All subjects gave informed, written consent prior to participation, and the study was approved by the Ethics Committee of the University Hospital Schleswig-Holstein in Kiel and by local data protection authorities. The DNA samples were analyzed for rs1801274 using a TaqMan SNP Genotyping Assay (Applied Biosystems, Foster City, CA). Power calculation was carried out by means of a program at 0.46, which would enable us to detect a factor with a comparatively low relative risk of 1.47 (at a significance level of 0.05 and a power of 80%). Pairwise comparison of allele and genotype frequency data between the three groups was performed with 2 statistics and the appropriate degrees of freedom using the Web-based sisa (Simple Interactive Statistical Analysis) tool, available at http://home.clara.net/sisa.Pneumonia caused by H. influenzae and S. pneumoniae is a leading cause of death among the elderly (Jokinen et al., 2001). As carriers of the FCGR2A-Arg131 variant are less likely to resist and/or recover from bacterial pneumonia (Yee et al., 2000), we aimed to investigate whether the FCGR2A-Arg131 variant is a significant mortality factor during aging. In this case, one might expect to observe a decrease in the 131Arg allele and a concurrent increase in the advantageous 131His variant in centenarians compared to 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 power calculations, the analyzed 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 genetically determined efficacy of the FCGR2A-based immune response does not significantly affect the ability to survive to old age or even attain exceptional life expectancy. However, an alternative mechanism must apparently compensate for the severely reduced ability of FCGR2A-131Arg carriers to eliminate encapsulated bacteria by FcR-mediated phagocytosis. We hypothesize that this finding could imply the existence of rather strong survival factors, especially in 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 longevity (Franceschi et al., 1995). The robust health of fit centenarians is likely to result from a proper lifestyle and/or a favorable genetic background; the latter may account for as much as one-third of the variance in human life expectancy (Skytthe et al., 2003). Key genes predisposing 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 additional support to the existence of longevity genes and highlights the need to further search for them.

Results

The analysis of the FCGR2A gene variant His131Arg was performed on a sample of 408 centenarians from Germany and 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 generations. The frequencies were compared pairwise between the three age groups. No evidence for a statistically significant difference was detected at the allele or genotype 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 acquired pneumonia in the adult population of municipalities in eastern Finland. Clinical Infectious Diseases,, Kochanek, K.D., Murphy, S.L., Anderson, R.N. & Scott, C. () Deaths: Final Data for (USA). National Vital Statistics Reports. National Center for Health Statistics, Hyattsville, MD,, available at: (http://www.cdc.gov/nchs/data/nvsr/nvsr / nvsr acc.pdf). Krawczak, M., Nikolaus, S., von Eberstein, H., Croucher, P., El Mokhtari, N. & Schreiber, S. () Po en: Population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships. Community Genetics,, Nebel, A., Croucher, P.J., Stiegeler, R., Nikolaus, S., Krawczak, M. & Schreiber, S. () No association between microsomal triglyceride transfer protein (MTP) haplotype and longevity in humans. Proceedings of the National Academy of Sciences, USA,, Platonov, A.E., Shipulin, G.A., Vershinina, I.V., Dankert, J., van de Winkel, J.G.J. & Kuijper, E.J. () Association of human FcRIIa (CD) polymorphism with susceptibility to and severity of meningococcal disease. Clinical Infectious Diseases,, Reilly,I'm sorry, there seems to be no complete sentence or context to this text. Can you please provide me with more information on what you need help with?