Abstract
Common variable immunodeficiency (CVID) is a heterogeneous group of primary immunodeficiency diseases. Cytokine production could be affected in CVID patients, whereas its alteration could be due to genetic polymorphisms within coding and promoter regions of the cytokine genes. This study was performed to analyse the proinflammatory cytokine single nucleotide polymorphisms in CVID. The allele and genotype frequencies of a number polymorphic genes coding tumour necrosis factor (TNF)-α, interleukin (IL)-1α, IL-1β, IL-1R, IL-1RA and IL-6 were investigated and compared between two groups of CVID patients and controls. The IL-6 GA genotype at position nt565 was significantly over-represented in the patient group (P < 0·001), while the IL-6 GG genotype at position −174 (P = 0·006) and the GG genotype at position nt565 (P < 0·001) were significantly lower than controls. The TNF-α AG genotype at position −308 in the patient group was increased significantly in comparison with controls (P = 0·027), but the GG genotype at the same position was significantly decreased (P = 0·011). IL-6 CA and GA haplotypes were the most frequent haplotypes in the patients (P < 0·005), whereas TNF-α GA (P = 0·002) and IL-6 GG (P < 0·001) haplotypes were decreased significantly in the patients in comparison with controls. Cytokine single nucleotide polymorphisms could have a role in pathophysiology of CVID. High production of TNF-α is expected in some CVID patients based on the frequency of genotypes/haplotypes of these cytokine gene polymorphisms.
Keywords: common variable immunodeficiency, cytokine, genetic polymorphism, IL-6, TNF-α
Introduction
Common variable immunodeficiency (CVID) is the most common symptomatic predominantly antibody deficiency disease, characterized by hypogammaglobulinaemia and increased susceptibility to recurrent infections, autoimmunity and cancers [1–5]. The pathogenesis of disease has still not been determined clearly [6,7]; however, several abnormalities in B cells differentiation, T cells and dendritic cells have been reported in some CVID patients [8–13].
Cytokine production, which has an important role in antibody synthesis, could be affected in CVID patients [14–17]. Although the alteration of cytokine expression and secretion could be due to the nature of the disease, it is possible that genetic polymorphisms within the coding and promoter regions of cytokine genes affect the cytokine production [18–20]. It appears that serum levels of proinflammatory cytokines, including interleukin (IL)-1, IL-6 and tumour necrosis factor-alpha (TNF-α), are associated with specific genotypes/haplotypes of the related genes [18–20].
While the role of cytokine single nucleotide polymorphisms (SNPs) in some immunological disorders has been reported previously [21–23], this study was designed to test the proinflammatory cytokine SNPs in CVID.
Patients and methods
Patients and controls
Thirty patients with CVID and 140 controls were enrolled into this study. The patients were selected from the cases that were being followed up regularly at our referral centre in Children's Medical Center Hospital. The controls were also selected randomly from blood donors at Iranian blood transfusion organizations [24]. This project was approved by the Ethical Committee of Tehran University of Medical Sciences. Written informed consent was obtained from all subjects before sampling.
The diagnosis of CVID was made based on standard criteria, including decreased serum levels of at least two of the immunoglobulins (IgG, IgA and IgM) and genetic exclusion of other well-defined antibody deficiencies [7,25]. Patients less than 2 years of age were excluded because of the possibility of transient infant hypogammaglobulinaemia.
Genotyping
Cytokine typing was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP assay kit; Heidelberg University, Heidelberg, Germany) [24]. Briefly, amplification was carried out using a thermal cycler Techne Flexigene apparatus (Rosche, Cambridge, UK). The presence or absence of polymerase chain reaction products was visualized by 2% agarose gel electrophoresis. After electrophoresis, the gel was placed on an ultraviolet transilluminator, and a picture for interpretation and documentation was taken. Each of the primer mixes contained a control primer pair that amplified either a part of the β-globin gene or a part of the C-reactive protein gene. The β-globin control primers produce a 89-base pairs (bp) fragment, while the primer pairs amplifying the CRP gene produced a 440-bp amplicon. The allele and genotype frequencies of the following cytokine genes were determined: TNF-α (A/G −308, A/G −238), IL-1α (C/T −889), IL-1β (C/T −511), IL-1β (C/T +3962), IL-1R (C/T Pst-I 1970), IL-1RA (C/T Mspa-I 11100) and IL-6 (C/G −174) and (A/G nt565).
