Association of interleukin 22 gene polymorphisms and serum IL‐22 level with risk of systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association between the single‐nucleotide polymorphisms (SNPs) of the interleukin 22 (IL‐22) gene and systemic lupus erythematosus (SLE) in a Chinese population. Three IL‐22 SNPs (rs2227485, rs2227513 and rs2227491) were genotyped using SNaPshot SNP genotyping assays and identified by sequencing in 314 SLE patients and 411 healthy controls. The IL‐22 level of serum was assessed by enzyme‐linked immunosorbent assay (ELISA) kits. Data were analysed by spss version 17.0 software. We found that rs2227513 was associated with an increased risk of SLE [AG versus AA: adjusted odds ratio (aOR) = 2·24, 95% confidence interval (CI) = 1·22–4·12, P = 0·010; G versus· A: adjusted OR = 2·18, 95% CI = 1·20‐3·97, P = 0·011]. Further analysis in patients with SLE showed that the AG genotype and G allele were associated with an increased risk of renal disorder in SLE (G versus A: aOR = 3·09, 95% CI = 1·30–7·33, P = 0·011; AG versus· AA: aOR = 3·25, 95% CI = 1·35–7·85, P = 0·009). In addition, the concentration of IL‐22 was significantly lower in the rs2227513 AG genotype compared with AA genotype (P = 0·028). These results suggest that rs2227513 polymorphism might contribute to SLE susceptibility, probably by decreasing the expression of IL‐22.     

Identification of susceptibility SNPs in CTLA-4 and PTPN22 for scleritis in Han Chinese

The aim of this study was to determine the association between 13 single nucleotide polymorphisms (SNPs) in the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes with scleritis in a Chinese Han population. We recruited 432 scleritis patients and 710 healthy controls. Four tag SNPs of CTLA4 and nine tag SNPs of PTPN22 were selected using Haploview. Genotyping was performed with the Sequenom MassArray® iPLEX GOLD Assay. Genotype and allele frequency differences were analyzed by χ² test and Bonferroni correction. Haplotype analysis was performed to further evaluate the association of these two genes with scleritis. In this study, CTLA4/rs3087243 G allele frequency and GG genotype frequency were significantly increased in scleritis patients compared to healthy controls [corrected P-value (Pc) = 0·02, odds ratio (OR) = 1·475, 95% confidence interval (CI) = 1·175–1·851; Pc = 0·04, OR = 1·546, 95% CI = 1·190–2·008, respectively]. None of the tested SNPs in the PTPN22 gene showed an association with scleritis. Haplotype analysis revealed a lower frequency of a CTLA4 TCAA haplotype (order of SNPs: rs733618, rs5742909, rs231775, rs3087243) (Pc = 4·26 × 10^–3, OR = 0·618, 95% CI = 0·540–0·858) and a higher frequency of a PTPN22 TTATACGCG haplotype (order of SNPs: rs3789604, rs150426536, rs1746853, rs1217403, rs1217406, rs3789609, rs1217414, rs3789612, rs2488457) (Pc = 2·83 × 10^–4, OR = 1·457, 95% CI = 1·210-1·754) in scleritis patients when compared to healthy controls. In conclusion, our findings indicate that CTLA4 and PTPN22 might confer genetic susceptibility to scleritis in a Chinese Han population.     

Serum immunoglobulin G antibody titer to Fusobacterium nucleatum is associated with unfavorable outcome after stroke

