Interleukin-13 gene polymorphism G4257A is associated with atopic dermatitis in Japanese patients

Interleukin (IL)-13 plays an important role in the induction of immunoglobulin E (IgE) and in the pathogenesis of atopic dermatitis (AD). We investigated the allele and genotype frequencies of three IL-13 single nucleotide polymorphisms (SNPs) (A704C and C1103T in the promoter region and G4257A in exon 4) in Japanese patients with AD. For A704C and C1103T SNPs, there were no significant differences in allele or genotype frequencies between AD patients and controls. For G4257A SNP, A allele was significantly increased in AD patients (39.5%) compared with controls (29.4%) (P = 0.016). The same proportion of each genotype and allele was observed in the patient subgroup with and without asthma. Serum IgE levels and peripheral eosinophil counts were not significantly different among genotypes in G4257A SNP. There was also no significant difference in allele or genotype frequencies between AD patients with mild disease and those with severe disease, between those with family history of AD and those without it, or between those with family history of atopic disorders and those without it. This result suggests that 4257A allele is associated with susceptibility to AD and that it may function in the pathogenesis of AD itself, presumably by other mechanisms than inducing IgE production.     

Most common inhalant allergens in atopic dermatitis, atopic dermatitis/allergic rhinitis, and atopic dermatitis/bronchial asthma patients: a five-year retrospective study

Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease with a distinctive clinical appearance and distribution. Around 85% of patients have positive immediate skin reaction or specific IgE to different airborne allergens that are in association with respiratory allergy. The aim of this retrospective, open and uncontrolled study was to identify the most common inhalant allergens in AD patients, AD/allergic rhinitis patients, and AD/bronchial asthma patients by skin prick test per year during the 2001-2005 period.     

Atopic disease and serum immunoglobulin-E

Fifty-seven subjects, forty-three with various combinations of atopic disease and fourteen non-atopic controls, were studied using a battery of immediate skin test allergens and a radio-immunoassay for serum Immunoglobulin-E (IgE). The geometric mean serum IgE level (units/ml) was 50 in strictly nonatopic controls, 170 in atopic respiratory disease (ARD) patients, 320 in atopic dermatitis (AD) patients and 772 in those patients with both AD-ARD. The marked elevation of the serum IgE in the latter group was not associated with respiratory disease activity and not closely correlated with extent of the dermatitis, but may relate to patients with both AD-ARD being 'highly atopic'. Overall, there was no correlation between the serum IgE level and the frequency of positive skin tests. Compared to ARD patients, the serum of AD patients contained more IgE, yet they reacted significantly less frequently to common extrinsic allergens.     

Eotaxin gene single nucleotide polymorphisms in the promoter and exon regions are not associated with susceptibility to atopic dermatitis,but two of them in the promoter region are associated with serum IgE levels in patients with atopic dermatitis

Eotaxin is believed to play an important role in atopic dermatitis (AD) as a potent chemoattractant and activator of eosinophils and Th2 lymphocytes. The eotaxin gene is located at chromosome 17q21.1-q21.2, and linkage findings of AD on chromosome 17 were reported. Recently we have identified single nucleotide polymorphisms (SNPs) of eotaxin gene (-426C > T, -384A > G, 67G > A). To learn whether eotaxin gene SNPs are associated with susceptibility to AD or phenotypes of AD, we investigated the genotype frequencies at each SNP of the gene in AD patients and in controls. We examined 140 Japanese AD patients and 140 healthy Japanese individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. No significant difference was observed in allele or genotype frequencies of any SNP between AD patients and controls. Serum immunoglobulin E (IgE) levels were significantly lower in CT and TT genotype than in CC (P = 0.038) in -426C > T SNP, and lower in GG than in AA and AG with borderline significance (P = 0.053) in -384A > G SNP in AD patients. Eotaxin gene SNPs in the promoter and exon regions are not associated with susceptibility to AD, but two of them in the promoter region are associated with phenotype of AD.     

