Association analysis of interleukin 5 receptor alpha subunit (IL5RA) polymorphisms and asthma

The alpha subunit of interleukin 5 receptor (IL5RA) on chromosome 3p26-p24 is known to regulate the development and function of eosinophils. In an effort to discover additional polymorphism(s) in genes whose variant(s) have been implicated in asthma, we investigated the genetic polymorphisms in IL5RA to evaluate the gene as a potential candidate for a host genetic study of asthma. By direct DNA sequencing in 24 individuals, we identified 22 sequence variants within exons and flanking regions including a 1.5-kb promoter region of IL5RA; 10 common polymorphic sites were selected for genotyping in our asthma cohort (n=587). Two haplotype blocks were identified in a Korean population. Statistical analysis revealed that one promoter SNP, c.-5993A>G, and one ins/del polymorphism in intron 3, c.-480_482insdelGTT, showed significant association with the risk of asthma development. The genetic effects of c.-5993A>G and c.-480_482insdelGTT on asthma were more apparent among atopic subjects. Our findings suggest that polymorphisms in IL5RA might be among the genetic risk factors for asthma development, especially in atopic populations. IL5RA variant/haplotype information identified in this study will provide valuable information for strategies for the control of asthma.Electronic Supplementary Material Supplementary material is available for this article at     

Polymorphisms in the IL2, IL2RA and IL2RB genes in multiple sclerosis risk

Interleukin (IL)-2/IL-2R signalling promotes proliferation and survival of activated T cells and has an essential non-redundant role in the production of regulatory T cells. Associations with different autoimmune diseases of polymorphisms in a linkage disequilibrium block in which the IL2/IL21 genes map (4q27), and also in genes encoding the IL2RA and IL2RB subunits (located in 10p15 and 22q13, respectively), were identified through genome-wide studies. Polymorphisms in these three genes were studied in 430 multiple sclerosis (MS) patients and in 550 ethnically matched controls from Madrid (Spain). Replication and meta-analysis with results from an independent cohort of 771 MS patients and 759 controls from Andalucía (Spain) confirmed the association of polymorphisms in the IL2RA gene (P_{Mantel–Haenszel,} odds ratio (OR)_M–H (95% confidence interval, CI) for rs2104286: 0.0001, 0.75 (0.65–0.87); for rs11594656/rs35285258: 0.004, 1.19 (1.06–1.34); for rs41295061: 0.03, 0.77 (0.60–0.98)); showed a trend for association of the IL2/IL21 rs6822844 (P_M–H=0.07, OR_M–H (95% CI)=0.86 (0.73–1.01)), but did not corroborate the association for IL2RB. Regression analyses of the combined Spanish cohort revealed the independence of two IL2RA association signals: rs2104286 and rs11594656/rs35285258. The relevant role of the IL2RA gene on MS susceptibility adds support to its common effect on autoimmune risk and the suggestive association of IL2/IL21 warrants further investigation.     

Interleukin 3 (IL3) polymorphisms associated with decreased risk of asthma and atopy

Cytokines, having central functions in immunological and inflammatory process, are always expected to play important roles in the pathogenesis of various diseases, such as asthma. Genetic polymorphisms of those cytokine and cytokine receptor genes are the focus of genetic association studies. In an effort to identify gene(s) whose variant(s) are involved in the development of asthma, we examined the genetic effects of 19 single nucleotide polymorphisms in eight cytokine and cytokine receptor genes, including IL1A, IL1B, IL2, IL3, IL4, IL8, IL10, and IL5RA, on asthma and atopy. Nineteen single nucleotide polymorphisms in eight cytokine and cytokine receptor genes were genotyped using the single-base extension method in a Korean asthma cohort (n=723). Logistic regression and multiple regressions were used for statistical analyses controlling for smoking, age, and gender as covariables. Genetic association analysis of polymorphisms revealed that one exonic (exon 1), IL3+79T>C (Ser27Pro), showed significant association with the risk of asthma and atopy. The Pro allele had shown dominant and protective effects on development of asthma in nonatopic subjects (P=0.002) and also showed significant association with the risk of atopy in normal control subjects (P=0.007). This information about the genetic association of important genes with asthma might provide valuable insights into strategies for the pathogenesis of asthma and atopy.     

