Differences in the average number of years of life or years of healthy life according to inflammation and thrombosis gene promoter genotype in women, by

Genotype Years of life (95% CI) P Years of healthy life (95% CI) P White women (n=981) TAFI −438 0.81 0.82 G/G 0 (referent) 0 (referent) G/A −0.11 (−0.50, +0.26) 0.56 +0.01 (−0.52, +0.54) 0.96 A/A +0.05 (−0.57, +0.68) 0.88 +0.32 (−0.69, +1.33) 0.54 PAI-1 −675 0.35 0.05 4G/4G −0.29 (−0.69, +0.11) 0.15 −0.75 (−1.35, −0.14) 0.01 4G/5G 0 (referent) 0 (referent) 5G/5G −0.12 (−0.63, +0.39) 0.65 −0.28 (−0.95, +0.38) 0.38 Interleukin-6 −174 0.63 0.57 G/G 0 (referent) 0 (referent) G/C +0.08 (−0.31, +0.46) 0.69 +0.11 (−0.44, +0.66) 0.69 C/C +0.25 (−0.26, +0.75) 0.34 +0.38 (−0.32, +1.09) 0.29 Fibrinogen −455 0.82 0.88 G/G 0 (referent) 0 (referent) G/A +0.10 (−0.26, +0.47) 0.58 −0.08 (−0.62, +0.46) 0.78 A/A −0.11 (−1.06, +0.83) 0.82 −0.29 (−1.56, +0.98) 0.65 Black women (n=217) TAFI −438 0.13 0.23 G/G 0 (referent) 0 (referent) G/A +0.43 (−0.18, +1.04) 0.16 +0.01 (−0.99, +1.02) 0.82 A/A −0.94 (−2.54, +0.66) 0.25 −1.56 (−3.41, +0.28) 0.05 PAI-1 −675 0.80 0.49 4G/4G +0.31 (−0.65, +1.26) 0.53 +0.96 (−0.67, +2.59) 0.25 4G/5G 0 (referent) 0 (referent) 5G/5G +0.03 (−0.67, +0.72) 0.94 +0.19 (−0.91, +1.29) 0.73

a Adjusted for age at baseline and clinic site. Shown in bold are the adjusted P-values for the composite genotype test of association at each locus. Also shown are the adjusted P-values for the individual genotypes.

ated with reduced cancer-related mortality in men and women.

cause of death (Table 5). When men carrying 438 A/A genotype were compared against the combined G/G + G/A genotype groups, the all-cause mortality hazard ratio (HR) was 0.53 (95% CI 0.32–0.87) and cause-specific hazard ra- tios were similar for cardiovascular and non-cardiovascular mortality (Fig. 1). In contrast there was little association − of TAFI 438 A/A genotype and mortality in women. − The TAFI 438 A/A genotype appeared to be associ-

All-cause mortality was slightly lower in men with the PAI-1 4G/4G genotype, but slightly greater in women (Table 5 and Fig. 1). Although neither of these sex-specific associations was statistically significant, the P-value for a sex–PAI-1 genotype interaction was 0.01, perhaps because the PAI-1 4G/4G genotype was associated with increased

Table 5

Associations between TAFI and PAI-1 gene promoter genotypes and all-cause and cause-specific mortalitya

Genotype White and black men (n=1026) White and black women (n=1198) All causes Cardiovascular Non-cardiovascular All causes Cardiovascular Non-cardiovascular causes causes causes causes TAFI −438 G/G 1 (referent) 1 (referent) 1 (referent) 1 (referent) 1 (referent) 1 (referent) G/A 1.00 (0.77–1.29) 1.30 (0.89–1.88) 0.85 (0.59–1.21) 1.13 (0.85–1.51) 0.99 (0.64–1.51) 1.26 (0.86–1.86) A/A 0.53 (0.32–0.88) 0.73 (0.39–1.38) 0.39 (0.19–0.81) 1.11 (0.60–2.06) 0.92 (0.39–2.18) 1.28 (0.54–3.04) PAI-1 −675 4G/4G 0.81 (0.61–1.07) 0.95 (0.63–1.43) 0.69 (0.47–1.02) 1.38 (1.00–1.89) 1.99 (1.28–3.09) 1.07 (0.69–1.67) 4G/5G 1 (referent) 1 (referent) 1 (referent) 1 (referent) 1 (referent)b 1 (referent) 5G/5G 0.81 (0.59–1.11) 0.80 (0.50–1.29) 0.81 (0.53–1.26) 1.17 (0.83–1.67) 1.52 (0.92–2.48) 1.00 (0.63–1.60)

represent hazard ratio (95% CI). a Adjusted for race, age at baseline, and clinic site. b The composite PAI-1 4G/5G genotype test of association P-value was ≤0.01 for cardiovascular mortality in

A.P. Reiner et al. / Atherosclerosis 181 (2005) 175–183

CAUSE OF DEATHCAUSE OF DEATHMENWOMEN Non-CVD.CHD1.01.02.0 3.00.0HAZARD RATIOMEN2.0 3.00.0HAZARD RATIO1.02.0WOMEN1.02.03.0 3.0

3. Discussion

The primary finding of this longitudinal population-based study of older adults is the association of a common TAFI − promoter genotype, 438 A/A, with increased longevity in men. In contrast, we observed little association between TAFI promoter genotype and longevity in women. The restriction of the observed association to individuals homozygous for the rare TAFI allele and only men may suggest the possibil- ity of a false-positive association due to type 1 error. On the other hand, gender-specific genetic influences on longevity have been reported in both humans [1–5] and rodents [16]. In addition, TAFI promoter genotypes of our male study partic- ipants deviated significantly from Hardy–Weinberg equilib- rium, a finding previously noted among healthy middle-aged men of European descent [17]. The excess homozygosity of − the TAFI 438 A allele we observed in men at baseline rein- force the possibility of an age- and sex-specific influence of TAFI genotype on survival.

TAFI is a pro-carboxypeptidase that regulates the bal- ance between coagulation and fibrinolysis by removing the C-terminal lysine residues from fibrin clots [18]. The associ- ation of TAFI genotype with longevity in older men raises the possibility that TAFI may influence aging beyond its effects on thrombosis, especially since the risk reduction associated with the TAFI promoter genotype was not limited to cardio- vascular mortality. Activated TAFI can cleave a broad range of substrates, including complement proteins, kinins, and os- teopontin, and thus may be involved in several acute inflam- matory and stress responses, including vasomotor stability, vascular permeability, cellular adhesion, leukocyte chemo- taxis, and wound healing [19,20].

Fig. 1. Hazard ratios and 95% confidence intervals for all-cause and cause- specific mortality in men and women associated with: (A) TAFI −438 A/A genotype compared to carriers of the −438 G TAFI allele, or (B) PAI-1 4G/4G genotype compared to carriers of the 5G PAI-1 allele. Risk estimates and confidence intervals are adjusted for race, clinic site, and birth cohort. CVD: cardiovascular disease; CHD: coronary heart disease.