TNFSF4基因多态性与系统性红斑狼疮的相关性研究

目的 探讨湖北汉族人群OX40配体蛋白基因rs844648位点和rs3850641位点基因多态性与SLE的相关性.方法 SLE患者82例和正常人对照组100例,采用PCR及限制性片段长度多态性方法(PCR-RFLP)检测TNFSF4基因rs844648和rs3850641位点多态性分布.结果 ①SLE组rs844648位点AA、AG和GG基因型频率分别为20.7％、62.2％、17.1％,正常人对照组为14.0％、55.0％、31.0％.SLE组rs844648多态性位点A等位基因携带者显著高于正常人对照组[73.2％比69.0％％,x2=4.69,P＜0.05,OR值=2.182( 1.068～ 4.458)],SLE组与正常人对照组间差异有统计学意义;②SNP位点rs3850641的正常人对照组AA、AG和GG基因型频率分别是76.0％、21.0％和3.0％,而SLE组分别为62.2％、31.7％和6.1％,SLE组rs3850641位点G等位基因携带者显著高于正常人对照组[37.8％比24.0％,x2=4.07,P＜0.05,OR值=1.925 (1.015 ～ 3.651)],SLE组与正常人对照组间差异有统计学意义.结论 TNFSF4基因rs844648和rs3850641位点存在单核苷酸多态性变异,该多态性与湖北地区汉族人群SLE的发病有相关性.     

Polymorphisms in the PTPN22 region are associated with psoriasis of early onset

BACKGROUND: Psoriasis, a chronic inflammatory skin disease, affects approximately 2% of the population worldwide. Although the aetiology of psoriasis is poorly understood, patients with disease of early onset (Type I, age of onset相似文献   

Raf kinase inhibitor protein expression correlates with differentiation but not with ERK phosphorylation in cutaneous squamous cell carcinoma

BackgroundThe acute skin lesions of atopic dermatitis (AD) are associated with Th2 cells; however, the chronic skin lesions of AD are associated with Th1 cells via the action of IL-12.ObjectiveWe evaluated the associations of single nucleotide polymorphisms (SNPs) and haplotype in the IL-12 and IL-12 receptor genes, and determined the gene–gene interactions between the SNPs of these genes and the SNPs of the IL-18 gene that we previously reported.MethodWe genotyped 24 SNPs from 4 IL-12/IL-12R genes for 1089 case–control samples (631 AD patients and 458 normal controls). We measured the serum IL-12 concentrations in 89 individuals (79 AD patients and 10 controls) by ELISA. We analyzed the SNPs and haplotypes in each gene and also searched for the gene–gene interactions.ResultThe rs582504 (IVS ? 798A/T) SNP and the haplotype TA (rs582054 and rs2243151) in the IL-12A gene, and the rs438421 (IVS12 + 1266T/C) SNP and the haplotype CCA (rs375947, rs438421, and rs1870063) in the IL-12RB1 gene were significantly associated with the AD phenotype. We showed that the rs438421 polymorphism in the IL-12RB1 (TT) gene and the rs2066446 polymorphism in the IL-12RB2 (AA) gene had a significant interaction to develop the ADe phenotype (allergic type of AD), and those individuals with the risk alleles, TT/AA/CC (IL-12RB1/IL-12RB2/IL-18), have more than a 10-fold increased risk to develop ADe.ConclusionThis study provides evidence for a significant interaction between the IL-12RB1 and IL-12RB2 genes that contribute to a 4-fold increased risk for developing ADe. In addition to the IL-12R interaction, we suggest that the IL-18 gene can significantly interact with the IL-12R gene to develop ADe. In addition to the interaction, the SNPs and haplotypes in the IL-12A and IL-12RB1 genes are independently and significantly associated with the AD phenotype, and especially with the ADe phenotype. This data may contribute to our understanding of AD genetic interactions and account for the additional risk of certain patients to develop AD.     