Genetic variants in IL4RA,IL6, and IL12B genes and susceptibility to hepatitis B and C virus infections among Iraqi patients

Hepatitis B and C viruses (HBV and HCV) are common causative pathogens of viral hepatitis. Progression of both infections is determined by virus- and host-related factors. Cytokines are important host genetic factors that may have a predisposing role in HBV and HCV infections. This case-control study evaluated the genetic association of IL4RA₊₁₉₀₂ (rs1801275), IL6₋₁₇₄ (rs1800795), IL6₋₅₉₇ (rs1800797), and IL12B₋₁₁₈₈ (rs3212227) variants with chronic HBV and HCV infections among Iraqi patients. A total of 220 viral hepatitis patients were enrolled in the study (113 HBV and 107 HCV), together with 141 healthy subjects. Sequence-specific primer polymerase chain reaction assay was the genotyping method. Results revealed that under a dominant genetic model, IL6₋₁₇₄ variant was significantly associated with HBV infection, whereas no association with the HCV risk was reported. However, the risk for both infections was markedly associated with IL6₋₅₉₇ variant under recessive, dominant, and codominant genetic models. Estimation of IL6₋₁₇₄-IL6₋₅₉₇ haplotypes depicted that G-A haplotype was significantly associated with an increased risk to develop HBV infection, whereas a significantly decreased risk was associated with G-G and C-G haplotypes. For HCV, G-G and C-A haplotypes were significantly associated with risk of HCV infection. IL4RA₊₁₉₀₂ and IL12B₋₁₁₈₈ variants showed no association with HBV or HCV risk. Analysis of variance revealed no significant association between genotypes of the four determined single-nucleotide polymorphisms and HBV or HCV viral load. In conclusion, the study supports the concept that IL6₋₅₉₇ variant is associated with susceptibility to HBV and HCV infections among Iraqis. The risk of HBV infection is further associated with IL6₋₁₇₄ variant.     

Study of polymorphisms in 4q27, 10p15, and 22q13 regions in autoantibodies stratified type 1 diabetes patients

Type 1 diabetes (T1D) is a multifactorial disease mainly associated with the human leukocyte antigen region. Previous studies suggested the association of interleukin-2 (IL2) gene polymorphisms and its alpha- and beta-chain receptor (IL2RA and IL2RB) variants with different autoimmune diseases such as T1D, celiac disease, multiple sclerosis, and rheumatoid arthritis. All T1D studies were conducted in diabetic patients younger than 17 years at diagnosis. The aim of our study was to replicate these associations not only in pediatric patients, but also in individuals with late onset. We performed a genetic association study of chromosomal regions 4q27, 10p15, and 22q13 containing the IL2, IL2RA, and IL2RB genes in 445 T1D subjects and 828 healthy controls. Seven single nucleotide polymorphisms (SNPs) were selected, previously described as genetic factors related to several autoimmune diseases, and were analyzed by TaqMan assays. The reported association with T1D patients of the IL2RA-rs41295061 located in the 10p15 region was replicated and our data suggest a trend of association of the polymorphisms IL2-rs17388568 and IL2-rs6822844 in 4q27. The effect of these markers was independent of the age at disease onset. Furthermore, the polymorphisms studied in 4q27 were not dependent on the presence of autoantibodies; however, the effect of the associated SNP in 10p15 (IL2RA-rs41295061) was specific of patients sera positive for diabetes antibodies. In conclusion, our results seem to indicate that late-onset and young T1D patients share most genetic factors located in the studied regions, but some markers could correlate with the presence of T1D specific autoantibodies.     