Stroke can be a cause of death, while in non-fatal cases it is a common cause of various disabilities resulting from associated brain damage. However, whether a specific periodontal pathogen is associated with increased risk of unfavorable outcome after stroke remains unknown. We examined risk factors for unfavorable outcome following stroke occurrence, including serum antibody titers to periodontal pathogens. The enrolled cohort included 534 patients who had experienced an acute stroke, who were divided into favorable (n = 337) and unfavorable (n = 197) outcome groups according to modified ranking scale (mRS) score determined at 3 months after onset (favorable = score 0 or 1; unfavorable = score 2–6). The associations of risk factors with unfavorable outcome, including serum titers of IgG antibodies to 16 periodontal pathogens, were examined. Logistic regression analysis showed that the initial National Institutes of Health stroke scale score [odds ratio (OR) = 1·24, 95% confidence interval (CI) = 1·18–1·31, P < 0·001] and C-reactive protein (OR = 1·29, 95% CI = 1·10–1·51, P = 0·002) were independently associated with unfavorable outcome after stroke. Following adjustment with those, detection of the antibody for Fusobacterium nucleatum ATCC 10953 in serum remained an independent predictor of unfavorable outcome (OR = 3·12, 95% CI = 1·55–6·29, P = 0·002). Determination of the antibody titer to F. nucleatum ATCC 10953 in serum may be useful as a predictor of unfavorable outcome after stroke.     

Association of single nucleotide polymorphisms in TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 with the risk of nonsyndromic cleft lip with or without cleft palate in a sample of the Iranian population,a preliminary report

Several lines of evidence support an association between tropomyosin 1 (TPM1) and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present study aimed to investigate the association between TPM1 polymorphisms and the risk of NSCL/P in an Iranian population. This case‐control was done on 105 NSCL/P patients and 110 unrelated healthy controls. TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 polymorphisms were genotyped by the polymerase chain reaction‐restriction fragment length polymorphism method. The finding showed that rs11071720 polymorphism significantly increased the risk of NSCL/P in homozygous codominant (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.14–5.69, p = 0.023, TT vs. CC), recessive (OR = 2.33, 95% CI = 1.06–5.18, p = 0.021, TT vs. CT + CC), and allele (OR = 1.53, 95% CI = 1.02–2.30, p = 0.030, T vs. C). The rs12148828 polymorphism was associated with protection against NSCL/P in codominant (OR = 0.27, 95% CI = 0.15–0.48, p < 0.001, TC vs. TT) and allele (OR = 0.38, 95% CI = 0.22–0.64, p < 0.001, C vs. T). Regarding rs3803499, the findings proposed that this polymorphism significantly increased the risk of NSCL/P in codominant (OR = 3.86, 95% CI = 1.19–12.56, p = 0.025, CC vs. TT) and recessive (OR = 3.74, 95% CI = 1.09–14.15, p = 0.018, CC vs. CT + TT). No significant association was practical between rs1972041 polymorphism and NSCL/P. In conclusion, the findings proposed that TPM1 polymorphisms may contribute to the etiology of NSCL/P in a sample of the Iranian population.     

Association of PTPN22+1858C/T polymorphism with Type 1 diabetes in the North Indian population

A nonsynonymous SNP +1858C/T (rs2476601) in the protein tyrosine phosphatase, nonreceptor type 22(PTPN22) gene leading to Arg 620 Trp substitution is known to be associated with susceptibility to type 1 diabetes (T1D) and several other autoimmune diseases. We studied this polymorphism in 145 T1D patients and 210 healthy controls from North India. The minor allele +1858T was observed to be significantly increased among patients as compared to healthy controls (2.76% vs 0.5%, P = 0.027, OR = 5.93; 95% CI = 1.4–24.8). The association was also observed at the level of heterozygous C/T genotype (5.5% vs 0.95%, P = 0.026, OR = 6.07; 95% CI = 1.43–25.6). The T allele and C/T genotype were predominantly found among patients who were positive for both glutamic acid decarboxylase 65 (GAD65) and insulin antigen 2 (IA2) autoantibodies and showed significantly increased frequencies (10%, P = 0.034, OR = 11.67; 95% CI = 1.58–84.1 and 20%, P = 0.031, OR = 13.0; 95% CI = 1.66–97.5, respectively) as compared to patients negative for these autoantibodies (0.95% and 1.9%, respectively). The results suggest that the PTPN22+1858T allele is positively associated with T1D in the North Indian population.     

