Homozygosity in centenarians

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HLA-DR homozygotes were more frequent in centenarians than in controls (16.3% versus 11.1%, P < 0.01) both in males (18.2%) and females (15.8%), as shown in Table 3. The proportion of homozygotes in centenarians was also slightly, but not significant- ly, higher than the proportion expected from allele frequencies under Hardy–Weinberg equilibrium. Both observations concurred to suggesting a survival advantage of homozygotes in individual centenarians. The proportion of homozygotes was not higher in the SIB groups (11.3% and 11.7% in men and women SIB, respectively), nor was it higher in the SIB-centenarians (10.7%).

Interaction between sex and HLA-DR alleles in longevity

In order to estimate the statistical significance of the allelic associations, taking into account putative interactions between gender and specific alleles in the effect on survival, we applied a model of logistic regression. Computations were done for each allele, comparing controls with either VIE or SIB groups. Allele frequencies were assumed to be identical in male or female adult controls. Results are presented in Table 4 for the seven most common alleles, including the only three comparisons—out of 13—that reached statistical significance, namely for alleles DR7, DR11 and DR13. For DR7, the trend of sex–allele interaction due to higher frequencies in long-lived males, whether from the VIE or SIB group, did not reach significance. Male and female SIB were

Figure 1. Major allelic contributions to differential longevity. 95% confidence intervals for allele frequencies are, respectively: DR7, 13.1%, 14.9% in controls versus 16.7%, 26.1% in longevous men (VIE + SIB) and 10.95%, 18.65% in longevous women (VIE + SIB); DR11, 11.95%, 13.65% in controls versus 8.8%, 14.4% in female centenarians, 2.5%, 11.1% in male centenarians and 17.7%, 32.3% in SIB women; DR13, 11.75%, 13.45% in controls versus 14.5%, 20.3% in centenarians.

therefore pooled, yielding an OR of 1.50 (P < 0.01) in this group for DR7 carriers. There was a significant sex–allele interaction for DR11 in the SIB group (OR = 0.43 for men versus women, P < 0.01) and the OR for SIB women was 2.02 (P < 0.001; 95% CI: 1.38–2.9). DR13 frequency was equally elevated in male and female centenarians, yielding an OR of 1.44 (P < 0.01).

observed (23.9%) and almost reached significance, despite small number of male centenarians. The increase in DR13 was too (17.8%, P < 0.05 for the allele-specific comparison controls and this new cohort). Since the previously distribution pattern in centenarians was conserved, we entitled to merge the two cohorts into one population 533 centenarians, 89 men and 444 women. Table 5 the overall allele frequencies. The logistic regression applied to these data provides a better estimate of ORs for The interaction with sex was now detected as for DR7, with an OR of 1.72 (95% CI: 1.19–2.5, = 0.004) for male centenarians. DR13 displayed no sex but was significantly increased with an OR of 1.46 CI: 1.22–1.75, P < 0.0001) for centenarians. Interestingly, overall allele distributions do not differ significantly between and female centenarians (P > 0.3).

Second cohort and conclusions

One year after obtaining the above data, our collection of centenarians had grown and we decided to evaluate the previously identified associations in a new cohort. Therefore, 208 more centenarians were genotyped, 185 women and 23 men. The allelic distributions were again significantly different between controls and this second cohort of centenarians (P < 0.05, c 2 = 22 for df = 12), whereas the distributions were similar in the two cohorts of centenarians. The male-specific increase in DR7 was

Table 4. Sex–genotype interaction and odds ratios for associated alleles

HLA-DRB1 allele Centenarians versus controls Siblings versus controls Sex–genotype interaction, OR, centenarians Sex–genotype interaction, OR, siblings males versus females versus controls males versus females versus controls DR1 1.68 (0.93–3.05, P = 0.08) 0.87 (0.67–1.14, P = 0.3) 0.9 (0.4–1.96, P = 0.76) 0.7 (0.48–1.06, P = 0.33) DR3 0.75 (0.37–1.5, P = 0.4) 0.93 (0.71–1.21, P = 0.6) 1.24 (0.62–2.46, P = 0.55) 1.13 (0.8–1.6, P = 0.5) DR4 Not done 0.98 (0.78–1.26, P = 0.93) 0.95 (0.46–1.94, P = 0.88) 0.79 (0.55–1.13, P = 0.2) DR7 1.52 (0.92–2.5, P = 0.1) 1.22 (0.97–1.52, P = 0.09) 1.64 (0.92–2.9, P = 0.09) 1.5a (1.14–2.0, P = 0.0044) DR11 0.56 (0.27–1.18, P = 0.13) 0.78 (0.6–1.02, P = 0.07) 0.43 (0.23–0.8, P = 0.0075) 2.03b (1.4–3.0, P = 0.0003) DR13 1.0 (0.6–1.7, P = 0.99) 1.43c (1.15–1.8, P = 0.0015) 0.79 (0.4–1.55, P = 0.49) 0.96 (0.68–1.34, P = 0.8) DR15 1.14 (0.59–2.2, P = 0.7) 0.76 (0.58–1.0, P = 0.05) 0.94 (0.43–2.07, P = 0.9) 0.69 (0.47–1.02, P = 0.06)

In the absence of significant sex–genotype interaction, the adjusted odds ratio was computed with both aOR adjusted for all SIBs. bOR for SIB females.

Table 5. HLA-DRB1 allele frequencies and homozygotes among controls and pooled centenarians

Allele Controls Centenarians Male centenarians Female centenarians n = 2950 Cohort I + II Cohort I + II Cohort I + II n = 535 n = 89 n = 446 DR1 11.5 10.5 12.4 10.1 DR3 11.0 9.5 6.7 10.1 DR4 13.3 12.0 11.2 12.1 DR7 14.0 15.3 21.9 14.0 DR8 2.8 3.6 1.7 3.9 DR9 0.7 0.7 0.6 0.7 DR10 0.8 0.8 0.6 0.8 DR11 13.1 11.8 10.7 12.0 DR12 1.6 1.6 0.6 1.8 DR13 12.8 17.7 16.3 17.9 DR14 3.8 3.0 2.3 3.1 DR15 12.4 10.6 11.2 10.4 DR16 2.3 3.2 3.9 3.0 Homozygotes 192/1727 80/535a 14/89 66/446 11.1% 15% 15.7% 14.8%

aP < 0.05 for homozygotes more frequent in centenarians than in controls.

DISCUSSION