Statistical analysis
Data analysis was performed using the Epi Info statistical software and the spss statistical software package. Allele frequencies were estimated by direct gene counting. Allele frequencies of various genotypes were compared using the χ2 test. The odds ratio (OR) and P-values were calculated for each allele, genotype and haplotype in the patient and control groups. The ORs were calculated, and a P-value of less than 0·05 was considered significant with 95% confidence intervals.
Results
Characteristics of the patients
Thirty patients with CVID (18 male and 12 female), with mean ages of 16·6 ± 10·3 years were investigated in this study. The patients‘ characteristics are presented in Table 1. Recurrent infections, especially gastrointestinal and respiratory infections, were the most predominant manifestations; among them diarrhoea (83%) and pneumonia (80%) were the most common, followed by upper respiratory tract infections (sinusitis in 70% and otitis media in 53%). Other less frequent infections were septic arthritis, pyelonephritis, osteomyelitis and meningitis. More than half the patients developed bronchiectasis (53%). Splenomegaly was detected in 13 cases, while eight patients showed complications with autoimmune diseases (Table 1).
Table 1.
Characteristics of common variable immunodeficiency patients investigated in this study.
| Number | Study age (years) | Sex | Serum IgG (mg/dl) | Serum IgA (mg/dl) | Serum IgM (mg/dl) | Recurrent infectious complications | Autoimmunity | Splenomegaly | Bronchiectasis |
|---|---|---|---|---|---|---|---|---|---|
| P1 | 50 | Male | 250 | 0 | 0 | GI | – | No | Yes |
| P2 | 47 | Male | 20 | 0 | 25 | GI, URT, LRT | – | No | Yes |
| P3 | 25 | Male | 80 | 20 | 10 | GI, URT, LRT | – | No | No |
| P4 | 23 | Female | 250 | 35 | 50 | GI, LRT, UT | – | No | No |
| P5 | 22 | Female | 355 | 15 | 7 | GI, URT, LRT | – | No | Yes |
| P6 | 21 | Male | 130 | 10 | 60 | GI, URT, LRT, CNS | – | Yes | No |
| P7 | 21 | Female | 290 | 0 | 30 | URT, LRT | – | No | Yes |
| P8 | 20 | Male | 0 | 0 | 30 | GI, LRT, UT | – | No | Yes |
| P9 | 20 | Female | 500 | 45 | 10 | GI, LRT, UT, OA | CAH | Yes | Yes |
| P10 | 20 | Female | 220 | 10 | 15 | GI, URT, LRT, OA | – | No | Yes |
| P11 | 18 | Female | 390 | 75 | 50 | GI, URT, LRT | Alopecia areata | Yes | Yes |
| P12 | 17 | Male | 90 | 10 | 90 | GI, URT, LRT | – | Yes | No |
| P13 | 16 | Male | 80 | 5 | 5 | GI, URT, LRT, UT | – | Yes | Yes |
| P14 | 16 | Male | 105 | 30 | 30 | GI, URT, LRT | – | Yes | Yes |
| P15 | 14 | Male | 340 | 10 | 20 | GI, URT, OA | ITP + AHA | Yes | Yes |
| P16 | 13 | Male | 255 | 70 | 50 | GI, URT, LRT, CNS | Coeliac disease | No | No |
| P17 | 13 | Female | 115 | 50 | 30 | GI, URT, LRT, OA | – | No | No |