TNIP1基因多态性与汉族人系统性红斑狼疮相关性研究

目的 探讨人肿瘤坏死因子α诱导蛋白3（TNFAIP3）相互作用蛋白1（TNIP1）基因多态性与汉族人系统性红斑狼疮（SLE）的遗传关联性。 方法 收集284例汉族人SLE和630例汉族人对照,选择TNIP1基因区域120个单核苷酸多态性（SNP）,利用连接酶检测反应（LDR）对其进行基因分型,对分型数据利用PLINK 1.07和Haploview软件进行统计分析。 结果 经过数据质控,最终105个SNP的分型数据进入最终统计分析。rs3805433 C、rs12516176 C、rs6869605 C和rs4958882 G的等位基因频率在SLE组（参考等位基因频率0.301 ~ 0.306）高于对照组（参考等位基因频率0.221 ~ 0.225）,差异有统计学意义（OR：1.50 ~ 1.53,均P < 4.72 × 10-4）。这4个SNP间存在强连锁不平衡（r2 ≥ 0.871,D′ ≥ 0.938）,且与既往报道的SLE相关SNP rs10036748间存在中等程度的连锁不平衡（r2 ≥ 0.073,D′ ≥ 0.868）。单倍型分析发现,单倍型（H2：CCCGT）在病例组中的频率（0.290）显著高于对照组（0.210）,差异有统计学意义（OR = 1.54,P < 4.72 × 10-4）。 结论 TNIP1基因多态性与汉族人SLE具有相关性。     

Association of polymorphisms in genes encoding IL-4, IL-13 and their receptors with atopic dermatitis in a Korean population

Th2-dominated immune responses are believed to contribute to the pathogenesis of atopic dermatitis (AD). IL-4 and IL-13 are typical pleiotropic Th2 cytokines that play a central role in IgE-dependent inflammatory reactions. Single-nucleotide polymorphisms (SNPs) in IL-4 and IL-13 have been reported in patients with allergic disease from numerous countries. Gene-gene interactions among genes have been identified in patients with asthma, although negative results have been reported. To investigate the associations of SNPs in these genes and the interactions between these genes in AD, we genotyped 23 SNPs of the IL-4, IL-13, IL-4R, IL-13Rα1 and IL-13Rα2 genes for 1089 case-control samples (631 AD patients and 458 controls) and analysed the SNPs and haplotypes in these genes. We also searched for gene-gene interactions among these five genes. Our data identified an association between rs3091307 and rs20541 in the IL-13 gene and between rs2265753 and rs2254672 in the IL-13Rα1 gene and the AD phenotype. In particular, three of the four SNPs were especially predictive of the allergic type of AD (ADe), and the haplotype TCGG in the IL-13Rα1 gene showed significant association with AD, especially ADe. Furthermore, the combination of rs3091307 GG/ rs2265753 GG (IL-13/IL-13Rα1) conveyed a significantly higher risk for developing ADe. However, we did not identify any SNPs in the IL-4, IL-4R and IL-13Rα2 genes that were associated with AD. As IL-13Rα1 is most likely expressed in Th17 cells rather than in Th2 cells, these data suggest diversity in the classification of Th cells that needs to be verified in future studies.     

The natural history of sensitizations to food and aeroallergens in atopic dermatitis: a 4-year follow-Up

The natural history of atopic dermatitis (AD) is variable. Generally the dermatitis disappears during the first years of life, but it is often followed by the appearance of allergic respiratory diseases (ARDs). Our aim was to establish the risk factors for developing an ARD in children with AD. We followed up for 4 years 78 children (51 boys, 27 girls) with mild (26%), moderate (48%), and severe (26%) AD (clinical score proposed by Rajka and Langeland). In all the patients IgE serum levels were checked and skin prick tests (SPTs) were performed at the first examination. The SPTs were repeated in 68 children at the end of the study. The children with severe AD had significantly higher IgE serum levels than those with mild or moderate AD. SPTs at the first observation were positive in 47% of cases, mostly in patients with severe AD, with a prevalence of food allergens, particularly in younger patients. At the second observation, SPTs were positive in 65% of cases, including 100% of children with severe AD. Inhalants were the most common allergens. An ARD appeared in 38% of all patients: in 75% of those with severe AD and in 54% of those with a positive first SPT. Allergic screening should be carried out at an early age, especially in severe AD, since SPT positivity to food allergens, associated with severe clinical AD symptoms and a high IgE serum level, identifies those children ages 0-3 years at high risk of development of ARD.     