IL8 and IL17A polymorphisms associated with multibacillary leprosy and reaction type 1 in a mixed population from southern Brazil

We evaluated the influence of the IL8 T‐738A (nonidentified rs), IL8 T‐353A (rs4073), IL17A G197A (rs2275913), and IL17F T7488C (rs763780) single‐nucleotide polymorphisms on leprosy. The AA genotype of IL8 T‐353A was observed as a risk factor for multibacillary leprosy, regardless of gender and age‐of‐onset of disease, considering the recessive model (OR, 3.8; 95% CI, 1.1–13.5; P, 0.023). Furthermore, the AA genotype of IL17A G197A was associated with leprosy type 1 reaction (OR, 2.4; 95% CI, 1.1–5.1; P, 0.026) when compared to the group without reaction, which was adjusted for gender and age‐of‐onset of disease by the model log additive. These results indicate association of IL8 and IL17A polymorphisms with the progression to multibacillary leprosy and with the type 1 reaction, respectively.     

Genetic variant association of PTPN22, CTLA4, IL2RA,as well as HLA frequencies in susceptibility to alopecia areata

ABSTRACT

Alopecia areata (AA) is characterized by a genetically complex inheritance. HLA frequencies, as well as the single nucleotide polymorphism (SNP) in PTPN22, CTLA4, and IL2RA genes, have been described to be associated with AA susceptibility. So far, no independent replication of these studies has been reported, and no data exist on a possible association between AA disease and these SNPs or influence of HLA frequencies in Iranian population. A possible association between HLA-DRB1*11 alleles as well as a single variation in PTPN22, CTLA4, and IL2RA genes and patchy AA disease have been investigated in a cohort from Iran. Patient and control subjects were genotyped for PTPN22 (rs2476601), CTLA4 (rs3087243), and IL2RA (rs3118470) variations as well as HLA frequencies. Gene expression levels were analyzed by real-time RT-PCR. In contrast to PTPN22 and CTLA4 gene polymorphisms, a significant association was found between IL2RA SNP and susceptibility to AA in Iranian cohort. While gene expression levels of IL2RA and PTPN22 were higher in the patients than that of controls, CTLA4 expression levels found significantly lower in the patients. Despite a significant association between AA and HLA-DRB1*11 frequencies, the presence of DRB1*11 is not associated with PTPN22, CTLA4, or IL2RA gene SNPs. Although the minor allele in IL2RA SNP can be a significant determinant of AA disease development in Iranian population, reported an association between the PTPN22 and CTLA4 variations was not confirmed by our study. Furthermore, these genetic risk factors might act independently from HLA alleles.     

Significant association of interleukin 8 −251T/A polymorphism with smoking behavior in a Japanese population

Accumulating evidence indicates that the genotype may impact on smoking behavior and a deeper understanding of the molecular basis could lead to more effective strategies for preventing initiation of the habit and to help smokers to quit. Since individual variation in airway responsiveness to cigarette smoke might have an important influence, we have focused on associations between smoking behavior and polymorphisms affecting the inflammatory cytokine, IL-8. In the present study, 453 Japanese non-cancer outpatients (191 males and 262 females) who visited Aichi Cancer Center Hospital were genotyped for the IL8 –251T/A polymorphism, and age- and sex-adjusted odds ratios (aORs) for smoking were estimated using a logistic regression model. The aORs for IL8 251-TA and AA combined, genotypes associated with high production of IL-8, were 0.52 (95% CI 0.33–0.82, P=0.004) for ever having smoked and 0.55 (0.33–0.92, P=0.023) for being a current smoker. Our results suggest that the inflammatory-prone genotype of IL8 may act to deter initiation or characteristics of the smoking habit.     