| P18 | 13 | Male | 470 | 35 | 45 | GI, URT | ITP | Yes | Yes |
| P19 | 12 | Male | 310 | 10 | 50 | GI, URT, LRT | No | No | |
| P20 | 12 | Female | 350 | 0 | 35 | URT, LRT | – | Yes | No |
| P21 | 11 | Female | 0 | 0 | 40 | GI, LRT | – | No | No |
| P22 | 10 | Male | 140 | 15 | 15 | GI, URT, LRT | AHA | Yes | Yes |
| P23 | 10 | Male | 20 | 5 | 20 | GI, LRT | – | No | No |
| P24 | 9 | Male | 320 | 55 | 15 | GI, URT, LRT, UT | CAH | Yes | Yes |
| P25 | 9 | Female | 100 | 5 | 10 | URT, LRT | – | No | No |
| P26 | 9 | Female | 0 | 0 | 30 | GI, LRT | – | Yes | Yes |
| P27 | 9 | Male | 380 | 5 | 50 | GI, URT, LRT | ITP | No | Yes |
| P28 | 8 | Female | 80 | 5 | 15 | URT, LRT | – | Yes | No |
| P29 | 5 | Male | 120 | 220 | 0 | GI, URT, LRT | – | No | No |
| P30 | 4 | Male | 90 | 90 | 30 | GI, LRT, OA | – | No | No |
GI, gastrointestinal tract infections (diarrhoea); URT, upper respiratory tract infection (sinusitis, otitis media); LRT, lower respiratory tract infection (pneumonia); UT, urinary tract infection (pyelonephritis); CNS, central nervous system infection (meningitis); OA, skeletal infection (osteomyelitis, arthritis); ITP, idiopathic thrombocytopenic purpura; AHA, autoimmune haemolytic anaemia; CAH, chronic active hepatitis; Ig, immunoglobulin.
Alleles and genotype frequencies
Allelic and genotype frequencies in CVID patients and healthy control subjects are shown in Table 2. The IL-6 GA genotype at position nt565 was over-represented significantly in the patient group (79·3% in patients versus 30·2% in controls, P < 0·001). TNF-α AG genotype at position −308 in the patient group was also increased significantly in comparison with controls (51·7% in patients versus 28·5% in controls, P = 0·027). The frequencies of the following genotypes in the patient group were significantly lower than control group: IL-6 GG at position −174 (3·4% in patients versus 30·2% in controls, P = 0·006), IL-6 GG at position nt565 (13·8% in patients versus 66·9% in controls, P < 0·001) and TNF-α GG at position −308 (44·8% in patients versus 71·5% in controls, P = 0·011).
Table 2.
Allele and genotype frequencies of proinflammatory cytokine gene polymorphisms in common variable immunodeficiency patients in comparison with normal controls.
| Cytokine | Position | Alleles/genotypes | Patients (n = 30) N (%) | Controls (n = 140) N (%) | P-value | OR (95%CI) |
|---|---|---|---|---|---|---|
| TNF-α | −308 | A | 17 (29·3%) | 39 (14·2%) | 0·009 | 2·50 (1·23–5·06) |
| G | 41 (70·7%) | 235 (85·8%) | 0·024 | 0·40 (0·20–0·82) | ||
| AA | 1 (3·4%) | 0 (0) | 0·175 | – | ||
| AG | 15 (51·7%) | 39 (28·5%) | 0·027 | 2·69 (1·10–6·59) | ||
| GG | 13 (44·8%) | 98 (71·5%) | 0·011 | 0·32 (0·13–0·79) | ||
| TNF-α | −238 | A | 7 (10·3%) | 59 (21·5%) | 0·144 | 0·50 (0·20–1·22) |
| G | 51 (89·7%) | 215 (78·5%) | 0·144 | 2·00 (0·82–5·10) | ||
