of inflammatory response genotypes with three risk factors that influence inflammation: cigarette smoking, obesity (body mass index >30 kg/m2), and baseline use of any medication having anti-inflammatory properties (aspirin, NSAIDs, ACE inhibitors, or statins). Models were adjusted for sex, sex-by-genotype interaction, baseline cardiovascular disease, current smoking, diabetes, and hypertension. P-values for interaction were calculated from Wald tests for the cross-product interaction terms. Because of the exploratory nature of these analyses, we set statistical significance at P < 0.05.

Among white participants, the alleles of the TAFI 438 G/A polymorphism deviated significantly from Hardy-Weinberg proportions (Table 2). The Hardy-Weinberg disequilibrium was strongly present among men (P = 0.0007), but not among women (P = 0.26). When adjusted for multiple comparisons, the disequilibrium remained significant (P-values < 0.03 overall, < 0.01 in white men). Possible, but less extreme, deviations from Hardy-Weinberg equilibrium were noted for the PAI-1 4G/5G polymorphism.

2. Results

The mean age at study entry was 73 years, 84% of the participants were white, and 54% were women (Table 1). Demographic characteristics, overall health and functional status,

Years of life and years of healthy life differed by TAFI promoter genotypes among white men (Table 3), but there was little association of TAFI genotype with longevity in women (Table 4). The association with years of life in men remained significant in analyses that also adjusted for baseline socioeconomic (P = 0.007) or health-related variables (P = 0.003); similar results were seen for years of healthy life (P = 0.01 after adjustment for socioeconomic variables; P = 0.02 after adjustment for health-related variables). During 10 years of follow-up, men carrying the TAFI 438 A/A genotype had 0.9 additional years of life (95% CI 0.2-1.9 years) or 1.1 additional years of healthy life (95% CI 0.2-2.1 years) relative to men carrying at least one common TAFI 438 G allele.

Selected baseline characteristics of study participants

Characteristics n (%) or mean ± S.D. (range) Age, years (range) 73.4 ± 5.5 (64-94) White race 1954 (84) Female sex 1253 (54) Very good or excellent health 830 (36) Obesity a 682 (29) Current smoker 273 (12) Diabetes 727 (32) Hypertension 1097 (47) Prevalent cardiovascular disease b 727 (31) Previous diagnosis of cancer 321 (14) Anti-inflammatory medication use c 1161 (50)

Years of life and years of healthy life differed slightly, but not significantly, by PAI-1 675 4G/5G genotype among whites (Tables 3 and 4), albeit in opposite directions among men and women (interaction P = 0.10 for years of life, and P = 0.01 for years of healthy life). There was little association between the interleukin-6 or -fibrinogen promoter polymorphThis text appears to be a scientific study report featuring genetic associations with longevity and mortality in older adults. There are no obvious spelling mistakes or grammatical errors to correct, but the text is highly technical and may require domain knowledge to fully understand. As an AI language model, I do not have the necessary background knowledge to provide a summary or analysis of the study findings and their implications.Infectious diseases and other sources of inflammation may have contributed to the historical decline in old-age mortality [25]. Sex-related differences in immune function and infectious disease susceptibility may also partly explain the shorter lifespan of men compared to women [26]. In summary, a common promoter variant of the TAFI gene, and perhaps also the PAI-1 gene, may be associated with longevity in older men. These findings suggest that modulators of fibrinolytic activity or proteolysis may have a generalized influence on aging or age-related disease and merit further investigation in studies of genetic determinants of human longevity. Examination of additional TAFI gene variants, such as Thr325Ile, or multi-locus haplotypes, may be required to define more precisely the location of any functional longevity-associated allele(s). Interactions with additional lifestyle factors and interventions, as well as other gene pathways related to vascular disease and aging (oxidative and metabolic responses, insulin signaling) may also be appropriate for future study.

Our results for the PAI-1 promoter polymorphism were confusing and may just be due to chance. The 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men but with greater cardiovascular mortality in women. Smaller population studies examining the PAI-1 promoter polymorphism have also shown conflicting results. The 4G allele was associated with increased longevity in an Italian centenarian case-control study, but gender-specific was not noted [3]. There was no association between PAI-1 genotype in Danish centenarians [27], nor in a German octogenarian cohort [28]. The PAI-1 4G/5G variant has been shown to be functional in vitro [29,30]. The 4G sequence abolishes a binding site for a transcription repressor, thereby resulting in higher promoter activity and increased plasma levels of PAI-1 in vivo. In rodent models, the induction of PAI-1 expression in response to stress and the age-related increase in magnitude of this response influences the occurrence of vascular and tissue thrombosis [31,32]. These experimental findings might explain the trend toward increased cardiovascular mortality associated with the 4G/4G genotype observed here and by others [33,34].

Acknowledgements

The research reported in this article was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01-HC-15103 from the National Heart, Lung, and Blood Institute. WSB is supported by a grant from the National Institute of Health (AG 05407). SEH is supported by grants from the British Heart Foundation (RG2000/15).