Impact of interleukin 13 (IL13) genetic polymorphism Arg130Gln on total serum immunoglobulin (IgE) levels and interferon (IFN)‐γ gene expression

This cross‐sectional study was designed to investigate the extent of genetic susceptibility by targeting variants in interleukin (IL)?4/IL‐13 signalling pathways leading to atopic disease in early childhood. We evaluated involvement of five single nucleotide polymorphisms IL4 C‐590T, IL13 C‐1055T, IL13 Arg130Gln, IL4RA Ile50Val and IL4RA Gln576Arg, in the control of serum total and antigen‐specific immunoglobulin (Ig)E levels. Furthermore, we analysed their association with changes in gene expression of five cytokines having key roles in inflammatory and anti‐inflammatory immune response [IL‐4, IL‐13, interferon (IFN)‐γ, IL‐8 and IL‐10]. Total and antigen‐specific IgE levels in serum and gene expression of selected cytokines in peripheral blood were measured in 386 children aged 1–8 years. TaqMan allelic discrimination, amplification refractory mutation system–polymerase chain reaction (ARMS–PCR) and restriction fragment length polymorphisms (RFLP) methods validated by sequencing were used for genotyping. All genotypes for children with total and antigen‐specific IgE levels in the normal range were in Hardy–Weinberg equilibrium. Gene expression analyses were carried out using TaqMan gene expression assays. We found elevated total IgE levels in carriers of IL13 Arg130Gln variant allele [odds ratio (OR) = 1·84; 95% confidence interval (CI) = 1·16‐2·93]. This effect was more apparent for boys (OR = 2·31; 95% CI = 1·25‐4·28). However, no significant association was observed for the other four variants examined. We found up‐regulation of IFN‐γ in children with elevated serum total IgE levels carrying the Arg130 allele (P = 0·005). No differences were found for IL4, IL8 or IL10, while IL13 gene expression was under the detection limit. IL13 Arg130Gln genotypes can play a role in genetic susceptibility to allergy via regulation of serum total IgE levels and affecting IFN‐γ gene expression.     

IL15 gene variants are not associated with asthma and atopy

Background:  Interleukin 15 (IL15) promotes activation and proliferation of CD8+ T cells and enhances the differentiation into Th2 cells. A previous study described five polymorphisms in the IL15 gene to be associated with asthma in a haplotype analysis.
Aim:  We selected HapMap tagging single nucleotide polymorphisms (SNPs) from IL15 to systematically investigate these IL15 associations in a large population-based sample.
Methods:  Genotyping of seven IL15 SNPs was performed using MALDI-TOF MS in a cross-sectional study population of 3099 children from Dresden or Munich (age 9–11 years). All children were phenotyped by standardized and validated protocols for atopic phenotypes. Effects of single SNPs and haplotypes were studied using sas 9.1.3 and haploview . Equivalence tests were performed to prove the significance of negative results.
Results:  Neither single IL15 polymorphisms nor haplotype analyses showed associations with asthma or atopy after correction for multiple testing.
Conclusion:  These results do not confirm previous case–control studies and suggest that IL15 gene variants do not play an important role in the development for asthma or other atopic disorders.     

The IL17F and IL17RA Genetic Variants Increase Risk of Cerebral Malaria in Two African Populations

Cerebral malaria (CM) is a neurological complication of infection with Plasmodium falciparum that is partly caused by cytokine-mediated inflammation. It is not known whether interleukin-17 (IL-17) cytokines, which regulate inflammation, control the development of CM. To evaluate the involvement of IL-17 cytokines in CM, we analyzed 46 common polymorphisms in IL17A, IL17F, and IL17RA (which encodes the common receptor chain of the members of the IL-17 family) in two independent African populations. A case-control study involving 115 Nigerian children with CM and 160 controls from the community (CC) showed that IL17F reference single nucleotide polymorphism (SNP) 6913472 (rs6913472) (P = 0.004; odds ratio [OR] = 3.12), IL17F rs4715291 (P = 0.004; OR = 2.82), IL17RA rs12159217 (P = 0.01; OR = 2.27), and IL17RA rs41396547 (P = 0.026; OR = 3.15) were independently associated with CM. A replication study was performed in 240 nuclear Malian family trios (two parents with one CM child). We replicated the association for 3 SNPs, IL17F rs6913472 (P = 0.03; OR = 1.39), IL17RA rs12159217 (P = 0.01; OR = 1.52), and IL17RA rs41396547 (P = 0.04; OR = 3.50). We also found that one additional SNP, IL17RA rs41433045, in linkage disequilibrium (LD) with rs41396547, was associated with CM in both Nigeria and Mali (P = 0.002; OR = 4.12 in the combined sample). We excluded the possibility that SNPs outside IL17F and IL17RA, in strong LD with the associated SNPs, could account for the observed associations. Furthermore, the results of a functional study indicated that the aggravating GA genotype of IL17F rs6913472 was associated with lower IL-17F concentrations. Our findings show for the first time that IL17F and IL17RA polymorphisms modulate susceptibility to CM and provide evidence that IL-17F protects against CM.     