| AA | 0 (0%) | 1 (0·7%) | 0·825 | – | ||
| GA | 7 (20·7%) | 57 (41·6%) | 0·116 | 0·44 (0·16–1·18) | ||
| GG | 22 (79·3%) | 79 (57·7%) | 0·115 | 2·27 (0·84–6·30) | ||
| IL-6 | −174 | C | 33 (56·9%) | 101 (36·3%) | 0·006 | 2·31 (1·25–4·27) |
| G | 25 (43·1%) | 177 (63·7%) | 0·006 | 0·43 (0·23–0·80) | ||
| CC | 5 (17·2%) | 4 (2·9%) | 0·008 | 7·03 (1·49–34–23) | ||
| CG | 23 (79·3%) | 93 (66·9%) | 0·274 | 1·90 (0·67–5·61) | ||
| GG | 1 (3·4%) | 42 (30·2%) | 0·006 | 0·08 (0·00–0·60) | ||
| IL-6 | nt565 | A | 27 (46·6%) | 50 (18·0%) | < 0·001 | 3·97 (2·09–7·56) |
| G | 31 (53·4%) | 228 (82·0%) | < 0·001 | 0·25 (0·13–0·48) | ||
| AA | 2 (6·9%) | 4 (2·9%) | 0·277 | 2·50 (0·30–17·11) | ||
| GA | 23 (79·3%) | 42 (30·2%) | < 0·001 | 8·85 (3·12–26·36) | ||
| GG | 4 (13·8%) | 93 (66·9%) | < 0·001 | 0·08 (0·02–0·26) | ||
| IL-1α | −889 | C | 39 (65·0%) | 186 (68·4%) | 0·723 | 0·86 (0·46–1·61) |
| T | 21 (35·0%) | 86 (31·6%) | 0·723 | 1·16 (0·62–2·18) | ||
| CC | 11 (36·7%) | 62 (45·6%) | 0·492 | 0·69 (0·28–1·67) | ||
| TC | 17 (56·7%) | 62 (45·6%) | 0·369 | 1·56 (0·66–3·73) | ||
| TT | 2 (6·7%) | 12 (8·8%) | 0·518 | 0·74 (0·11–3·80) | ||
| IL-1β | −511 | C | 37 (61·7%) | 154 (55·4%) | 0·456 | 1·30 (0·71–2·39) |
| T | 23 (38·3%) | 124 (44·6%) | 0·456 | 0·77 (0·42–1·42) | ||
| CC | 8 (26·7%) | 36 (25·8%) | 0·808 | 1·24 (0·46–3·26) | ||
| TC | 21 (70·0%) | 82 (59%) | 0·361 | 1·62 (0·65–4·15) | ||
| TT | 1 (3·3%) | 21 (15·2%) | 0·131 | 0·19 (0·01–1·46) | ||
| IL-1β | +3962 | C | 39 (60·0%) | 198 (70·7%) | 0·472 | 0·77 (0·41–1·45) |
| T | 21 (40·0%) | 82 (29·3%) | 0·472 | 1·30 (0·69–2·44) | ||
| CC | 11 (36·7%) | 70 (50%) | 0·260 | 0·58 (0·24–1·40) | ||
| TC | 17 (56·7%) | 58 (41·4%) | 0·186 | 1·85 (0·78–4·42) | ||
| TT | 2 (6·7%) | 12 (8·6%) | 0·536 | 0·76 (0·11–3·92) | ||
| IL-1R | Pst-I 1970 | C | 44 (73·3%) | 174 (62·1%) | 0·136 | 1·68 (0·87–3·27) |
| T | 16 (26·7%) | 106 (44·2%) | 0·136 | 0·60 (0·31–1·15) | ||
| CC | 15 (50·0%) | 54 (38·6%) | 0·341 | 1·59 (0·67–3·78) | ||
| TC | 14 (46·7%) | 66 (47·1%) | 0·876 | 0·98 (0·41–2·32) | ||
| TT | 1 (3·3%) | 20 (14·3%) | 0·129 | 0·21 (0·01–1·56) | ||
| IL-1RA | Mspa-I 11100 | C | 19 (32·8%) | 64 (22·9%) | 0·154 | 1·64 (0·85–3·17) |
| T | 39 (67·2%) | 216 (77·1%) | 0·154 | 0·61 (0·32–1·18) | ||
| CC | 2 (6·9%) | 4 (2·9%) | 0·274 | 2·52 (0·30–17·23) | ||
| CT | 15 (51·7%) | 56 (40%) | 0·338 | 1·61 (0·67–3·86) | ||
| TT | 12 (41·4%) | 80 (57·1%) | 0·178 | 0·53 (0·22–1·28) |
IL, interleukin; TNF, tumour necrosis factor; CI, confidence interval; OR, odds ratio.
The allele and genotype frequencies of IL-1α at position −889, IL-1β at positions −511 and +3962, IL-1R at position Pst-I 1970 and IL-1RA at position Mspa-I 11100 were similar in two groups of patients and controls (Table 2).
