PubMed was searched using Entrez for articles published to Aug 5, 2008, by use of the terms “Streptococcus pneumoniae”, “Neisseria meningitidis”, “infection”, “sepsis”, “meningitis”, “pneumonia”, “genetic polymorphisms”, and “genetics”. We identified publications by a search of references listed in those published studies and personal communications with experts in the field. No language restrictions were set in these searches.
ReviewHost genetic susceptibility to pneumococcal and meningococcal disease: a systematic review and meta-analysis
Introduction
Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus) are important human pathogens that cause sepsis, pneumonia, and meningitis. These organisms cause substantial morbidity in high-income countries (table 1),1, 2, 3, 4, 5, 6, 7 and their impact in low-income countries can be many orders of magnitude greater. Pneumococci and meningococci are the most common causative organisms of meningitis.8 Invasive disease is preceded by nasopharyngeal colonisation. Asymptomatic colonisation of pneumococci and meningococci occurs in up to 100% and 18%, respectively, of the normal population.9, 10, 11 Although several similarities exist between both pathogens, host–pathogen interactions are distinct. Invasive pneumococcal disease has been associated with immunocompromise and with distant foci of infection.12, 13 Invasive meningococcal disease has been associated with smoking and living in the same household as a patient.14 One additional risk factor for development of meningococcal disease is disease in proxies,14 which might be explained by increased risk of nasopharyngeal colonisation or by genetic preponderance for the disease. In the 1980s, adoption and twin studies showed that genetics are major determinants of susceptibility to infectious diseases.15, 16, 17 Defects in innate immunity have been described to be associated with susceptibility to pneumococcal and meningococcal infections within families.18, 19, 20 These studies support the idea that genetics are important in this susceptibility. Single base-pair alterations (single-nucleotide polymorphisms [SNPs]) occur regularly in genes controlling the host response to microbes, and may theoretically explain interindividual differences in susceptibility, at least in part.21, 22, 23
Section snippets
Methods
Figure 1 shows how studies were selected. Retrieved studies were divided into two groups. The first group comprised studies on extreme phenotypes, such as recurrent or familial infections. In these studies, genetic polymorphisms were identified by the sequencing of genes coding for proteins that are absent or dysfunctional in blood tests. The second group consisted of genetic-association studies that analysed polymorphisms on susceptibility in a case–control design. These studies select
Extreme-phenotype studies
32 studies on extreme phenotypes were identified.19, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 Table 2 provides a summary of studies on pneumococcal disease, and table 3 summarises studies on meningococcal disease.
Cleavage of complement factor 2 (C2) into factors 2a and 2b is an essential step in the classic and lectin pathways.20 A Swedish study on C2 deficiency found that 90% of all cases of C2 deficiency are caused
Case–control studies
We identified 44 case–control studies (from 1994 through 2008): 15 on pneumococcal disease and 29 on meningococcal disease (table 4 and table 5; webtable). The studies included 9474 patients and 17 744 controls (2341 with pneumococcal disease and 7133 with meningococcal disease); 8992 (95%) patients were in European studies, although none of the studies were done countrywide. The population was limited to white patients in 25 studies, patients of mixed ethnicity in three studies, and those of
Discussion
Studies of extreme phenotypes have identified genetic correlates of increased susceptibility in the complement system and the signalling cascade after TLR and interleukin-1 receptor activation. These polymorphisms are rare in the normal population, but are associated with a substantial increase in susceptibility. Several protein deficiencies related to pneumococcal and meningococcal disease with currently unknown genetic basis have been identified in extreme-phenotype studies. Most case–control
Conclusion
In conclusion, despite intensive research efforts, no polymorphism has been shown to affect susceptibility to meningococcal and pneumococcal disease beyond any doubt. The polymorphisms or haplotypes in IL1RA, SFTPA2, CEACAM3, CEACAM6, and CFH were found to be associated with meningococcal disease, and those in MBL2, NFKBIA, NFKBIE, PTPN22, and TIRAP were associated with pneumococcal disease. Most studies done on this topic had methodological flaws and, more importantly, had insufficient sample
Search strategy and selection criteria
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