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Genetic factors have been estimated to account for about 25% of the variation in an adult's life span. The complement component C4 with the isotypes C4A and C4B is an effector protein of the immune system, and differences in the overall  C4  copy number or gene size (long  C4L ; short  C4S ) may influence the strength of the immune response and disease susceptibilities. Previously, an association between  C4B  copy number and life span was reported for Hungarians and Icelanders, where the  C4B*Q0  genotype, which is defined by  C4B  gene deficiency, showed a decrease in frequency with age. Additionally, one of the studies indicated that a low  C4B  copy number might be a genetic trait that is manifested only in the presence of the environmental risk factor “smoking”. These observations prompted us to investigate the role of the  C4  alleles in our large German longevity sample (∼700 cases; 94–110 years and ∼900 younger controls). No significant differences in the number of  C4A ,  C4B  and  C4S  were detected. Besides, the  C4B*Q0  carrier state did not decrease with age, irrespective of smoking as an interacting variable. However, for  C4L*Q0  a significantly different carrier frequency was observed in the cases compared with controls (cases: 5.08%; controls: 9.12%; p = 0.003). In a replication sample of 714 German cases (91–108 years) and 890 controls this result was not replicated (p = 0.14) although a similar trend of decreased  C4L*Q0  carrier frequency in cases was visible (cases: 7.84%; controls: 10.00%).

Investigation of Complement Component C4 Copy Number Variation in Human Longevity