Association of interleukin‐18 promoter polymorphisms with chronic obstructive pulmonary disease in male smokers

Chronic obstructive pulmonary disease (COPD) is considered a complex genetic disorder and it is expected that many genes play a role in the pathogenesis of this disease. Previous studies have reported that several variations within the interleukin (IL)‐18 gene promoter region have been associated with different inflammatory diseases such as asthma. However, the association of IL‐18 promoter polymorphisms with COPD has not been studied yet. We then performed a prospective case–control study to explore this association in male smokers of Chinese Han people. Our study recruited 112 COPD cases and 105 healthy controls matched for age. The genotyping of IL‐18 promoter polymorphisms (‐607 C/A and ‐137 G/C) was performed using TaqMan single nucleotide polymorphism genotyping assays. The frequencies of the alleles and genotypes in patients and controls were compared. We found that the frequency of IL‐18 ‐607 C allele was significantly increased in patients with COPD (odds ratio (OR) = 1.48, 95% confidence interval (CI) = 1.01–2.15, P = 0.04). The frequency of IL‐18 ‐607 C allele was significantly higher in the GOLD (Global initiative for Obstructive Lung Disease) 3–4 group compared with the GOLD 1–2 group (OR=2.06, 95% CI = 1.21–3.51, P = 0.01). There were no significant differences in the frequencies of the alleles and genotypes of IL‐18 ‐137 G/C polymorphism between the patients and healthy smokers or between GOLD 3–4 group and GOLD 1–2 group. Our study revealed that the IL‐18 ‐607 C/A polymorphism was associated with COPD susceptibility and severity of airflow limitation in male smokers of Chinese Han people.     

Association of Interleukin-10 promoter polymorphisms with neurosyphilis

Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine. Increased production of IL-10 has been found in late syphilis, presumably creating favorable conditions for bacteria persistence. Single-nucleotide polymorphisms (SNPs) within the promoter of IL-10 gene have been found to influence IL-10 production. We investigated whether SNPs in the IL-10 gene promoter are associated with cerebrospinal fluid (CSF) levels of IL-10 and neurosyphilis.Polymorphisms in the gene for IL-10 (G → A mutation at the position −1084 and C → A mutation at the position −592) were sought in 35 patients with syphilis and 24 healthy volunteers. CSF examination (i.e. routine laboratory tests and IL-10 levels) was performed in all syphilis patients. Neurosyphilis was defined as reactive CSF VDRL test or CSF white blood cells ⩾ 5/μL and CSF protein concentration ⩾ 45 mg/dL.Overall, 31% of patients with syphilis had neurosyphilis. CSF IL-10 levels were significantly higher in patients with neurosyphilis when compared to those with syphilis but not neurosyphilis. −1082 GG and −592 CC genotypes were significantly associated with higher CSF IL-10 levels. Moreover, these genotypes were found to be more frequent in individuals with neurosyphilis in comparison to those without neurosyphilis.Anti-inflammatory immune response seems to be important in pathogenesis of neurosyphilis. Our data suggest that host-related factors, such as SNPs of immune regulatory genes may influence the susceptibility to neurosyphilis.     

Association between an interleukin‐13 promoter polymorphism and atopy

Several studies indicate genetic involvement of Th2 cytokines in allergic diseases. Interleukin (IL)‐13 has been mapped to the cytokine cluster on chromosome 5q31–33, which has been associated with atopic conditions. Recently, an association was reported between the T allele in a promoter polymorphism in the IL‐13 gene (C to T exchange) at position ?1055 and allergic asthma in a population study in the Netherlands. This observation was apparently confirmed in a case–control study using probands and spouses from a Dutch asthma family study, but the polymorphism in that study was reported to occur at position ?1111. In the present study, we established that this polymorphism is located at position ?1024 relative to the ATG translation initiation codon, and investigated whether it confers a genetic predisposition to atopic conditions and the Th1 condition multiple sclerosis (MS) in Caucasian subjects. We confirmed the association between the IL‐13 ?1024TT genoype and inhalation allergy (P = 2.4E‐02). By combining the data from the three studies, we demonstrated a strong association (P = 1.09E‐05) between the IL‐13 ?1024 marker and inhalation allergy. Furthermore, we showed for the first time that this association also exists in atopic dermatitis (P = 2.0E‐02). No association with MS was found.     