Serum sCD40L levels are increased in patients with psoriatic arthritis and are associated with clinical response to apremilast

The pathogenesis of psoriatic arthritis (PsA) involves several pathways, including the CD40/CD40L signaling which promotes the release of multiple cytokines. Transmembrane CD40L is also released in soluble form (sCD40L) and phosphodiesterase 4 (PDE4) seems to be involved in its cleavage. We aimed to investigate whether apremilast, a PDE4 inhibitor, could modify circulating levels of sCD40L in PsA patients, and the possible associations of these changes with clinical response. Consecutive PsA patients starting apremilast in routine clinical practice were prospectively observed. Disease Activity of Psoriatic Arthritis (DAPSA), Psoriasis Area Severity Index (PASI), Leeds Enthesitis Score (LEI) and serum samples were collected at baseline and at 6 months. Samples were run in a Bio-Plex ProTM plate for sCD40L. To investigate the association of sCD40L level with DAPSA based minor response, low disease activity (LDA) and/or remission at 6 months of treatment, multivariate logistic regression models with backward selection (P < 0·05) were built. We studied 27 patients (16 of 27 women, 59·6%) with PsA and mean age [± standard deviation (s.d.)] of 58·4 ± 10 years. A significant reduction of the mean values of DAPSA, LEI and PASI was detected at 6 months. Mean serum levels of sCD40L decreased from baseline 5364 ± 2025 pg/ml to 4412 ± 2629 at 6 months (P = 0·01). Baseline DAPSA [odds ratio (OR) = 0·80, 95% confidence interval (CI) = 0·65–0·98] and sCD40L (OR = 1·001, 95% CI = 1·0001–1·0027) were independently associated with DAPSA LDA/remission at 6 months. In PsA patients, sCD40L levels decrease upon apremilast treatment and might predict short-term clinical response to apremilast.     

Helicobacter pylori infection in patients with selective immunoglobulin a deficiency

Selective immunoglobulin A (IgA) deficiency (IgAD) is the most common primary immunodeficiency in the western world. The aim of the study was to investigate the prevalence and clinical characteristics of Helicobacter pylori‐infected dyspeptic patients with IgAD. Case samples were drawn from all subjects ≥ 12 years of age (n = 104729) who had undergone serum total IgA measurements during 2004–14 for any reason at Leumit Healthcare Services (Israel) and had serum total IgA < 0·07 g/l. The control group was comprised of a random sample of remaining patients with a case–control ratio of 10 controls for each case. The dyspeptic diseases were identified and retrieved from Leumit Health Care Services electronic database using specific ICD‐9‐CM diagnostic codes. The case group included 347 subjects and the control group 3470 subjects. There were no significant differences in the prevalence of patients with dyspepsia [84 (24·2%) versus 821 (23·6%) for cases and controls, respectively]. Additionally, there was no difference in a proportion of dyspeptic H. pylori‐positive subjects [59 (17·1%) versus 524 (15·1%)] between the case and control groups. Only 59 (17%) among the 347 IgAD patients underwent gastroscopy. A significantly larger proportion of case subjects experienced several forms of gastritis [13 (61·9%) versus 38 (21·6%), P < 0·001), duodenal ulcers [seven (33·3%) versus 19 (10·8%); P = 0·01] and nodular lymphoid hyperplasia (NLH) [two (9·5%) versus none; P = 0·011]. IgAD is not associated with increased prevalence of H. pylori‐associated dyspepsia; nevertheless, H. pylori‐infected dyspeptic IgAD subjects experience more EGD‐proved gastritis, duodenal ulcers and NLH.     

