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Genetic Polymorphism of the Binding Domain of Surfactant Protein–A2 Increases Susceptibility to Meningococcal Disease

  1. Dominic L. Jack1,
  2. Joby Cole1,
  3. Simone C. Naylor1,
  4. Raymond Borrow2,
  5. Edward B. Kaczmarski2,
  6. Nigel J. Klein3, and
  7. Robert C. Read1
  1. 1Academic Unit of Infection and Immunity, Division of Genomic Medicine, University of Sheffield, Sheffield, Manchester
  2. 2Meningococcal Reference Unit for England and Wales, Manchester Health Protection Agency, Manchester
  3. 3Infectious Diseases and Microbiology Unit, Institute of Child Health, University College London, London, United Kingdom
  1. Reprints or correspondence: Dr. Dominic L Jack, Academic Unit of Infection and Immunity, Div. of Genomic Medicine, University of Sheffield Medical School, Sheffield, S10 2RX, UK (D.L.Jack{at}sheffield.ac.uk).
 
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Abstract

Background. Meningococcal disease occurs after colonization of the nasopharynx with Neisseria meningitidis. Surfactant protein (SP)–A and SP-D are pattern-recognition molecules of the respiratory tract that activate inflammatory and phagocytic defences after binding to microbial sugars. Variation in the genes of the surfactant proteins affects the expression and function of these molecules.

Methods. Allele frequencies of SP-A1, SP-A2, and SP-D were determined by polymerase chain reaction in 303 patients with microbiologically proven meningococcal disease, including 18 patients who died, and 222 healthy control subjects.

Results. Homozygosity of allele 1A1 of SP-A2 increased the risk of meningococcal disease (odds ratio [OR], 7.4; 95% confidence interval [CI], 1.3–42.4); carriage of 1A5 reduced the risk (OR, 0.3; 95% CI, 0.1–0.97). An analysis of the multiple single-nucleotide polymorphisms in SP-A demonstrated that homozygosity for alleles encoding lysine (in 1A1) rather than glutamine (in 1A5) at amino acid 223 in the carbohydrate recognition domain was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4–31.5). Carriage of alleles encoding lysine at residue 223 was found in 61% of patients who died, compared with 35% of those who survived (OR adjusted for age, 2.9; 95% CI, 1.1–7.7). Genetic variation of SP-A1 and SP-D was not associated with meningococcal disease.

Conclusions. Gene polymorphism resulting in the substitution of glutamine with lysine at residue 223 in the carbohydrate recognition domain of SP-A2 increases susceptibility to meningococcal disease, as well as the risk of death.

Meningococcal disease remains a substantial cause of morbidity and mortality worldwide, with approximately 2500–3000 infections occurring annually in the United States [1]. Despite the widespread introduction of a protein-conjugate vaccine against serogroup C in the United Kingdom, ∼1500 confirmed cases of meningococcal disease occur each year in England and Wales [2], with a case-fatality rate of 8% [3]. Meningococcal disease is a consequence of invasion of the bloodstream by Neisseria meningitidis after a period of nasopharyngeal colonization. Organisms adhere to the epithelial surface of the nasopharynx, transcytose, and finally penetrate capillary blood [4]. Risk factors for meningococcal disease include the acquisition of an invasive strain and environmental risk factors including smoking, population density, and preceding viral infections [5]. However, genetic variation between hosts may also be important, because disease has a familial component [6].

Studies from the late 1960s suggested that the major correlate of protection against meningococcal disease was the acquisition of specific antibodies able to activate complement. The highest titers of these antibodies are observed in older children and in adults [7]. However, the attack rate remains relatively low, even among younger children who lack appreciable titers of bactericidal antibody, despite relatively common nasopharyngeal carriage of N. meningitidis [8].

The absence of disease in the majority of the at-risk population suggests that innate immune mechanisms are important for protection against meningococcal disease. Variation within the genes involved in the inflammatory response has been associated with modification of disease susceptibility and disease progression and outcome [3, 9]. Genetic deficiency of the serum protein, mannose-binding lectin (MBL), which is able to recognize N. meningitidis and activate complement on the bacterial surface [10, 11], has been suggested to increase susceptibility to meningococcal disease [12].