Lack of association of histamine-N-methyltransferase (HNMT) polymorphisms with asthma in the Indian population

Histamine plays a major role in allergic disorders, including asthma. A major pathway of histamine biotransformation in the lungs is mediated by histamine N-methyltransferase (HNMT). We investigated the association of a functional SNP C314T; a SNP A929G, a (CA)_n repeat in intron 5, and a novel (CA)_n repeat (BV677277), 7.5 kb downstream of the HNMT gene with asthma and its associated traits such as total serum IgE levels in a case-control as well as in a family-based study design. In contrast to a previous study, no association was observed for the polymorphisms investigated with asthma (P>0.05). When haplotypes were constructed for these loci and compared, no significant difference was observed in the distribution between cases and controls. In the family-based design, no biased transmission was observed for any of the polymorphisms and haplotypes with asthma using the additive model of inheritance in family-based association test (FBAT). Thus, consistent with the case-control findings, the polymorphisms and haplotypes in the HNMT gene are not associated with asthma in the Indian population.Accession No.: BV677277     

Polymorphisms in IL13, total IgE, eosinophilia, and asthma exacerbations in childhood

BACKGROUND: It is unclear whether single nucleotide polymorphisms (SNPs) in the gene for IL-13 (IL13) influence asthma severity and/or asthma morbidity. OBJECTIVES: To examine the relation between IL13 SNPs and asthma-related phenotypes in 2 independent populations. METHODS: We used family-based methods to test for association between SNPs in IL13 and asthma-related phenotypes in Costa Rican children with asthma. We attempted to reproduce significant findings in white (non-Hispanic) children with asthma in the Childhood Asthma Management Program (CAMP). RESULTS: In Costa Rica and in CAMP, the A allele (Gln) of IL13 coding SNP (rs20541) was significantly associated with increased eosinophil count (P < .011 in both studies) and increased serum total IgE (P < .054 in both studies). The T allele of IL13 promoter SNP (rs1800925) was inversely associated with asthma exacerbations in Costa Rica (P = .069). Although this SNP (rs1800925) was not associated with asthma exacerbations among all white children in CAMP, it was associated with increased risk of asthma exacerbations among children on inhaled corticosteroids (P = .02). CONCLUSION: Polymorphisms in IL13 were significantly associated with serum total IgE and eosinophil count in 2 populations. IL13 polymorphisms may also be associated with asthma exacerbations, and this effect may be dependent on medication use. Our study is the first to report a potential negative interaction between a genetic polymorphism and response to inhaled corticosteroids. CLINICAL IMPLICATIONS: Polymorphisms in IL13 are associated with serum total IgE and eosinophil count and may be associated with asthma exacerbations.     

Identification of single-nucleotide and repeat polymorphisms in two candidate genes, interleukin 4 receptor (IL4RA) and signal transducer and activator of transcription protein 6 (STAT6), for Th2-mediated diseases

 We report here the identification of 26 single-nucleotide polymorphisms (SNPs) spanning a total of 147 kb in two candidate genes, IL4RA and STAT6, for atopic disorders. Fourteen novel SNPs were found in our population. We also report the identification of three novel polymorphic (CA) repeat regions in these genes. No insertion/deletion polymorphisms in AluY elements were detected. The encoded proteins of these two genes are part of a single signaling pathway, and therefore, functional polymorphisms in these genes could potentially lead to higher risk and susceptibility to atopic disorders. We also examined the allelic frequency and haplotypes of these polymorphisms in a control population. These data will be potentially useful for association studies designed to investigate the role of these genes in atopic disorders such as asthma, eczema, and allergic rhinitis. This is the first report on the polymorphic content of these two genes in the Indian population. Received: August 5, 2002 / Accepted: September 30, 2002     