Specific IgE to Staphylococcus aureus in patients with atopic dermatitis

It is a well-known feature of atopic dermatitis (AD) that the patient's skin is heavily colonized by Staphylococcus aureus. S. aureus-derived antigens may be important triggers of the immune response and may significantly contribute to the genesis of the cutaneous pathology of AD. Therefore, serum samples of 52 patients with AD, all of whom had signs of moderate to severe disease activity, were tested for antistaphylococcal IgE antibodies with RAST discs coupled to antigens derived from Wood 46 strain. Total IgE concentrations and specific IgE to nine different common allergens were also determined. Only 2 patients showed significant levels of specific IgE antibodies to S. aureus (RAST class greater than or equal to 2). Both these patients were found to have high total IgE and significant levels of specific IgE to all nine common allergens tested. One of the patients had marked eosinophilia. We conclude that the presence of specific IgE to S. aureus is not correlated with the disease activity in AD. Specific antistaphylococcal IgE does not represent an important diagnostic feature in AD, but may be of importance for the detection of subgroups within patients affected by AD.     

延边朝鲜族AD患者FLG基因SNPs与血清生化指标相关性分析

目的研究延边地区朝鲜族特应性皮炎患者丝聚蛋白基因单核苷酸多态性与血清IgE及IL-13相关性分析。方法选择70例特应性皮炎患者和90例正常对照人群作为研究对象,使用PCR法,研究丝聚蛋白基因2个SNPs位点(rs11584340及rs3126085)的基因型分布,并进行生化指标在各基因型间比较。结果延边朝鲜族特应性皮炎组血清IgE及IL-13水平显著高于正常组(P<0.01);rs11584340多态在特应性皮炎组内基因型AG有增高血清IgE趋势(P=0.05),但与IL-13不相关(P>0.05)。结论血清IgE及IL-13与延边朝鲜族人群特应性皮炎有明显相关性,是特应性皮炎的危险因素;延边朝鲜族特应性皮炎患者中rs11584340多态基因型AG有增加血清IgE趋势。     

Genetic variations in NALP1 are associated with generalized vitiligo in a Romanian population

Generalized vitiligo is a common, multifactorial, polygenic disease in which autoimmune loss of melanocytes results in depigmented spots of skin, overlying hair, and mucous membranes. In Caucasian families from the United States of America and United Kingdom, susceptibility to generalized vitiligo and associated autoimmune diseases is genetically associated with variants of NALP1, encoding NACHT leucine-rich repeat protein 1. Here, we describe a population-based case-control association analysis of single-nucleotide polymorphisms (SNPs) distributed through the NALP1 region in Caucasian generalized vitiligo patients and controls from Romania. This study confirms genetic association of generalized vitiligo with variation in NALP1, which contains at least two independent risk signals, one tagged by SNP rs6502867 and another tagged by SNPs rs2670660 and rs8182352. Individuals carrying high-risk alleles of both rs6502867 and rs2670660 had an odds ratio of 4.20 compared with individuals carrying a high-risk allele from only one signal. These findings support the involvement of NALP1 in predisposition to generalized vitiligo.     