MBL is a member of a family of proteins called the collectins, which also includes surfactant protein (SP)–A and SP-D. SP-A and SP-D are expressed in the nasopharynx and respiratory tract and, therefore, are present at the site of initial meningococcal colonization [13]. SP-A and SP-D bind to microorganisms by pattern recognition and modify immune responses, such as phagocytosis and inflammation. SP-A and SP-D do not activate the complement system and are therefore unlikely to contribute directly to the serum bactericidal response.

A large number of single-nucleotide polymorphisms (SNPs) exist in the 2 human genes for SP-A (SP-A1 and SP-A2, which are 99% homologous to one another) and the single SP-D gene. Within SP-A, many polymorphisms are missense mutations (figure 1), but some are silent. Because of the proximity of SNPs in SP-A, only certain combinations of the common and rare SNPs occur (table 1) [14]. These haplotypes are by convention referred to as SP-A alleles. Common SP-A alleles are shown in table 2, and the frequencies in a number of populations have been described elsewhere [14, 15].

Figure 1
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Figure 1

Surfactant protein (SP)–A and SP-D: protein structure and location of single-nucleotide polymorphisms (SNPs). The genes for SP-A1, SP-A2, and SP-D are clustered on chromosome 10q, with SP-A1 in reverse transcriptional orientation relative to SP-A2 and SP-D. They encode polypeptide chains that form trimeric subunits, which then further assemble into oligomers of subunits. A number of missense and silent mutations exist. Only certain combinations of SNPs are found in the SP-A genes; these combinations are called alleles (table 2). RSV, respiratory syncytial virus.

Table 1
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Table 1

Missense and silent mutations in SP-A1 and SP-A2.

Table 2
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Table 2

Common SP-A alleles.

Carriage of missense mutations in SP-A, SP-D, or certain SP-A alleles is associated with a modification of certain infectious disease susceptibilities [16–18] (figure 1). The likely mechanism is an effect on the capacity to initiate phagocytosis [19] and inflammatory responses [20]. Furthermore, different SP-A alleles express different levels of protein [21]. The effect of SNPs in SP-D are less clear, but one mutation leading to an amino acid change at residue 11 reduces serum levels of the protein [22].

The location of SP-A and SP-D at the site of acquisition of N. meningitidis, as well as the presence of mutations that potentially affect function, led us to test the hypothesis that polymorphisms in SP-A and SP-D are involved in the acquisition or progression of meningococcal disease. Therefore, we studied the distribution of polymorphisms in these 3 genes in a cohort of patients with microbiologically proven meningococcal disease.

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Methods

Patients. This cohort of patients with meningococcal disease has been described previously [3]. The Meningococcal Reference Unit (Manchester, UK) for England and Wales offers a service for PCR detection of N. meningitidis in blood and CSF samples obtained from patients with suspected meningococcal disease, in addition to culture confirmation of disease. From July 1998 through November 1999, all whole-blood samples obtained from patients with confirmed meningococcal disease (confirmed by either culture or PCR detection of N. meningitidis in blood or CSF specimens) were stored. After informed consent had been obtained from patients and/or their families, samples were coded and anonymized before genetic testing. The serogroup of the infecting organism, the disease outcome (in terms of death or survival), and the age of the patient were recorded. The age of patients ranged from 0 to 84 years, and 24.0% of patients were aged ⩾18 years. Samples were chosen at random from the cohort for SP-A/SP-D genotyping. The control group comprised healthy volunteers aged 18–45 years who were recruited from among the staff and students of the Sheffield Teaching Hospitals. The healthy control population was older than the case population; however, analysis of genotype frequencies of the related collectin, MBL, in developed countries has revealed no significant differences in genotype frequency associated with age [23]. The ethics committees of the Public Health Laboratory Service for England and Wales and of the South Sheffield Health District (Sheffield, UK) approved the study.

SP-A and SP-D genotyping. The sequence-specific priming technique of Pantelidis et al. [24] was used to determine genotypes. This technique determines the identity of SNPs at key points in the genes SP-A1 (encoding amino acids 19, 50, 62, 133, and 219), SP-A2 (encoding amino acids 9, 91, 140, and 223), and SP-D (encoding amino acids 11 and 160). The haplotypes of polymorphisms in SP-A1 and SP-A2 distinguished the different SP-A alleles, as shown in table 2 [25]. By convention, SP-A1 alleles are prefixed 6A, and SP-A2 alleles are prefixed 1A [25].