Polymorphisms in the interleukin 17F gene (IL17F) and asthma

Interleukin17F (IL17F) is a regulatory cytokine for T-cell-mediated immune responses. The gene coding for IL17F (IL17F) is located on chromosome 6p, a genomic region linked to asthma and asthma-related phenotypes in multiple genome scans. IL17F is expressed in lung tissue, in bronchoalveolar lavage fluid from asthmatic subjects, and in activated CD4+ cells. We were thus interested in testing for association between single-nucleotide polymorphisms (SNPs) and haplotypes in IL17F and asthma. To characterize polymorphisms in IL17F, we sequenced this gene in a group of African Americans and a group of European Americans. A total of 50 SNPs (30 not previously reported in a public database (dbSNP build 118)) and two insertions/deletions were detected in IL17F; five of these polymorphisms were genotyped in participants of the Nurses' Health Study. We then tested for association between SNPs and haplotypes in IL17F and physician-diagnosed asthma in subjects with (cases) and without (control subjects) physician-diagnosed asthma. None of the SNPs or haplotypes tested in IL17F were associated with asthma. The polymorphisms identified in this study may be used in future studies of association between IL17F and phenotypes related to immune responses.     

An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic effects in these conditions are unclear. Toll-like receptors (TLRs) play an essential role in innate host defense and in the control of adaptive immune responses. IL-1R-associated kinase-M (IRAK-M) and single immunoglobulin IL-1R-related molecule (SIGIRR) negatively regulate TLR-signaling pathways. To investigate whether polymorphisms in these genes were associated with asthma or asthma-related phenotypes, we screened these genes for polymorphisms by direct sequencing of 24 asthmatics and identified 19 variants in IRAK-M and 12 variants in SIGIRR. We next conducted linkage disequilibrium mapping of the genes, and examined the association of polymorphisms and haplotypes using 391 child patients with asthma, 462 adult patients with asthma, and 639 controls. None of the alleles or haplotypes of IRAK-M and SIGIRR were associated with asthma susceptibility or asthma-related phenotype. Our results indicate that polymorphisms in IRAK-M and SIGIRR are not likely to be associated with the development of asthma in the Japanese population.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

Association of single nucleotide polymorphisms on Interleukin 17 receptor A (IL17RA) gene with aspirin hypersensitivity in asthmatics

Aim

To investigate the association of single nucleotide polymorphisms (SNP) on IL17RA gene with Aspirin Exacerbated Respiratory Disease (AERD) and the functional effect of these variants on expression of IL17RA gene products.

Material & methods

15 SNPs of IL17RA gene were analyzed in 825 normal controls and 143 subjects with AERD and 411 with aspirin-tolerant asthma (ATA) and functionally characterized using measurement of protein and m-RNA expression.

Result

Minor alleles frequencies of the three SNPs (−1075 A > G, −947 A > G, −50 C > T) and one haplotype (BL1_ht1) were significantly lower in AERD compared to those in ATA (p^corr = 0.002–0.03). IL17RA protein expression and mRNA amount in CD14⁺ peripheral blood monocytes and mononuclear cells were significantly increased in subjects carrying the common alleles homozygote compared with those carrying the minor alleles.

Conclusions

The minor alleles of the three SNPs may decrease the risk of AERD via attenuation of IL17RA gene expression.     