Association of IL‐1β +3954 C/T and IL‐10‐1082 G/A Cytokine Gene Polymorphisms with Susceptibility to Tuberculosis

Tuberculosis (TB) constitutes the major cause of death due to infectious diseases. Cytokines play a major role in defence against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Household contacts (HHC) are at increased risk of developing the disease. In this study, we examined the association of IL‐1β and IL‐10 cytokine gene polymorphisms with risk of developing tuberculosis in TB patients, their HHC and healthy controls (HC) using JavaStat and SPSS. Multifactor dimensionality reduction (MDR) analyses were performed to explore the potential gene–gene interactions. The genotype and allele frequencies of IL‐1β +3954C/T polymorphism did not vary significantly between TB patients and HC. GG (P < 0.005, OR = 0.219 and 95% CI = 0.059–0.735) and GA (P < 0.0001, OR = 2.938 and 95% CI = 1.526–5.696) genotypes of IL‐10‐1082 G/A polymorphism were found to be significantly associated with patients versus HC. HHC with CC (P < 0.03, OR = 1.833 and 95% CI = 1.1–3.35) genotype in IL‐1β and GA (P < 0.0001, OR = 4.612 and 95% CI = 2.225–9.702) genotype in IL‐10 were at increased risk of developing tuberculosis. MDR tests revealed high‐risk genotypes in IL‐1β and IL‐10 based on the association model. Our results demonstrate that the polymorphisms of IL‐1β and IL‐10 genes may be valuable markers to predict the risk for the development of TB in household contacts.     

HLA class II allele polymorphism in an outbreak of chikungunya fever in Middle Andaman,India

A sudden upsurge of fever cases with joint pain was observed in the outpatient department, Community Health Centre, Rangat during July–August 2010 in Rangat Middle Andaman, India. The aetiological agent responsible for the outbreak was identified as chikungunya virus (CHIKV), by using RT‐PCR and IgM ELISA. The study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. One hundred and one patients with clinical features suggestive of CHIKV infection and 104 healthy subjects were included in the study. DNA was extracted and typed for HLA‐DRB1 and DQB1 alleles. Based on the amino acid sequences of HLA‐DQB1 retrieved from the IMGT/HLA database, critical amino acid differences in the specific peptide‐binding pockets of HLA‐DQB1 molecules were investigated. The frequencies of HLA‐DRB1 alleles were not significantly different, whereas lower frequency of HLA‐DQB1*03:03 was observed in CHIKV patients compared with the control population [P = 0·001, corrected P = 0·024; odds ratio (OR)  = 0, 95% confidence interval (95% CI) 0·0–0·331; Peto's OR = 0·1317, 95% CI 0·0428–0·405). Significantly lower frequency of glutamic acid at position 86 of peptide‐binding pocket 1 coding HLA‐DQB1 genotypes was observed in CHIKV patients compared with healthy controls (P = 0·004, OR = 0·307, 95% CI 0·125–0·707). Computational binding predictions of CD4 epitopes of CHIKV by NetMHCII revealed that HLA‐DQ molecules are known to bind more CHIKV peptides than HLA‐DRB1 molecules. The results suggest that HLA‐DQB1 alleles and critical amino acid differences in the peptide‐binding pockets of HLA‐DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV.     

Association of NKG2D gene variants with susceptibility and severity of rheumatoid arthritis

NKG2D (KLRK1) is a C‐type lectin receptor present on natural killer (NK) cells, γδ, CD8⁺ and CD4⁺ T cells. Upon ligand binding, NKG2D mediates activatory and co‐stimulatory signals to NK cells and activated CD4⁺ T cells, respectively. Polymorphisms in NKG2D predispose to infectious diseases, cancer, transplantation and autoimmune disorders. We studied the influence of this NK receptor polymorphism on predisposition to and modification of the disease phenotype in patients with rheumatoid arthritis (RA). Eight different single nucleotide polymorphisms (SNP) in the NKG2 gene were genotyped in 236 patients with RA and 187 controls using Taqman 5' nuclease assays. NKG2D genotype/allele frequency did not differ between patients and controls. Subgroup analysis showed that the frequency of A allele of NKG2D9 and T allele of NKG2D10 was significantly higher in patients with deformities (a marker of severe disease) [11 versus 5%, Pc = 0·03, odds ratio (OR) = 2·44, 95% confidence interval (CI) = 1·09‐5·98 and 10 versus 4%, Pc = 0·04, OR = 2·45, 95% CI = 1·05‐6·39, respectively], while the frequency of alleles G of NKG2D9 and A of NKG2D10 was greater in patients without deformities (Pc = 0·03, OR = 0·41, 95% CI = 0·17‐0·91 and Pc = 0·04, OR = 0·41, 95% CI = 0·16‐0·96). Similar trends of association were observed with deforming phenotype of RA in female patients and deforming young onset RA subgroups. Haplotype analysis revealed that the frequency of haplotype G‐C‐A‐G‐A‐T‐C‐C was higher in patients than in controls (12 versus 8%, P = 0·04, OR = 1·61, 95% CI = 1·01‐2·55), suggesting that it may predispose to RA. Our study suggests that the NKG2D gene polymorphisms may modify the risk of development and severity of RA.     