Statistical analysis. HWDIAG software [26] was used to determine whether SNPs were in Hardy-Weinberg equilibrium. Haplotype analysis was performed using HPlus [27], which uses an estimating equation to determine the likelihood of diplotypes in heterozygous individuals, followed by logistic regression analysis to determine ORs [28, 29]. All other statistical tests were performed using SPSS software, version 11 (SPSS). SP-A alleles were recoded as separate, binary variables for recessive effect (a homozygote for the allele has a quantitative effect different from that of a heterozygote for the allele or if the allele is absent) and dominant effect (heterozygosity and homozygosity have an equal effect different from that of the absence of the allele). All effects were entered simultaneously into a multivariate logistic regression analysis. The dominant and recessive effects of the rarer SNP in SP-A1, SP-A2, or SP-D on disease susceptibility were analyzed similarly. Logistic regression was used to estimate the influence of SP-A or SP-D genotype on the risk of death due to meningococcal disease, with age included in the logistic. χ2 Analysis was used for comparison of allele and SNP frequencies with other populations.

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Results

Genotyping. In total, 302 patients were genotyped for polymorphisms at all loci in SP-A2, and 303 were genotyped for polymorphisms at all loci in SP-A1. Data for SP-D polymorphisms at amino acid 11 were available for 294 patients and at amino acid 160 for 301 patients. In the control group, 218 and 222 individuals were typed successfully for all positions in SP-A2 and SP-A1, respectively, and 227 were typed for both positions in SP-D.

The frequency of the SNPs in SP-A and SP-D did not deviate significantly from the Hardy Weinberg equilibrium (data not shown), and the frequencies in the control population were not significantly different from those from a previously reported UK control population (data not shown) [24]. This previous study did not use SP-A SNPs to determine SP-A allele frequencies; therefore, we compared our control subjects with other European populations. The frequency of SP-A1 and SP-A2 alleles in our control population was significantly different from the published frequencies for 2 other large European control populations from Germany [14] and Finland [15] (P = .001 and P < .001 for SP-A1 in Germans and Finns, respectively, by χ2 test; P = .021 and P < .001 for SP-A2 in Germans and Finns, respectively, by χ2 test); this appeared to be the result of a higher frequency (0.08) of both 6A (SP-A1) and 1A (SP-A2) in the UK population, compared with frequencies of 0.04 and 0.05 in Finns and Germans, respectively.

SP-A alleles. Two alleles of SP-A2 had a significant association with susceptibility to meningococcal disease (table 3). Homozygosity for 1A1 was associated with an increased risk of meningococcal disease (OR, 7.4; 95% CI, 1.3–42.4), with 6.3% of the patient population homozygous for 1A1, compared with only 0.9% of the control population. The population-attributable fraction of cases resulting from 1A1 homozygosity is 5.5% (95% CI, 4.7%–23.8%). Carriage of 1A1 was not associated with an altered risk of disease. A dominant effect of 1A5 was associated with a reduced risk of meningococcal disease (OR, 0.3; 95% CI, 0.1–0.97). No SP-A1 alleles were significantly associated with disease.

Table 3
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Table 3

Surfactant protein (SP)–A alleles and meningococcal disease.

SNP analysis. We next analyzed the individual SNPs in SP-A and SP-D. Significant changes in disease susceptibility were observed for only 1 SNP, which was in SP-A2 at codon 223 (table 4). Homozygosity for the rare SNP at amino acid 223 (223AA), which is located in the carbohydrate recognition domain, was associated with an increased risk of meningococcal disease (OR, 6.7; 95% CI, 1.4–31.5). This rare SNP is found in allele 1A1. No significant effect was observed for SNPs in SP-A1 or SP-D.

Table 4
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Table 4

Single-nucleotide polymorphisms (SNPs) in surfactant protein (SP)–A and SP-D in meningococcal disease.