Interleukin‐4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

Signaling via the IL‐7 receptor complex (IL‐7Rα/CD127 and IL‐2Rγ/CD132) is required for T‐cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL‐2Rγ‐sharing (γ_C) cytokines decrease CD127 expression on CD4⁺ and CD8⁺ T cells in mice (IL‐2, IL‐4, IL‐7, IL‐15) and in humans (IL‐2, IL‐7), suggesting a common function. IL‐4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL‐4 in regulating CD127 expression and IL‐7 activity in human thymocytes and mature CD8⁺ T cells is unknown and was therefore investigated. IL‐4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA⁺) CD8⁺ T cells, without altering membrane‐bound CD127 mRNA expression. Pre‐treatment of thymocytes or CD8⁺ T cells with IL‐4 inhibited IL‐7‐mediated phosphorylation of STAT5 and decreased proliferation of CD8⁺ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8⁺ T cells, IL‐4 is a potential contributor to impaired CD8⁺ T‐cell function in some anti‐viral and anti‐tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL‐7 activity is impaired and IL‐4 concentrations are elevated.     

Evidence for increased expression of regulatory cytokine receptors interleukin-12R and interleukin-18R in common variable immunodeficiency

We investigated the expression of T helper (Th)1/Th2 regulatory cytokine receptors on lymphocytes from patients with common variable immunodeficiency (CVID), a disorder associated with raised Th1 cytokine production, comparing the results with those from healthy individuals and atopic asthmatics, the latter generally considered to have a Th2‐driven disease. We proposed that alterations in some of the relevant receptors might be related to the observed imbalances in Th1/Th2 cytokines. Cells from CVID patients showed an increase in the percentages of CD212 [interleukin (IL)‐12Rβ1] cells within the CD4⁺ CD45RA⁺ and CD8⁺ CD45RA⁺ subsets (24% and 41%, respectively), as compared to CD4⁺ CD45RA⁺ and CD8⁺ CD45RA⁺ in healthy subjects (6% and 23%, respectivey). Approximately 21% of the CD4⁺ CD45RA⁺ naïve cells expressed IL‐18Rα, compared with 11% in healthy subjects. In contrast, the cytokine‐receptor expression in asthmatics was similar to that of controls. In spite of the above differences, after 72 h of stimulation with anti‐CD3 and anti‐CD28, cytokine receptor up‐regulation was similar in all three groups, with up to 80% of both CD45RA⁺ and CD45RO⁺ lymphocytes expressing CD212 (IL‐12Rβ1) and IL‐18Rα. Approximately 50% of the ‘naïve’, and 25% of the ‘memory’ subpopulations up‐regulated IL‐12Rβ2. These findings provide further evidence of a polarization towards a Th1 immune response in CVID, the mechanism possibly involving up‐regulation of IL‐12‐mediated pathways.     

Eotaxin polymorphisms and serum total IgE levels in children with asthma

BACKGROUND: Eotaxin (chemokine, CC motif, ligand; CCL11) is a potent eosinophil chemoattractant strongly implicated in the pathobiology of asthma. Genetic variation at the CCL11 locus has been correlated with serum total IgE, blood eosinophil counts, and circulating eotaxin protein levels in several case-control asthma studies. Family-based association studies of CCL11 genetic variants have not been reported to date. OBJECTIVE: To evaluate 9 common CCL11 single nucleotide polymorphisms (SNPs) in nuclear families ascertained through patients with asthma participating in the Childhood Asthma Management Program study. METHODS: Single nucleotide polymorphism genotyping was performed by using minisequencing and probe hybridization platforms. Family-based association analysis for asthma and 4 asthma-related intermediate quantitative phenotypes was performed by using FBAT. RESULTS: One SNP, -384A>G, was associated with asthma among African American families (P = .01). CCL11 SNPs and haplotypes were not associated with asthma among white or Hispanic families. Two low-frequency alleles in strong pairwise linkage disequilibrium, -426C and IVS2+199A, were associated with lower serum total IgE levels (P = .0006 and P = .009, respectively) in white families, whereas 2 more common variants, -576C and g.4438C, were associated with higher IgE levels in African American families (P = .01-.04). Haplotype analysis in the white cohort provided additional evidence of association with serum total IgE, implicating 2 haplotypes. No single SNP or haplotype associations were observed with blood eosinophil levels, FEV(1), or airway responsiveness. CONCLUSION: These findings provide further evidence that genetic variation at the CCL11 locus is an important determinant of serum total IgE levels among patients with asthma.