SNP/haplotype associations of CCR2 and CCR5 genes with severity of chagasic cardiomyopathy

Background

Chronic inflammation plays a major role in the tissue injury seen in the chronic chagasic cardiomyopathy. The CCR2 and CCR5 chemokine receptors are involved with the type of cellular infiltrate present in cardiac tissue and CCR5-gene variants were previously associated with this pathology.

Methods and results

This is a replication study in an independent cohort with larger sample size. Nine SNPs of CCR5 and CCR2 were typified to confirm the association previously found with Chagas disease. Evidence of association with severity was found for the A allele of rs1799864 of CCR2 (p_ad = 0.02; OR = 1.91, 95% CI = 1.10–3.30), the T allele of the rs1800024 of CCR5 (p_ad = 0.01; OR = 1.95, 95% CI = 1.13–3.38), and the HHF^∗2 haplotype (p = 0.03, OR = 1.65, 95% CI = 1.03–2.65). These results were replicated in the study combined with previous data. In this analysis it was replicated the allele T of rs2734648 (p_ad = 0.009, OR = 0.52, 95% CI = 0.32–0.85) with protection. In addition, the allele G of rs1800023 (p_ad = 0.043, OR = 0.61, 95% CI = 0.38–0.98), and the HHC haplotype (p = 0.004, OR = 0.62, 95% CI = 0.44–0.86) were also associated with protection. In contrast, the allele A of rs1799864 of CCR2 (p_ad = 0.009; OR = 1.90, 95% CI = 1.17–3.08); and the allele T of rs1800024 of CCR5 (p_ad = 0.005, OR = 1.98, 95% CI = 1.22–3.23) were associated with greater severity. No evidence of association between symptomatic and asymptomatic patients was observed.

Conclusions

These results confirm that variants of CCR5 and CCR2 genes and their haplotypes are associated with the severity but not with susceptibility to develop chagasic cardiomyopathy.     

IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL‐1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence‐specific primers (PCR‐SSP). IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 were evaluated for SNP study. The frequency of the IL‐1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385–0.886; P‐value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176–2.111; P‐value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047–0.484; P‐value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL‐1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.     

Anti‐C1q autoantibodies are linked to autoimmune thyroid disorders in pregnant women

Anti‐C1q antibodies (anti‐C1q) have been implicated in the pathogenesis of autoimmune diseases, including autoimmune thyroid disorders (AITD). The aim of this study was to evaluate the association between anti‐C1q and thyroid function in pregnancy‐associated AITD. In 96 pregnant women screened positive for AITD (thyroid dysfunction and/or antibodies against thyroperoxidase – TPOAb), anti‐C1q were measured during the 9‐11th gestational week and after delivery (median 16 months after delivery), and compared to the corresponding serum levels of thyroid hormones. As controls, 80 healthy pregnant women, 72 non‐pregnant AITD patients and 72 blood donors were included. In the non‐pregnant AITD group, two serum samples ≥ 6 months apart were analysed. Compared to blood donors, anti‐C1q levels were substantially higher in all pregnant women analysed. In pregnancy, anti‐C1q levels were higher in the TPOAb‐positive women than in controls (37 versus 17·5%, P < 0·0001). Anti‐C1q‐positive pregnant women screened positive for AITD had higher thyroid‐stimulating hormone (TSH) levels than anti‐C1q‐negative women (2·41 versus 1·94 mU/l, P = 0·01), and TSH correlated positively with anti‐C1q (r = 0·226, P = 0·045) in the TPOAb‐positive women. After delivery, serum levels of anti‐C1q decreased in the positively screened TPOAb‐negative women (8·8 versus 5·9 U/l, P = 0·002), but not in the TPOAb‐positive ones, and they no longer correlated with TSH. Anti‐C1q antibody levels increase during pregnancy in general and even more in the context of AITD, where they correlate with thyroid stimulating hormone levels.     

Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren

During a 15‐year period, the incidence of type 1 diabetes has doubled in Lithuania, while increasing by a third in England; however, England still has a higher incidence. Analysis of sera collected from non‐diabetic schoolchildren from Lithuania and England more than 20 years ago showed a similar number of multiple autoantibody‐positive schoolchildren between the populations, but a higher prevalence of islet antigen‐2 autoantibodies (IA‐2A) in English schoolchildren. We aimed to use recently developed, more specific islet autoantibody tests to characterize differences in humoral autoimmunity between these two general population cohorts in greater detail. Samples from 88 Lithuanian and 133 English schoolchildren previously found islet autoantibody‐positive were selected for measurement of additional islet autoantibodies by radioimmunoassay. Samples were tested for autoantibodies to zinc transporter 8 (ZnT8A), GAD (96–585), the protein tyrosine phosphatase region of islet antigen‐2 (PTPA) and the related IA‐2βA, while autoantibodies to IA‐2A were reassayed using the current harmonized method. IA‐2‐related autoantibodies PTPA (0·13 versus 0·45%, P = 0·027) and IA‐2βA (0 versus 0·35%, P < 0·001), but not IA‐2A measured using the harmonized method, were less common in Lithuanian compared to English schoolchildren. Lithuanian schoolchildren who were islet autoantibody‐positive were positive for fewer biochemical autoantibodies compared with English schoolchildren (P = 0·043). Background rates of islet autoimmunity in childhood differ subtly between countries, which have different incidences of type 1 diabetes. The optimal screening strategy (age and combination of markers) for detection of islet autoimmunity may vary between countries, dependent upon the pattern of autoantibodies found in the general population.     

Bronchiectasis and deteriorating lung function in agammaglobulinaemia despite immunoglobulin replacement therapy

Immunoglobulin replacement therapy enhances survival and reduces infection risk in patients with agammaglobulinaemia. We hypothesized that despite regular immunoglobulin therapy, some patients will experience ongoing respiratory infections and develop progressive bronchiectasis with deteriorating lung function. One hundred and thirty‐nine (70%) of 199 patients aged 1–80 years from nine cities in the United Kingdom with agammaglobulinaemia currently listed on the UK Primary Immune Deficiency (UKPID) registry were recruited into this retrospective case study and their clinical and laboratory features analysed; 94% were male, 78% of whom had Bruton tyrosine kinase (BTK) gene mutations. All patients were on immunoglobulin replacement therapy and 52% had commenced therapy by the time they were 2 years old. Sixty per cent were also taking prophylactic oral antibiotics; 56% of patients had radiological evidence of bronchiectasis, which developed between the ages of 7 and 45 years. Multivariate analysis showed that three factors were associated significantly with bronchiectasis: reaching 18 years old [relative risk (RR) = 14·2, 95% confidence interval (CI) = 2·7–74·6], history of pneumonia (RR = 3·9, 95% CI = 1·1–13·8) and intravenous immunoglobulin (IVIG) rather than subcutaneous immunoglobulin (SCIG) = (RR = 3·5, 95% CI = 1·2–10·1), while starting immunoglobulin replacement after reaching 2 years of age, gender and recent serum IgG concentration were not associated significantly. Independent of age, patients with bronchiectasis had significantly poorer lung function [predicted forced expiratory volume in 1 s 74% (50–91)] than those without this complication [92% (84–101)] (P < 0·001). We conclude that despite immunoglobulin replacement therapy, many patients with agammaglobulinaemia can develop chronic lung disease and progressive impairment of lung function.     