Haplotype frequencies
Interleukin-6 CA and GA haplotypes were the most frequent haplotypes in the patients (34·5% in patients versus 16·6% in controls, P = 0·003 and 12·1% in patients versus 1·4% in controls, P < 0·001 respectively), while TNF-α GA (3·4% in patients versus 21·5% in controls, P = 0·002) and IL-6 GG (32·8% in patients versus 62·2% in controls, P < 0·001) haplotypes were decreased significantly in the patients in comparison with controls (Table 3).
Table 3.
Haplotype frequencies of TNF-α and IL-6 gene polymorphisms in common variable immunodeficiency patients in comparison with normal controls.
| Cytokine | Haplotype | Patients (n = 30) N (%) | Controls (n = 140) N (%) | P-value | OR (95%CI) |
|---|---|---|---|---|---|
| TNF-α (−308, −238) | GG | 39 (67·2%) | 176 (64·2%) | 0·776 | 1·14 (0·60–2·18) |
| AG | 12 (20·7%) | 39 (14·2%) | 0·299 | 1·57 (0·72–3·40) | |
| GA | 2 (3·4%) | 59 (21·5%) | 0·002 | 0·13 (0·02–0·57) | |
| AA | 5 (8·6%) | 0 (0) | < 0·001 | – | |
| IL-6 (−174, nt565) | GG | 19 (32·8%) | 173 (62·2%) | < 0·001 | 0·30 (0·16–0·56) |
| CG | 12 (20·7%) | 55 (19·8%) | 0·981 | 1·06 (0·49–2·23) | |
| CA | 20 (34·5%) | 46 (16·6%) | 0·003 | 2·65 (1·35–5·19) | |
| GA | 7 (12·1%) | 4 (1·4%) | < 0·001 | 9·40 (2·36–39·90) |
IL, interleukin; TNF, tumour necrosis factor; CI, confidence interval; OR, odds ratio.
Genotype–phenotype association
In order to investigate the association of specific genotype/haplotype with severity of disease, the presence of some complications such as bronchiectasis and autoimmunity by different genotypes/haplotypes was analysed (Table 4). There was no significant association between the clinical phenotypes and the genotypes/haplotypes findings.
Table 4.
Comparison of some clinical manifestations of common variable immunodeficiency patients with specific genotypes/haplotypes.
| Cytokine | Haplotype/Genotype | Autoimmunity | Bronchiectasis | Splenomegaly | ||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Yes | No | P | Yes | No | P | Yes | No | P | ||
| TNF-α (−308) | AG | 3 | 12 | 0·41 | 8 | 7 | 0·72 | 6 | 9 | 0·96 |
| GG | 5 | 8 | 7 | 6 | 6 | 7 | ||||
| TNF-α (−238) | GA | 1 | 6 | 0·63 | 4 | 3 | 0·54 | 2 | 5 | 0·66 |
| GG | 7 | 15 | 11 | 11 | 10 | 12 | ||||
| TNF-α (−308, −238) | GG/GG | 5 | 7 | 0·53 | 7 | 5 | 0·45 | 6 | 6 | 0·67 |
| GG/AG | 2 | 8 | 4 | 6 | 4 | 6 | ||||
| GG/AA | 1 | 3 | 3 | 1 | 1 | 3 | ||||
| IL-6 (−174) | CC | 1 | 4 | 0·55 | 1 | 4 | 0·33 | 2 | 3 | 0·67 |
| CG | 7 | 16 | 13 | 10 | 9 | 14 | ||||
| IL-6 (nt565) | GA | 7 | 16 | 0·66 | 12 | 11 | 0·67 | 9 | 14 | 0·55 |
| GG | 1 | 3 | 2 | 2 | 2 | 2 | ||||
| IL-6 (−174, nt565) | GG/CA | 4 | 11 | 0·52 | 8 | 7 | 0·83 | 5 | 10 | 0·45 |
| CG/* | 4 | 8 | 6 | 6 | 6 | 6 | ||||
Yes, number of patients with this manifestation; No, number of patients without this manifestation; P, P-value; CG/*, CG/CA and CG/GA and CG/GG. IL, interleukin; TNF, tumour necrosis factor; CI, confidence interval; OR, odds ratio.