Association of DOCK8, IL17RA,and KLK12 Polymorphisms with Atopic Dermatitis in Koreans

BackgroundEarly-onset and severe atopic dermatitis (AD) in patients increase the probability of the development of allergic rhinitis or asthma. Treatment and prevention strategies in infants and young children with AD are targeted toward treating the symptoms, restoring skin barrier functions, and reducing the absorption of environmental allergens in an attempt to attenuate or block the onset of asthma and food allergy.ObjectiveGiven that the initiating events in AD remain poorly understood, identifying those at risk and implementing strategies to prevent AD is necessary.MethodsWhole-exome sequencing (WES) was performed in a 43 control group and a disease group with 20 AD patients without atopic march (AM) and 20 with AM. Sanger sequencing was carried out to validate found variants in cohorts.ResultsDOCK8, IL17RA, and KLK12 single-nucleotide polymorphisms were identified by WES as missense mutations: c.1289C>A, p.P97T (rs529208); c.1685C>A, p.P562G (rs12484684); and c.457+27>C, rs3745540, respectively. A case-control study show that total immunoglobulin E (IgE) level was significantly increased in the AA genotype of DOCK8 compared to the CA genotype in allergic patients. The rs12484684 of IL17RA increased risk of adult-onset AD (odds ratio: 1.63) compared to the control for (A) allele frequency. AD and AM Patients with the IL17RA CA genotype also had elevated IgE levels. rs3745540 of KLK12 was associated with AD in dominant model (odds ratio: 2.86).ConclusionDOCK8 (rs529208), IL17RA (rs12484684), and KLK12 (rs3745540), were identified using a new WES filtering method. the result suggests that polymorphism of DOCK8 and IL17RA might be related to increase the total IgE level.     

Hint for association of single nucleotide polymorphisms and haplotype in SPINK5 gene with atopic dermatitis in Koreans

Clinical studies, including twin studies, support the concept that the risk of atopic dermatitis (AD) may be mediated through skin-specific genes, rather than simply through systemic immune or atopy risk genes. The SPINK5 gene is expressed on epithelial surfaces and may provide protection against other allergenic serine proteases. Mutations in the SPINK5 gene result in Netherton syndrome, a disorder characterised by AD, ichthyosis, and elevated serum IgE levels. We genotyped 21 single nucleotide polymorphisms (SNPs) from the SPINK5 gene for 1090 case-control samples (631 patients with AD and 459 normal controls) and analysed the SNPs and haplotypes in this gene and also searched for gene-gene interactions between SPINK5 and the DEFB1 gene that we previously reported. Six SNPs [rs17718511 (P = 0.026), rs17860502 (P = 0.024), KN0001820 (P = 0.045), rs60978485 (P = 0.007), rs17718737 (P = 0.02), and rs1422985 (P = 0.038)] and the haplotype TAA (rs60978485, rs6892205, rs2303064; P = 0.023) in the SPINK5 gene showed significant different allelic or genotypic distributions between the AD group and the control group. We also found that four SNPs [rs17718511 (P = 0.033), rs17860502 (P = 0.031), rs60978485 (P = 0.005), rs17718737 (P = 0.023)] and the haplotype TAA (P = 0.02) in the SPINK5 gene showed associations with the susceptibility of the allergic type of AD (ADe). In addition to this finding, we speculate that the SNPs from DEFB1 and SPINK5 affect the individual susceptibility to development of ADe in an additive manner. This study provides evidence for a significant interaction between allergens and the SPINK5 gene that may contribute to ADe susceptibility.     

Beta defensin‐1 gene (DEFB1) polymorphisms are not associated with atopic dermatitis in children and adolescents from northeast Brazil (Recife,Pernambuco)