Association of IL10 promoter polymorphisms with idiopathic achalasia

Idiopathic achalasia is an esophageal motor disorder of unknown etiology. A wealth of evidence supports the concept that achalasia is an immune-mediated disease. According to this evidence, achalasia has been significantly associated with specific alleles of the human leukocyte antigen class II, PTPN22 and IL23R. Several studies have demonstrated association of the IL10 gene with different inflammatory disorders. Our aim was to evaluate the role of functional IL10 promoter polymorphisms in susceptibility to idiopathic achalasia. A case-control study was performed with the -1082, -819, and -592 IL10 promoter polymorphisms in 282 patients and 529 controls and in an independent replication set of 75 patients and 575 controls. The GCC haplotype of the IL10 promoter was reported to be associated with a lower risk of achalasia in the discovery sample (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p = 0.029). This association was validated in a replication set (OR = 0.69, 95% CI = 0.48-1.00, p = 0.04). In the combined analysis no heterogeneity was observed between the 2 sample sets and the GCC haplotype was significantly associated with the disease (OR(MH) = 0.76, 95% CI = 0.63-0.91, p = 0.003). Our results provide the first evidence for an association between IL10 promoter polymorphisms and idiopathic achalasia, suggesting that the interleukin-10 cytokine may contribute to the pathogenesis of this disease.     

Association of interleukin‐16 polymorphisms with disease progression and susceptibility in endometriosis

Interleukin‐16 (IL‐16) is a multifunctional pro‐inflammatory cytokine that was previously found in association with complex disorders, and it is now cleared that this cytokine plays a critical role in regulation of cellular functions such as homoeostasis. Due to the complexity of endometriosis and its resemblance to cancer, we designed present case–control study to determine the effects of genetic polymorphisms of the human IL‐16 gene on Iranian women's susceptibility to endometriosis. A total of 126 patients with endometriosis (stages I–IV) and 144 healthy women as control group were recruited to the study. We genotyped four single nucleotide polymorphisms of IL‐16 gene (rs11556218 T>G, rs4778889 T>C, rs4072111 C>T and rs1131445 C>T). Genotyping was performed using PCR and restriction fragment length polymorphism. Our results showed that genotype distribution in two exonic polymorphisms including rs11556218 and rs4072111 was significantly different between Endometriosis patients and healthy individuals (P < 0.05). We have also found an association between rs4072111 and rs1131445 with progression to the severe stages (III–IV) of endometriosis (P < 0.05). Finally, we may conclude that IL‐16 gene polymorphisms are highly associated with increased risk of endometriosis and could be considered as a susceptibility factor for endometriosis.     

Correlation between polymorphisms at interleukin‐6 but not at interleukin‐10 promoter and the risk of human T lymphotropic virus type I‐associated myelopathy/tropical spastic paraparesis in Brazilian individuals

HTLV‐1 is the etiologic agent of ATL and HAM/TSP. The majority of HTLV‐1‐infected individuals remain asymptomatic, indicating that the infection alone is not sufficient to cause the diseases. It has been reported that cytokine gene polymorphisms, including polymorphisms at IL‐6 and IL‐10 gene, might be important. We analyzed SNP in the promoter region of the IL‐6: ?174, ?572, ?597, and ?634 positions, and IL‐10: ?592 position to evaluate the role of these polymorphisms in the HAM/TSP pathogenesis in 133 HTLV‐1 infected individuals and in 100 healthy individuals from Salvador, Bahia, Brazil. The ?634C allele frequencies were higher among HAM/TSP patients (21.2%) than among oligosymptomatic (6.5%; P = 0.038) and asymptomatic (9.5%; P = 0.025) subjects. Similarly, the ?174G allele frequencies were higher in HAM/TSP patients than in oligosymptomatic patients (P = 0.02). Moreover, the ?634GC/?174GG genotype combination was identified at a higher frequency (38.5%) in the HAM/TSP patients than in subjects with other clinical status (8.7%; P = 0.016 for oligosymptomatic and 15.5%, P = 0.012 for asymptomatic patients). However, the multivariate logistic regression including the genotypes of the three studied loci showed that only ?634 C IL‐6 carriers remain as significant and independent TSP/HAM predictor (odds ratio [OR] = 5.31; 95% [CI] = 1.60–17.56; P = 0.006). We suggest that ?634 G C in IL‐6 could contribute to HAM/TSP development and that identification of the collective influence of several cytokine polymorphisms, their prevalence, and their interaction could help to better understand this disease. J. Med. Virol. 80:2141–2146, 2008. © 2008 Wiley‐Liss, Inc.     