BOS is associated with decreased HDAC2 from steroid resistant lymphocytes in the small airways

Immunosuppression therapies including corticosteroids fail to prevent bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways, following lung transplantation. We reported increases in steroid-resistant proinflammatory lymphocytes and their loss of histone deacetylase 2 (HDAC2), an important mediator of steroid action, in the blood of stable lung transplant recipients. We noted similar increases in the steroid-resistant lymphocytes in both the blood and small airways in BOS compared with the large airways. We hypothesized that these small airway cells would also exhibit a loss of HDAC2, and that these changes could be reversed by treatment with theophylline (HDAC2 activator). Blood, bronchoalveolar lavage and large and small airway brushings were collected from lung transplant patients with BOS (n = 12) or stable lung function (n = 18) and healthy aged-matched controls (n = 13). Intracellular proinflammatory cytokines [interferon (IFN-γ) and tumour necrosis factor (TNF)-α and HDAC2 were measured in CD8⁺ T, natural killer (NK) T-like and NK cells from cultured small airway brushings ± 5 mg/l theophylline ± 1 µM prednisolone using flow cytometry. Increased small airway CD8 T, NK T-like and NK cells were identified in BOS versus stable transplant and controls. In BOS, these cells exhibited increased IFN-γ/TNF-α and a loss of HDAC2. HDAC2 expression by small airway CD8⁺ T cells correlated with forced expiratory volume in 1 s (FEV₁) (R = 0·880, P = 0·031). Theophylline and prednisolone synergistically up-regulated HDAC2 in CD8⁺ T cells. BOS is associated with loss of HDAC2 from steroid-resistant proinflammatory CD8⁺ T, NK T-like and NK cells in the small airways. Therapeutically increasing HDAC2 in these lymphocytes may reduce steroid resistance and improve graft survival.     

Predictors and moderators of outcome in different brief interventions for smoking cessation in general medical practice

Objective

To explore demographic-, health-, and smoking-related predictors and moderators of outcome in smokers who participated in two different brief smoking cessation interventions.

Methods

Data were acquired using a quasi-randomized controlled trial that tested the efficacy of computer-generated tailored letters and physician-delivered brief advice against assessment only. Daily smokers (n = 1499) were recruited from 34 general medical practices. We used Generalized Estimating Equation analyses to investigate the relationship between 6-month prolonged smoking abstinence assessed at 12-, 18-, and 24-month follow-ups and potential predictors and moderators.

Results

Female gender (OR = 1.49, 95% CI = 1.01–2.19), higher level of education (OR = 1.82, 95% CI = 1.18–2.82), intention to quit smoking (OR = 1.66, 95% CI = 1.16–2.38), and smoking cessation self-efficacy (OR = 1.30, 95% CI = 1.03–1.64) were positively, nicotine dependence (OR = 0.84, 95% CI = 0.76–0.94) and the presence of a smoking partner (OR = 0.60, 95% CI = 0.42–0.85) were negatively associated with smoking abstinence. Compared to assessment only, physician advice was less effective for people without an intention to quit smoking and for unemployed.

Conclusion

Smoking cessation interventions might be improved by tailoring them to demographic- and smoking-related variables which were identified as predictors in this study.

Practice implications

The results suggest that tailored letters are a more universally applicable brief intervention in general medical practice than physician advice.     

Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer

Numerous enzymes, including Cytochrome P450s (phase I) and Glutathione-S-transferases (phase II), are involved in the metabolic activation and detoxification of carcinogens. Epidemiological studies have consistently demonstrated that bladder cancer is strongly associated with cigarette smoking, and the risk for the development of this neoplasia may be modified by individual differences in carcinogen-metabolizing genes. We investigated the relationship between polymorphisms in the CYP1A1, GSTM1, GSTT1, and GSTP1 genes in a case–control study with 100 bladder cancer patients and 100 controls matched for age, gender, race, and smoking status. The GSTM1, GSTT1, CYP1A1 (A2455→G), and GSTP1 (A313→G) genotypes were determined using a multiplex PCR, an allele specific PCR, and a restriction fragment length polymorphism-PCR method. The present case–controlled association study did not detect any positive or negative association for the GSTM1 and GSTP1 genes [odds ratios (OR) = 1.35; 95% confidence interval (CI) = 0.76–2.41 and OR = 0.75; 95% CI = 0.41–1.38, respectively]. Notably, the genes GSTT1 and CYP1A1 exhibited a statistically significant association with bladder cancer (OR = 1.77; 95% CI = 1.01–3.12 and OR = 1.99; 95% CI = 1.07–3.73). No differences for GSTM1 and GSTP1 genotype prevalence between the bladder cancer cases and the controls were observed, however, the null genotype for the GSTT1 gene and the A/G and G/G variants of the CYP1A1 gene may contribute to the development of bladder cancer.     

Genetic polymorphisms of glutathione S-transferase T1 and bladder cancer risk: a meta-analysis

In recent years, there have been numerous papers emphasizing the relationship between Glutathione S-transferases polymorphisms and bladder cancer risk, but the findings have not reached a consensus. The relationship between glutathione S-transferase T 1 null genotype and bladder cancer susceptibility is now even more disputable. Therefore, we present a meta-analysis of (nested) case–controlled, genotype-based studies (including 37 studies, 6,986 cases and 9,166 controls) examining this association. Using a fixed-effect model, statistically significant increase was observed between glutathione S-transferase T 1 deletion and bladder cancer risk for the overall studies (OR = 1.12; 95% confidence interval (CI): 1.04–1.21; P = 0.004 for Z test; I ² = 47.43 for heterogeneity). After adjusting the result using trim-and-fill method, the outcome still had significant difference with little downgrade (OR = 1.10, 95% CI = 1.02–1.18). Three potential sources of heterogeneity including ethnicity, source of control and smoking status were also assessed. Minor increased correlation was found only in population-based studies (OR = 1.16; 95% CI = 1.03–1.30; I ² = 47.16). Our analysis suggests that glutathione S-transferase T 1 null status is associated with a modest increase in the risk of bladder cancer and the difference exiting in source of control has been confirmed. Due to limited sample size, various confounding variables as well as discrepancy in study design, a valid conclusion still cannot be confirmed.     

The association of CTLA‐4 A49G polymorphism with colorectal cancer risk in a Chinese Han population

Cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) is expressed in T cells and plays an important role in the regulation of T cell. CTLA‐4 has long been considered to be associated with various kinds of diseases. With the attempt to examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk in a Chinese Han population, we employed TaqMan assay to genotype the CTLA‐4 A49G polymorphism in 311 colorectal cancer cases and 389 cancer‐free controls. We found evidence of the association between CTLA‐4 A49G polymorphism and colorectal cancer risk (GG vs. AA: OR = 2.01, 95% CI = 1.29–3.07, P = 0.002; GA vs. AA: OR = 2.32, 95% CI = 1.53–3.57, P = 0.001; GA + GG vs. AA: OR = 2.16, 95% CI = 1.46–3.21, P = 0.001). Next, we performed a meta‐analysis to comprehensively examine the association between CTLA‐4 A49G polymorphism and colorectal cancer risk. We found a significant association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Asians, which is consistent with our result. However, we found no evidence for the association between CTLA‐4 A49G polymorphism and colorectal cancer risk among Caucasians. In conclusion, we demonstrated that the CTLA‐4 A49G polymorphism increased the susceptibility of colorectal cancer in Asian population.