Background Atopic dermatitis (AD) is a common inflammatory skin disease resulting from the interplay between environmental, immunological and genetic factors. In our study, we investigated the role of three single nucleotide polymorphisms (SNPs) at 5′‐UTR of DEFB1 gene, encoding for the human beta defensin‐1, on the susceptibility to develop AD in a group of Brazilian children and adolescents. Methods Three SNPs, ?20 G/A (rs11362), ?44 C/G (rs1800972), and ?52 G/A (rs1799946) at 5′‐UTR of DEFB1 gene were genotyped in two groups of children and adolescents, one affected by AD (96 subjects), the other healthy (191 individuals), from northeast Brazil. Results ?44 C/G frequencies were comparable between the two groups. The ?20 GG genotype was more frequent in AD subjects than in healthy controls; the ?52 GG, conversely, was more frequent in healthy controls than in AD. However, both these differences did not reach statistical significance. Also, association between SNPs and AD severity has been shown. The analysis of DEFB1 haplotypes did not highlight any association of the three SNPs with AD development or disease severity. Conclusions Our results seem to exclude a role for the ?44 C/G DEFB1 SNPs on the pathogenesis and severity of AD, while for the ?20 C/G and ?52 G/A, even if not statistically significant, we evidenced a slight trend for susceptibility (?20 GG) and protection (?52 GG) for the development of AD. However, as controversial findings have been reported in the literature, the role of DEFB1 in the development of AD and in the severity of the phenotype deserves further investigation.     

PTPN22 is genetically associated with risk of generalized vitiligo, but CTLA4 is not

Generalized vitiligo is an acquired, multifactorial, polygenic disease in which depigmented spots of skin, overlying hair, and mucus membranes result from autoimmune-mediated loss of melanocytes from affected areas. We examined single-nucleotide polymorphisms (SNPs) in the PTPN22 and CTLA4 genes in 126 Caucasian families with multiple cases of generalized vitiligo and associated autoimmune diseases, using a family-based association study design. The PTPN22 1858T allele of SNP rs2476601 is significantly associated both with generalized vitiligo and with an expanded autoimmunity phenotype. Individuals carrying the PTPN22 1858T allele had an allelic odds ratio (OR) of 2.16 for generalized vitiligo and a genotypic OR of 2.35 as C/T heterozygotes. Similarly, individuals carrying the PTPN22 1858T allele had an allelic OR of 2.05 for the expanded autoimmunity phenotype, and a genotypic OR of 2.19 for C/T heterozygotes. Examination of five SNPs in the CTLA4 gene (rs1863800, rs231775, rs3087243, rs11571302, rs11571297, rs10932037) in the same 126 families yielded no evidence of allelic or genotypic association with either generalized vitiligo or the expanded autoimmune phenotype. These results implicate PTPN22 in mediating susceptibility to generalized vitiligo and associated autoimmune diseases, but do not support a role for CTLA4.     

An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population

Background

The genes encoding IL-9 and IL-9R have recently been implicated in the genetic basis of asthma and allergy. Although studies performed on transgenic and knockout mice have shown conflicting results, no evidence of skin changes has ever been reported in these animals.

Objective

To find association of the SNPs in IL-9 and IL-9R genes and interaction of these genes in atopic dermatitis.

Method

We genotyped 5 SNPs from the IL-9 and IL-9R genes of 1090 subject samples (631 AD patients and 459 normal controls). A luciferase assay was then performed for the rs31563 (−4091G/A) SNP located in the IL-9 gene promoter region.

Result

The rs31563 (−4091G/A) SNP in the IL-9 gene was significantly associated with the AD phenotype, especially allergic-type AD. In the luciferase assay, the rs31563 G construct was observed to have 1.54 times higher activity than the rs31563 A construct. Although no association was found between SNPs in IL-9R gene and AD, the rs3093467 SNP showed association with non-allergic AD. In the gene-gene interaction analysis, we found that IL-9/IL-9R genotype rs31563 GG/rs3093467 TT conveyed a greater risk for AD phenotype development.

Conclusion

Significant evidence exists to suggest that the rs31563 SNP (−4091G/A) located in the IL-9 gene is associated with an increased susceptibility to AD. Similarly, the rs3093467 SNP in IL-9R gene seems to be associated with an increased risk for developing non-allergic AD. In a subsequent gene-gene interaction analysis, the rs31563 GG/rs3093467 TT genotype combination (IL-9/IL-9R) was found to exert a synergistic effect in the development of the AD phenotype. As the classes of helper T cells are diverse and the function of IL-9 cytokine has not been fully described, the cutaneous function of IL-9 needs to be further explored in future studies.