Association study of interleukin‐1 family and interleukin‐6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin‐1 (IL‐1) and IL‐6 are the most potent pro‐inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL‐1 and IL‐6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL‐6 and IL‐1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL‐1α C ?889 T, IL‐1β C ?511 T, IL‐1β C +3962 T, IL‐1R C pst‐I 1970 T, IL‐1Ra C Mspa‐I11100 T, IL‐6 C ?174 G and IL‐6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence‐specific primers (PCR‐SSP). The frequency of C ?174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL‐6 gene at position ?174 which located in promoter have association with predisposition of individuals to RAS.     

Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus

Several lines of evidence suggest interleukin-10 gene (IL-10) is a candidate gene in susceptibility to systemic lupus erythematosus (SLE). We investigated the association of IL-10 promoter single-nucleotide polymorphisms (SNPs) (-3575T/A, -2849G/A, -2763C/A, -1082A/G, -819T/C and -592A/C) and microsatellites (IL10.R, IL10.G) with SLE in 554 Hong Kong Chinese patients and 708 ethnically matched controls. Six haplotypes (hts) were identified from the SNPs. The genotype distribution of the ht1 (T-C-A-T-A), which is associated with low IL-10 production, was different in patients and controls (P=0.009). The homozygous genotype of non-ht1 was significantly increased in patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15-2.82). The frequency of IL10.G4 of IL10.G was also significantly increased in patients (P=0.017, OR=2.53, 95% CI: 1.18-5.40). We found that the homozygous non-ht1 combined with short allele (CA repeat number < or =21) of IL10.G has a dose-dependent effect on SLE susceptibility: non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, 95% CI: 1.27-13.2, P=0.018) of association with SLE than the genotype of non-ht1/non-ht1 with heterozygous short/long allele (OR=2.98, 95% CI: 1.26-7.07, P=0.013) and homozygous long allele (OR=1.05, 95% CI: 0.62-1.78, P=0.848). The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55-3.80). In conclusion, the high expression promoter genotype is associated with SLE in Chinese.     

New polymorphisms in the IL-10 promoter region

Interleukin-10 (IL-10) is an important immunoregulatory cytokine. We searched for new sequence variations in the 5' flanking region of the IL-10 gene by denaturing high performance liquid chromatography. A 3996 bp region spanning position -3934 to +61 was amplified in 12 polymerase chain reaction (PCR) fragments and each fragment was screened for variations in 23 Italian individuals. The following eight sequence variations all consisting of single base pair substitutions were identified: -3533A/T, -2769A/G, -2739A/G, -2013A/G, -1349A/G, -1255C/T, -851A/G, -657A/G. The new polymorphisms were analysed in an additional panel of random Italian individuals. The same samples were also tested for the IL10.G and IL10.R microsatellites, and for the two previously described single nucleotide polymorphisms (SNPs) at positions -1082 and -592. Highly significant pairwise linkage disequilibria were observed between alleles at most SNPs. Three major haplotypic combinations of alleles at multiple SNP sites were observed.     

Association analysis of polymorphisms at the interleukin‐1 locus in essential hypertension

Infection with microorganisms such as Helicobacter pylori and Chlamidia pneumoniae has been associated with coronary heart disease (CAD) and hypertension (HT). Infection increases the release of pro‐inflammatory cytokines, thus facilitating interactions that lead to vascular damage and other effects. We hypothesized that genetically determined differences in activity or responsiveness of cytokine(s) might contribute to HT. The interleukin‐1 gene (IL1) cluster on chromosome 2q14 contains three related genes (IL1A, IL1B, and IL1RN) located within a 430‐kb region. These encode IL‐1α and IL‐1β, as well as their endogenous receptor antagonist, IL‐1ra. The IL1RN gene has a penta‐allelic 86‐bp tandem repeat in intron 2. Allele IL1RN* 2 is associated with a wide range of chronic inflammatory and autoimmune conditions, and its combination with the ? 31T variant of an IL1B C(? 31)T polymorphism constitutes a pro‐inflammatory haplotype that leads to vigorous IL‐1β production. We therefore tested each of these polymorphisms for association with HT. Subjects were white Anglo‐Celtic residents of Sydney, Australia. Frequencies of IL1B C(? 31)T genotypes CC, CT, and TT were 0.50, 0.40, and 0.10 in normotensive (NT) and 0.46, 0.46, and 0.08 in HT, respectively (χ² = 1.2, P = 0.55). T allele frequency in NT (0.30) was similar to that in HT (0.31). For the IL1RN variant, frequencies of alleles IL1RN* 1 and * 2 and combined minor alleles * 3, * 4, and * 5 were 0.61, 0.36, and 0.03 in NT and 0.54, 0.36, and 0.10 in HT, respectively (χ² = 11, P = 0.004). In conclusion, no association of the IL1B C(? 31)T with HT was found, whereas combined frequency of the minor alleles of the IL1RN polymorphism was increased in the HT cohort studied. © 2001 Wiley‐Liss, Inc.     

