3.2. Longevity

The sex adjusted mortality risks were calculated using the Cox proportional hazard model with the most frequent homozygote genotype as the reference group (TT for the rs4880 MnSOD SNP and CC for the rs1050450 GPX1 SNP). The sex adjusted mortality risks according to the rs4880 MnSOD SNP showed a significantly decreased mortality of CT and CC genotype individuals (Hazard ratio, HR (CT) = 0.82; HR (CC) = 0.87), while the sex adjusted mortality risks according to the rs1050450 GPX1 SNP showed decreased mortality of CT and TT individuals (HR (CT) = 0.87; HR (TT) (HR) = 0.88, not being statistical significant for TT individuals). The estimates for the rs4880 MnSOD SNP suggest a dominant

effect of the C allele (a survival advantage of CC and CT Combining the CC and CT genotypes (and comparing to the genotype) shows a HR of 0.91 (P = 0.002).

With respect to the rs1050450 GPX1 SNP, there seems to be a heterozygote advantage, since there are less homozygotes (both CC and TT individuals) in the 1905 cohort than expected from the allele frequencies (using the Hardy–Weinberg equation). However, deviations from expected frequencies have been reported before for the oldest old (Bathum et al., 1998; Geesaman et al., 2003). In addition, the survival estimates obtained here have the same effect

Fig. 1. Kaplan-Meier Survival estimates for the 1905 cohort by (A) rs4880 MnSOD SNP genotype or by (B) rs1050450 GPX1 SNP genotype. N (MnSOD) = 1650, N (GPX1) = 1613.

Proportion survivingProportion surviving1.000.750.500.250.001.000.750.500.250.00MEAy So see seers. TTCT/ICC, T T T T0 1000 2000 3000 4000Analysis time (days)(B) Males—1— cticc T T T T0 1000 2000 3000 4000Analysis time (days)

The possible associations of the two SNPs to the functional ability and to the cognitive function of the elderly were also investigated.

With respect to self reported health, a lower frequency of CC/CT rs4880 MnSOD individuals reported a ‘‘poor/very poor’’ health (9.02% (CC/CT) versus 13.75% (TT), N = 1586, P = 0.007). For the rs1050450 GPX1 SNP genotype 11.31% (CC), 9.31% (CT) and 11.11% (TT) (combined CT/TT: 9.58%) reported a ‘‘poor/very poor’’ health (N = 1551, P = 0.446) When applying the Activity of Daily Living (ADL) strength score, the rs4880 MnSOD SNP CC/CT genotype showed a positive (although not statistical significant) sex adjusted coefficient of 0.0359 (P = 0.296, 95%CI = [(cid:3)0.0189– 0.0622], N = 1633). With respect to the rs1050450 GPX SNP, a positive statistical significant sex adjusted coefficient of 0.0783 (P = 0.039, 95%CI = [0.0039–0.1528], N (CT) = 726) was found for the CT genotype, while a positive but non-significant coefficient of 0.0359 (P = 0.605, 95%CI = [(cid:3)0.1001–0.1719], N (TT) = 129) was found for the TT genotype. The combined CT/TT group showed a statistical significant coefficient of 0.0216 (P = 0.049, 96%CI = [0.0002–0.0717], N = 1596). Still, a moderate increased ADL score may indicate that the individuals holding the genotypes associated with decreased mortality tended to be less disabled, which corresponds well with a tendency of a better self reported

Finally, the MMSE criteria showed a positive coefficient for the rs4880 MnSOD SNP CC/CT group; sex adjusted coefficient CC/ CT = 0.404 (P = 0.015, 95%CI = [0.0790–0.7296], N = 1582. With respect to the rs1050450 GPX1 SNP, a coefficient of 0.307 (P = 0.309, 95%CI = [(cid:3)0.2855–0.9001], N (CT) = 708) for the CT genotype and a coefficient of (cid:3)0.267 (P = 0.627, 95%CI = [(cid:3)1.3484– 0.8131], N (TT) = 126) for the TT genotype were found. Never- theless, a moderate increased MMSE for the rs4880 MnSOD SNP genotype individuals indicates a moderate increased cognitive function of the individuals holding the genotypes associated with decreased mortality.

Fig. 2. Kaplan-Meier Survival estimates for the 1905 cohort by sex and rs4880 MnSOD SNP genotype. (A) Females and (B) males. N (females) = 1185, N (males) = 465.

4. Discussion

3.3. Gender related difference in survival

In this paper we show associations of the rs4880 MnSOD SNP and of the rs1050450 GPX1 SNP with longevity, indicating that variation in the genes encoding MnSOD and GPX1 may influence the variation in human life span. Due to minimal immigration into the Danish 1905 cohort, population stratification is minimized, hence, the cohort must be considered to be genetically homo- genous.

When looking at males and females separately, it was observed that the effect of the advantageous rs4880 MnSOD and of the rs1050450 GPX1 SNP genotypes on mortality seemed to be most pronounced for males (data not shown). Fig. 2 shows an example of this difference in survival: the Kaplan-Meier Survival estimates for the rs4880 MnSOD SNP CC/CT and TT genotypes for females (Fig. 2A) and males (Fig. 2B) separately. When calculating the HR for the CC/CT genotype it was 0.86 for males (P = 0.011, 95% confidence interval (CI): [0.775–0.967], N = 465), while it was 0.93 for females (P = 0.045, 95%CI: [0.875– 0.998], N = 1185).