Discussion
Common variable immunodeficiency is a heterogeneous group of disorders with a wide variety of clinical and immunological manifestations, as well as heterogeneity of underlying mechanisms. The genetic polymorphisms of proinflammatory cytokines have been analysed in this study, and some differences were found in TNF-α and IL-6 SNPs between two groups of patients and controls. Although the functional importance of several polymorphisms is doubtful, these could suggest the involvement of other unidentified linked allelic variants in the pathogenesis of disease [26].
The TNF-α, which is an important immunoregulatory cytokine, is encoded by human leucocyte antigen class III region on chromosome 6. The uncommon TNF-α A allele at position −308 was significantly over-represented in the patient group. In contrast, the G allele, which is more frequent in the normal population, was decreased significantly in CVID patients. This finding is in agreement with a previous study by Mullighan et al.[27]. In that study 65% of patients with CVID had TNF-α G allele at position –308, while 98% of controls has this allele (P < 0·001) [27]. Although this allele was introduced as having a positive association with granulomatous disease in CVID patients [26,27], none of the patients in this study had granulomata at the time of study. However, it should be noted that accurate diagnosis of granulomata is difficult, and there might be some clinically silent lesions that were not detected until the time of study. The TNF-α genotype GG (−308) frequency in CVID patients was significantly lower than controls. Genotypes GA and AA of TNF-α (−308) are associated with higher production of TNF-α, while the GG genotype is associated with lower production of this cytokine [18,19]. Therefore, higher production of TNF-α is expected in CVID patients, considering the higher frequency of a high cytokine-producing genotype (GA) and the lower frequency of a low cytokine-producing genotype (GG) in this group of patients. This is in agreement with previous studies that indicated higher levels of this cytokine in a subgroup of CVID patients [16,28,29].
There were some significant differences in alleles, genotypes and haplotypes frequency of IL-6 gene polymorphisms. To the best of our knowledge, this is the first time that such associations have been found between these polymorphisms and CVID. Considering the important role of IL-6 in host defence, the alteration of this cytokine could be important in CVID. IL-6 CC (−174) and GA (nt565) were significantly over-represented in the patient group, while IL-6 GG genotypes at both positions −174 and nt565 were decreased significantly in the patient group. IL-6 GG and GC genotypes (−174) are associated with higher production of IL-6, whereas the CC genotype leads to lower production of this cytokine [18]. Although, based on these results, decreased production of IL-6 is expected in some CVID patients, it is in contrast with previous studies that show normal or insignificantly increased levels of this cytokine in CVID [16,30]. IL-6 CA and GA haplotypes (−174, nt565) were also over-represented in CVID patients, while the IL-6 GG haplotype was decreased significantly.
There was no significant difference in allele and genotype frequencies of IL-1α (−889), IL-1β (−511 and +3962), IL-1R (Pst-I 1970) and IL-1RA (Mspa-I 11100) between two groups of patients and controls. These results are in contrast with a previous study, which indicated a significant association between IL-1α and CVID [26]. Mullighan et al. showed a decreased frequency of the IL-1α T allele at position of −889 in their CVID patients. It should be noted that there was no significant difference in the frequency of this allele between our study and this study (35% versus 46%, P = 0·21), whereas this allele was over-represented significantly in their control group (32% versus 61%, P < 0·001) [26]. Although SNPs can affect the production of IL-1 [18], there is no evidence of alteration of this cytokine in CVID.
While we did not find any association between IL-1 cytokines and CVID, some polymorphisms in IL-6 and TNF-α proinflammatory cytokines were over-represented in CVID patients. High production of TNF-α is expected in some CVID patients, based on the frequency of genotypes/haplotypes of these cytokine gene polymorphisms. However, further studies are needed to test the association between cytokine gene polymorphisms and immunological phenomena in this group of patients.
Acknowledgments
This research was supported by the Tehran University of Medical Sciences and Health Services grant 4305-30-04-85. The authors are very grateful to all colleagues in the Department of Allergy and Clinical Immunology of Children's Medical Center Hospital and the Immunogenetic Laboratory of Department of Immunology, School of Medicine, Tehran University of Medical Sciences for their kind help and advice in the laboratory, and all the patients and their families for their kind collaboration in this study.
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