Association of Interleukin-10 gene promoter polymorphisms in Saudi patients with vitiligo

The promoter region of human Interleukin -10 gene is highly polymorphic and has been associated with numerous autoimmune diseases. Recent studies have linked vitiligo with defective autoimmune system. This study is aimed to explore a possible association between IL-10 gene polymorphism and vitiligo in Saudi population. This case control study consisted of 184 Saudi subjects including 83 vitiligo patients (40 males, 43 females mean age 27.85 +/- 12.43 years) and 101 matched controls. Genomic DNA was extracted from the blood samples of healthy controls and Vitiligo patients visiting out patient clinic of Department of Dermatology, Riyadh Armed Forces Hospital, using QIA ampR DNA mini kit (Qiagen CA, USA). Interleukin-10 gene was amplified by polymerase chain reaction (PCR) using Arms primers to detect any polymorphism involved at positions -592, -819 and -1082. The frequencies of GG genotype at -1082, and CC genotype at positions -592 and 819 were significantly higher in vitiligo patients compared to healthy subjects suggesting that GG and CC genotypes might be susceptible to vitiligo in Saudis. On the other hand genotypes -1082 GA, -819 CT, and -592 CA of IL-10 were more prevalent in healthy controls suggesting protective effects of GA, CT and CA genotypes against vitiligo. This study indicates that the IL-10 gene may play a significant role in the etiology of vitiligo among Saudis.     

The association of interferon‐gamma,interleukin‐4 and interleukin‐17 single‐nucleotide polymorphisms with susceptibility to tuberculosis

Susceptibility to tuberculosis and progression of the disease depend on interactions between the bacterial agent, host immune system, and environmental and genetic factors. In this case‐controlled study, we aimed to determine the role of single‐nucleotide polymorphisms of interferon‐gamma, interleukin‐4 and interleukin‐17 in susceptibility to tuberculosis. Genomic DNA was extracted from peripheral blood samples of patients and controls. The association of single‐nucleotide polymorphisms in interleukin‐4 (?590C/T), interleukin‐17 (?152A/G) and interferon‐gamma (+874T/A) was investigated by polymerase chain reaction (PCR)‐restriction fragment length polymorphism and amplification refractory mutation system‐PCR. A total of 76 tuberculosis patients and 119 healthy individuals were included in this study. The interferon‐gamma (+874T/A) TA genotype was significantly associated with susceptibility to tuberculosis in patients compared to controls (OR = 1.76; 95%CI = 0.84–3.71; p = 0.007), while the interferon‐gamma (+874T/A) TT genotype (OR = 0.51; 95%CI = 0.19–1.36; p = 0.007) had protective effects against tuberculosis and was related to a low risk of tuberculosis development. The difference between allelic and genotypic frequencies of interleukin‐4 (?590C/T) between patients and controls was not significant (p = 0.46). Multivariate logistic regression analysis revealed that the interleukin‐17 (?152A/G) AG genotype (OR = 2.27; 95%CI = 1.19–4.34; p = 0.03) and AA genotype (OR = 1.03; 95%CI = 0.43–2.44; p = 0.03) were significantly different between patients and controls. In conclusion, single‐nucleotide mutations in different cytokine genes may have protective effects or increase the risk of tuberculosis.     

Association between interleukin‐21 gene polymorphisms (rs12508721) and HBV‐related hepatocellular carcinoma

