n, number of individuals tested.

0.46, we would be able to detect a factor with a com- paratively low relative risk of 1.47 (at a significance level of 0.05 and a power of 80%).

rs1801274 (His131Arg) in the FCGR2A gene (Table 1). The unrelated and healthy study participants were drawn anonymously from population-based samples. The elderly and centenarian individuals were recruited as described in Nebel et al. (2005); the adult subjects were controls from the PopGen biobank (Krawczak et al., 2006). The three samples were matched by ethnical ancestry (all Germans) and sex ratio (80% females vs. 20% males). All subjects gave informed, written consent prior to participation. The study was approved by the Ethics Committee of the University Hospital Schleswig-Holstein in Kiel and by the local data protection authorities. The DNA samples were analysed for rs1801274 using a TaqMan® SNP Genotyping Assay (Applied Biosystems, Foster City, CA). The accuracy of the typing was demonstrated by testing 37 DNA samples that had previously been examined for the same mutation by poly- merase chain reaction with sequence-specific primers (PCR– SSP) (Flesch et al., 1998). For each test sample, the two methods yielded consistent results. Pairwise comparison of allele and genotype frequency data between the three groups was performed with χ2 statistics and the appropriate degrees of freedom using the Web-based sisa (Simple Interactive Statistical Analysis) tool, available at http:// home.clara.net/sisa. Power calculation was carried out by means of a program at http://calculators.stat.ucla.edu/pc.

Discussion

Pneumonia caused by H. influenzae and S. pneumoniae is a major cause of death in the very old (Jokinen et al., 2001). As carriers of the FCGR2A-Arg131 variant are less likely to resist and/or to recover from bacterial pneumonia (Yee et al., 2000), we wanted to test whether the FCGR2A-Arg131 variant is a significant mortality factor during ageing. In this case, one might expect to observe a decrease in the 131Arg allele and a concurrent increase in the advantageous 131His variant in the centenarians compared to the elderly and adult individuals. However, our data obtained from the three different groups do not show any age-dependent distribution of the FCGR2A-His131Arg variants. Based on the power calculation, the analysed 131Arg polymorphism does not seem to be a major risk factor in the elderly, despite the particularly high incidence and mortality rate of bacterial pneumonia in this age group. Thus, the ability to survive to old age, and to reach even exceptional life expectancy, is largely unaffected by the genetically determined efficacy of the FCGR2A-based immune response.

However, the severely reduced ability of FCGR2A- 131Arg carriers to eliminate encapsulated bacteria by γ Fc R-mediated phagocytosis must apparently be com- pensated by an alternative mechanism. We hypothesize that this finding could imply the existence of (a) rather strong survival factor(s), especially in the 131Arg- homozygous centenarians, which allowed them to attain such an advanced age. Studies on centenarians confirm that the immune system plays a major role in the attainment of longevity (Franceschi et al., 1995). The robust health of fit centenarians is likely to result from a proper lifestyle and/or a favourable genetic background; the latter may account for as much as of a third of the variance in human life expectancy (Skytthe et al., 2003). Key genes predispos- ing to a healthy and long life have indeed been proposed but, apart from APOE, none of the other suggested candidates have been confirmed (Christensen et al., 2006). Yet such ‘longevity’ genes might be able to compensate for the negative effects of other genetic factors, like the FCGR2A-131Arg variant. Thus, our finding lends

Results

The analysis of the FCGR2A gene variant His131Arg was performed on a sample of 408 centenarians from Germany and on two younger groups (Table 1), 446 elderly individuals (60–75 years) and 454 young-to-middle-aged volunteers (18–49 years). Using these extensive samples, we investigated whether there is a shift in the allele and genotype distribution of the functional FCGR2A SNP rs1801274 across the generations. The frequencies were compared in a pairwise manner between the three age groups. No evidence for a statistically significant difference was detected, at the allele or at the geno- type levels (for each comparison P > 0.05; Table 1). The His131Arg polymorphism was found to be in Hardy– Weinberg equilibrium in all three samples (P > 0.05). The observed frequencies are well within the range reported previously for Caucasians (Bredius et al., 1994; Reilly et al., 1995). A power calculation revealed that given our sample sizes and an average 131Arg allele frequency of

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