BTlackwelhl Publishieng Ltd FCGR2A — Arg131 variant is no major mortality factor in the elderly — evidence from a German centenarian study

B. K. Flesch,* S. Nikolaus,† N. E. El Mokhtari,‡ S. Schreiber§ & A. Nebel§

by the encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae combined (Jokinen et al., 2001). Aside from pneumonia, S. pneumoniae and H. influenzae cause also other serious infectious diseases like meningitis, otitis media and acute sinusitis. Findings in immunocompetent patients with bacteraemic pneumo- coccal pneumonia (Yee et al., 2000) and in invasive meningococcal disease patients (Bredius et al., 1994; Platonov et al., 1998) suggest that susceptibility to S. pneumoniae and H. influenzae infections is partly influ- enced by variation in the FCGR2A gene that codes for γ the Fc receptor for human immunoglobulin G (Fc RIIa). A functional single nucleotide polymorphism (SNP) in the FCGR2A gene (rs1801274) results in a histidine to arginine exchange at codon 131 (His131Arg). Of the two γ variants, only Fc RIIa-His131 can efficiently bind IgG2 (Warmerdam et al., 1991). IgG2 is the main immunoglobin type produced in response to bacterial polysaccharides and encapsulated bacteria (Ferrante et al., 1990). Previous studies showed a statistically significant overrepresenta- tion of the FCGR2A-Arg131/Arg131 type in patients with bacteraemic pneumonia (Yee et al., 2000) and with meningococcal disease (Bredius et al., 1994; Platonov et al., 1998), suggesting that Arg131-positive individuals are more susceptible to be adversely affected by these bacterial diseases.

Summary

The functional single nucleotide polymorphism rs1801274 in the FCGR2A gene (His131Arg) influences the efficiency of hIgG2 binding, the main isotype produced in response to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. In contrast to the receptor with the His131 allele, Fcγ RIIa-Arg131 binds hIgG2 poorly and carriers of this variant have been shown to be much more susceptible to succumb to bacterial pneumonia or meningitis. As bacteraemic pneumonia is one of the leading causes of death in elderly individuals, we hypoth- esized that the Arg131 variant could be a major mortality factor in the old. We analysed the FCGR2A-His131Arg polymorphism in a group of 408 German centenarians and two samples of younger Germans aged 60–75 and 18–49 years, respectively. No statistically significant differences were observed between the three age groups, neither at the allele nor at the genotype level. Apparently, the ability to reach old age 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 must apparently be compensated by an alterna- tive mechanism, possibly involving other genetic survival factors.

In elderly individuals, pneumonia is a major threat to the health and survival as the death rate of pneumonia is 25-fold higher for people between 65 and 74 years, and for individuals older than 84 years it is even 458-fold higher than that for 25- to 44-year-olds (Kochanek et al., γ 2004). If the Fc RIIa-His131 indeed has such a key role in the defence of polysaccharide-coated bacteria, we would expect the Arg131 polymorphic form to decrease in frequency as a population ages, with carriers of the unfavourable variant being more prone to succumb to bacteraemic pneumonia. Hence, we analysed the FCGR2A- His131Arg polymorphism in a large group of German centenarians and in two samples of younger Germans aged 60–75 and 18–49 years, respectively.

Introduction

Bacteraemic pneumonia is the fourth leading cause of death in elderly individuals (Centers for Disease Control and Prevention, 1995). More than half of all bacterial pneumonia infections at the age 60 and above are caused

* Institute of Transfusion Medicine, University Hospital Schleswig- Holstein, Kiel, Germany, † Hospital for General Internal Medicine, University Hospital Schleswig-Holstein, Kiel, Germany, ‡ Department of Cardiology, University Hospital Schleswig-Holstein, Kiel, Germany, and § Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.

Received 15 March 2006; revised 2 June 2006; accepted 2 June

Correspondence: Dr. Stefan Schreiber, Institute of Clinical Molecular Biology, Christian-Albrechts-University and University Hospital Schleswig-Holstein, Kiel Campus, Schittenhelmstrasse 12, 24105 Kiel, Germany. Tel: +49-431-597-2350; Fax: +49-431-597-1842; E-mail:

Subjects and methods

Three different age groups (adult, elderly and centenarian) were examined for the non-synonymous mutation

Table 1. Distribution of FCGR2A-His131Arg alleles and genotypes in German centenarians and in two younger age groups

FCGR2A allele Age frequencies FCGR2A genotype frequencies Age group Range/mean (years) n 131Arg 131His Arg/Arg Arg/His Adult 18–49/37.2 454 0.464 0.536 0.220 0.487 0.293 Elderly 60–75/67.3 446 0.435 0.565 0.184 0.502 0.314 Centenarian 100–110/101.3 408 0.468 0.532 0.210 0.515 0.275

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%).