Interleukin‐21 (IL‐21), as a multifunctional cytokine, plays an important role in many diseases, such as cancer, inflammatory and autoimmune diseases. We aimed to investigate the relationship between polymorphisms of IL‐21 gene and susceptibility of hepatitis B virus (HBV)‐related hepatocellular carcinoma (HCC) in a Chinese population. Studied subjects were divided into three groups: 100 patients with HBV‐related HCC, 115 patients with chronic HBV infection and 127 healthy controls. Genomic DNA was isolated from peripheral blood, and the polymerase chain reaction–ligase detection reaction (PCR‐LDR) method was used to genotype the SNPs (rs2221903, rs907715 and rs12508721) within IL‐21 gene. Our results showed that IL‐21 polymorphisms were associated with the risk of HCC and chronic HBV infection when compared with healthy controls. The rs2221903A/G AG genotype was associated with a higher risk of chronic HBV infection when compared with healthy controls [AG versus AA + GG, P = 0.036, OR = 1.898, 95%CI = 1.038–3.471]. The rs12508721C/T TT genotype was related with a lower risk of chronic HBV infection and HBV‐related HCC than in healthy controls [TT versus CT + CC, P = 0.026, OR = 0.451, 95%CI = 0.221–0.920; P = 0.049, OR = 0.482, 95%CI = 0.231–1.005]. No significant difference in the genotype and allele distrubutions of rs907715G/A SNP was observed in the HBV‐related HCC group, chronic HBV‐infected group and the healthy control group when compared to each other. Our findings suggest that the rs12508721T/C and rs2221903A/G polymorphisms of IL‐21 gene are associated with the susceptibility of HBV‐related HCC and chronic HBV infection. The genetic variant may in fact cause protection against the HBV‐related HCC. However, the function in these SNPs of IL‐21 gene needs to clarify the mechanisms involved in the pathogenesis of HBV‐related HCC further.     

Association between polymorphisms in the promoter region of miR-143/145 and risk of colorectal cancer

Emerging evidence suggests that down-regulated miRNAs play an important role in the carcinogenesis of colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) in the promoter region of miRNAs may disturb miRNAs processing, alter their expression, and ultimately affect an individual’s susceptibility to CRC. We conducted a case-control study and analyzed twelve SNPs in the promoter region of miR-143/145 of 525 subjects including 242 cases with CRC and 283 controls using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) assay. The mutant genotypes or alleles of rs41291957, rs353292, rs353293, and rs4705341 were significantly associated with an increased risk of CRC compared with the wild genotypes or alleles, while rs4705343, rs17796757, rs3733845, and rs3733846 were significantly associated with a decreased risk of CRC. When stratification analysis was done by different variables, such as tumor size, tumor site, differentiated status, clinical stage, and metastasis status, we found that patients with the mutant allele of rs41291957 had an increased risk to develop a tumor size larger than 5 cm. These findings suggest that SNPs in the promoter region of miR-143/145 may be related to the etiology of CRC. However, further larger studies with different ethnic origins are needed to confirm our results due to limited sample sizes in the study.     

Association of serum interleukin‐33 level and the interleukin‐33 genetic variant with Japanese cedar pollinosis

Background IL‐33, an IL‐1‐like cytokine, is a ligand for IL1RL1, which is an important effector molecule of type 2 T helper responses. Although IL‐33/IL1RL1 interaction has been suggested to be important in induction of allergic airway inflammation, serum levels of IL‐33 and the genetic influences of the polymorphisms of IL‐33 in human allergic diseases are unclear. Objective The aim of this study was to examine whether the serum IL‐33 level and polymorphisms in IL‐33 are associated with Japanese cedar (JC) pollinosis, the most common form of allergic rhinitis, and a major public health problem, in Japan. Methods We performed linkage disequilibrium (LD) mapping of the gene using the HapMap database, and two selected tag single nucleotide polymorphisms were genotyped. We conducted an association study of IL‐33 (JC pollinosis, n=170; normal controls, n=100) and measured the IL‐33 levels in sera of the 270 subjects by ELISA. Results Serum levels of IL‐33 were significantly higher in patients with JC pollinosis (P=0.0018) than in controls. In genetic association analysis, we found a positive association between the polymorphism and JC pollinosis (P=0.048). Conclusion Our results support a role for IL‐33 in the pathogenesis of JC pollinosis.     

Interleukin-10 gene promoter polymorphisms and the risk of nasopharyngeal carcinoma

Genetic factors are known to be important in the development of nasopharyngeal carcinoma (NPC). Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. Interindividual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) at positions -1082 (A/G), -819 (T/C) and -592 (A/C) in the IL-10 gene promoter were involved in predisposing an individual to NPC. One hundred and ninety-eight patients with NPC and 210 age- and sex-matched controls, genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism. There were significantly differences in the genotype and allele distribution of -1082 A/G polymorphism of the IL-10 gene among cases and controls. The -1082 AG and GG genotypes were associated with a significantly increased risk of NPC as compared with the -1082 AA genotypes. Haplotype analysis showed that the homozygosity of the GCC haplotype (defined by SNPs at positions -1082, -819 and -592) of IL-10 gene conveys the highest risk for NPC compared with the homozygosity for the ATA haplotype. This study shows for the first time an association between IL-10 gene promoter -1082 A/G polymorphism and its haplotype may contribute to genetic susceptibility to NPC in a Chinese population.