Haplotype analysis of disease susceptibility. We found that the frequency of 6A2/1A1 was higher in patients (4.1%) than in control subjects (1.5%; OR, 2.35; 95% CI, 1.28–4.31) (table 5). Conversely, 6A4/1A5 was underrepresented in patients, compared with control subjects (OR, 0.51; 95% CI, 0.3–1.0).

Table 5
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Table 5

SP-A1/SP-A2 haplotypes in case patients and control subjects.

The SP-D locus is not linked to SP-A1 and SP-A2, and we used the same approach to determine whether any haplotype of SP-D SNPs was associated with susceptibility to disease. We found that there were no significant differences in SP-D haplotype frequencies between case patients and control subjects noted by logistic regression (data not shown). Because of the lack of linkage of SP-D with the SP-A locus, >25 common haplotypes of SP-A1, SP-A2, and SP-D were identified; this limited the number of observations for each haplotype. Therefore, the analysis of these extended haplotypes was omitted.

SP-A and SP-D SNPs and death due to meningococcal disease. There were 18 deaths in the cohort that we genotyped. We found that no SP-A alleles were significantly associated with an altered risk of death. Analysis of SNPs in SP-A and SP-D showed that carriage of the rare SNP at amino acid 223 in SP-A2 was associated with an increased risk of death (OR corrected for age, 2.9; 95% CI, 1.1–7.7).

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Discussion

SP-A is a soluble molecule directly involved in host defense at the mucosal level. We have found that a SNP that results in the substitution of glutamine by lysine in the carbohydrate recognition domain of SP-A results in an increase in the susceptibility to and the chance of dying of meningococcal disease. Unlike complement deficiencies, which most likely perturb the ability of the host to destroy organisms that penetrate the bloodstream, we describe (to our knowledge, for the first time) a defect in immunity at the mucosal level that results in host susceptibility to meningococcal disease. The manner of acquisition of meningococcal disease or an alteration in inflammatory response of individuals homozygous for the rare SNP at amino acid 223 then results in a higher risk of death.

The control population consisted of healthy adults with no previous history of meningococcal infection. The frequencies of SNPs in this control population were not significantly different from the frequencies in a previously reported UK control population [24]; therefore, we believe that we have an accurate representation of the healthy British population. This previous report did not describe allele typing for SP-A1 or SP-A2, so it is not possible to directly compare the equivalence of our control population with another UK control population. The frequency of SP-A alleles was significantly different from that in German and Finnish control populations reported elsewhere [14, 15], with higher frequencies of alleles 1A and 6A in the British population. In the present study, there was no significant difference between patients with meningococcal disease and British control subjects with regard to the frequency of either of these particular alleles.

Homozygosity of the SP-A2 allele, 1A1, was associated with an increased risk of meningococcal disease, suggesting that this allele is recessive. The carriage of another SP-A2 allele, 1A5, was significantly associated with a reduced risk of infection, suggesting a dominant effect of this allele. Allele 1A1 and 1A5 are identical at the codons that encode amino acids 9 and 140, but they differ at amino acids 91 and 223.

Logistic regression of the recessive or dominant effects of all SNPs in SP-A1, SP-A2, and SP-D suggested that the rare SNP at amino acid 223 was a recessive marker for susceptibility to meningococcal disease. Other alleles of SP-A2 than 1A1, such as 1A3 and 1A8, encode lysine at amino acid 223, but these alleles occurred at low frequency in this and in other studies, and we did not find any homozygotes for these alleles.

We did not find any effect of SP-A1 alleles or SNPs on susceptibility to meningococcal disease. Certain SP-A1/SP-A2 haplotypes were associated with altered risk of disease, but these were always related to the SP-A2 allele present. The expression of SP-A1 appears to be restricted to the lower respiratory tract, whereas SP-A2 appears to be expressed more generally throughout the airway [30].

This study was conducted in England and Wales. The frequencies of polymorphisms in SP-A and SP-D have been shown to differ between different ethnic populations [14]. Therefore, it may not be possible to extrapolate the findings of our study to other ethnic populations. Also, the majority of patients in the United Kingdom experience serogroup B or C disease [5], and results may not be the same in countries with different predominant serogroups, such as serogroup A. Serogroup C and age were significantly associated with increased mortality in a previous analysis of this cohort [3], but because of the low absolute numbers of patients who died in the current analysis, we were unable to correct for serogroup in our analysis of death due to disease.

The rare SNP-encoding amino acid 223 in SP-A2 is located within the carbohydrate recognition domain of the protein and codes for lysine, whereas glutamine is more common in this position. Glutamine is found in the most frequent SP-A2 allele, 1A0, which is carried by >70% of the British population, and it would appear that the possession of at least 1 allele encoding glutamine at amino acid 223 is sufficient to provide normal protection against meningococcus by the SP-A system.

Changes in the carbohydrate recognition domain of SP-A2 might lead to changes in the recognition of microbes. However, in contrast to mannose-binding lectin, which binds to meningococci and can activate complement [10, 11], SP-A does not bind avidly to meningococci (D.L.J., unpublished data). Therefore, the possibility exists that there is no direct interaction between SP-A2 and the meningococcus, and SP-A genotype may modify other factors important in susceptibility to meningococcal disease.

It has been suggested that SP-A can control inflammation in the absence of microorganisms by binding (via its carbohydrate recognition domains) to signal inhibitory regulatory protein α (SIRPα) on cells. When SP-A binds to microorganisms, the molecule appears able to change orientation to provide a different inflammatory effect [31]. Changes in the carbohydrate recognition domain could modify this ability of SP-A to bind to SIRPα. This could change the inflammatory response to the meningococcus itself or to environmental factors important in changing meningococcal disease susceptibility. The integrity of the nasopharyngeal mucosa is important in determining colonization with and invasion by N. meningitidis. Factors that decrease mucosal integrity, such as smoking [32], increase susceptibility to meningococcal infection.

Alternatively, changes in SP-A2 could lead to changes in the handling of upper respiratory tract pathogens. Prior upper respiratory tract infections increase the risk of meningococcal disease [33]. SP-A knockout mice infected with influenza A virus experience a greater early inflammatory response and greater damage to the airway epithelium than do healthy mice [34]. Importantly, the presence of lysine at amino acid 223 in humans has been associated with more-severe respiratory syncytial virus infection [17]. Perturbation of inflammatory homeostasis via SP-A2 polymorphism could potentially lead to increased damage to the nasopharyngeal epithelium during or after a mild upper respiratory tract infection, leading to enhanced susceptibility to meningococcal disease.

The inflammatory response is also important in determining the outcome of meningococcal disease. Genetic polymorphisms in the IL-1 system and polymorphisms in TNF have been shown to influence meningococcal disease severity [3, 9], and MBL can modify inflammatory responses to meningococci [35]. SP-A can enhance inflammatory responses, but differences exist in the ability of the gene products of different alleles to elicit TNF-α from the monocyte-like cell line, THP-1 [20]. Protein encoded by allele 1A1 has a lower ability to stimulate early TNF-α release than does protein encoded by 1A, 1A0, or 1A2. Lower initial TNF responses could be linked to an increased risk of death due to meningococcal disease [36].

It is widely considered that the serum bactericidal response is critical in determining susceptibility to meningococcal disease. Thus, individuals who lack specific bactericidal antibody depend on innate immunity for protection [7]. We have shown that a polymorphism in the recognition domain of a mucosally expressed protein is highly significant in determining susceptibility to this disease. This directly shows, for the first time, that humoral mucosal defence is important in immunity to meningococcal disease. Changes in acquisition of the organism or changes to the inflammatory response may also explain why the same polymorphism is also important in determining the survival of patients with the disease.

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Acknowledgments

We thank Dr. Kevin Walters of the Mathematical Modelling and Genetic Epidemiology Group, University of Sheffield Medical School, for statistical advice.

Financial support. Meningitis Research Foundation (project grant 07/02 to D.L.J., R.C.R., and N.J.K.). The collection of DNA by S.C.N. from patients with meningococcal disease was supported by Meningitis Research Foundation (project grant 4/00).

Potential conflicts of interest. All authors: no conflicts.

  • Received June 11, 2006.
  • Accepted July 31, 2006.
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  1. Clin Infect Dis. (2006) 43 (11): 1426-1433. doi: 10.1086/508775
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