Update on Recent Advances in the Management of Aspirin Exacerbated Respiratory Disease

Aspirin intolerant asthma (AIA) is frequently characterized as an aspirin (ASA)-exacerbated respiratory disease (AERD). It is a clinical syndrome associated with chronic severe inflammation in the upper and lower airways resulting in chronic rhinitis, sinusitis, recurrent polyposis, and asthma. AERD generally develops secondary to abnormalities in inflammatory mediators and arachidonic acid biosynthesis expression. Upper and lower airway eosinophil infiltration is a key feature of AERD; however, the exact mechanisms of such chronic eosinophilic inflammation are not fully understood. Cysteinyl leukotriene over-production may be a key factor in the induction of eosinophilic activation. Genetic studies have suggested a role for variability of genes in disease susceptibility and response to medication. Potential genetic biomarkers contributing to the AERD phenotype include HLA-DPB1*301, LTC4S, ALOX5, CYSLT, PGE2, TBXA2R, TBX21, MS4A2, IL10 -1082A > G, ACE -262A > T, and CRTH2 -466T > C; the four-locus SNP set was composed of B2ADR 46A > G, CCR3 -520T > G, CysLTR1 -634C > T, and FCER1B -109T > C. Management of AERD is an important issue. Aspirin ingestion may result in significant morbidity and mortality, and patients must be advised regarding aspirin risk. Leukotriene receptor antagonists (LTRA) that inhibit leukotriene pathways have an established role in long-term AERD management and rhinosinusitis. Aspirin desensitization may be required for the relief of upper and lower airway symptoms in AERD patients. Future research should focus on identification of biomarkers for a comprehensive diagnostic approach.     

Disease association of the interleukin-18 promoter polymorphisms in Taiwan Chinese systemic lupus erythematosus patients

Interleukin (IL)-18, an important mediator of innate and adaptive immunity, plays multiple roles in chronic inflammation, in autoimmune diseases, in a variety of cancers and in number of infectious diseases. IL-18 promoter polymorphisms have been also noted associated with various inflammatory diseases. We investigated the association of IL-18 promoter polymorphisms (-656T/G, -607A/C and -137C/G) with systemic lupus erythematosus (SLE) in Taiwan Chinese patients and controls. Six haplotypes (hts) were identified from the three promoter polymorphisms. The genotype distribution of the ht1 (GCC), ht2 (TAC), ht4 (GAC) and ht5 (TCC) were different in patients and controls (P<0.002). Moreover, the haplotype and genotype frequencies of ht1 were significantly increased in patients with discoid rash (P=0.045, odds ratio (OR): 2.01, 95% confidence interval (CI): 1.01-4.00; P=0.027, OR: 5.13, 95% CI: 1.41-18.68). In addition, the homozygous genotype ht1/ht1 was significant increased in patients with serositis (P=0.015, OR: 9.78, 95% CI: 1.55-61.73). These observations suggest that the three promoter polymorphisms contribute to the genetic background of SLE pathogenesis.     

Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis

It has been reported that a functional polymorphism in the promoter of the RANTES gene (-403G/A) is associated with atopic dermatitis in a German population. Although there are several reports on the association of RANTES promoter polymorphisms (-403G/A and -28C/G) with asthma, the association of these polymorphisms with atopic dermatitis has not yet been confirmed in other populations. We therefore aimed to test whether the RANTES promoter polymorphisms relate to atopic dermatitis in a well-defined Japanese population. We conducted an association study of upregulating promoter polymorphisms of RANTES (-403G/A and -28C/G) in 389 patients with atopic dermatitis and 177 healthy control subjects. There was a significant association between the upregulating variant of RANTES -28G and atopic dermatitis, while -403A variant showed a significant association with atopic dermatitis with high IgE productivity. These results support a role for RANTES promoter polymorphisms in susceptibility to atopic dermatitis.     

APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population

The apolipoprotein E (APOE, gene; apoE, protein) isoforms are associated with differential risk of Alzheimer's disease (AD). An additional involvement of APOE promoter polymorphisms in AD risk has recently been suggested by several studies. Indeed, three polymorphisms of the APOE regulatory region (-219 G/T, -427 C/T and -491 A/T) have been found associated with AD even after adjustment on the apoE status. We analysed these three promoter region polymorphisms in a large French case-control study (388 AD cases and 386 controls). We found that the -427 T and -491 A alleles were associated with an increased risk of developing AD, but not the -219 G/T alleles. However, a strong linkage disequilibrium was observed between the alleles of these promoter region polymorphisms and the APOE coding region alleles. We therefore retested association after adjustment on apoE status and found that the sole association which remained significant was the association with the -427 T allele. The alpha level was equal to 0.03 (0.09 after Bonferroni correction for multiple comparisons). Analysis of promoter haplotypes also yielded non-significant results. Thus our study does not reinforce the hypothesis of an independent involvement of the APOE promoter region polymorphisms in AD risk.     

Genetic mechanism of aspirin-induced urticaria/angioedema

PURPOSE OF REVIEW: Aspirin-induced urticaria/angioedema is a major aspirin-related hypersensitivity often associated with aspirin-intolerant asthma. Genetic studies on aspirin-intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes. The genetic analysis of aspirin-induced urticaria/angioedema is limited, however. RECENT FINDINGS: A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin-induced urticaria/angioedema. A polymorphism study that examined nine single-nucleotide polymorphisms of five leukotriene-related genes [ALOX5 (encoding 5-lipoxygenase), ALOX5AP (5-lipoxygenase-activating protein), PTGS2 (cyclooxygenase 2), LTC4S (leukotriene C4 synthase), and CYSLTR1 (cysteinyl leukotriene receptor 1)] found that promoter polymorphisms of ALOX5 (-1708A>G) and CYSLTR1 (-634C>T) were significantly different between aspirin-intolerant asthma and aspirin-induced urticaria/angioedema, suggesting different contributions to the lipoxygenase pathway. A second polymorphism study, conducted on histamine-related genes, did not find any significant associations with aspirin-induced urticaria/angioedema for the genes HNMT (encoding histamine N-methyltransferase), HRH1 or HRH2 (encoding histamine receptor types 1 and 2 respectively), or the gene encoding high-affinity IgE receptor Ibeta (FcepsilonRIbeta); however, the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin-induced urticaria/angioedema. This finding has been supported by in vitro functional studies. SUMMARY: The HLA alleles DRB11302 and DQB10609, and the ALOX5 and FcepsilonRIalpha promoter polymorphisms, may contribute to the pathogenesis of aspirin-induced urticaria/angioedema. Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition.     

Increased total serum IgE levels in patients with asthma and promoter polymorphisms at CTLA4 and FCER1B.

BACKGROUND: Increasing evidence indicates that total serum IgE levels are largely determined by genetic factors, and we recently established that the -109C/T promoter polymorphism at FCER1B is a genetic factor that affects total serum IgE levels. The gene encoding cytotoxic T lymphocyte antigen 4 (CTLA4) is another candidate factor in high IgE responsiveness, because B7-CD28/CTLA4 interaction can promote the differentiation and development of the T(H)2 lymphocyte subset. OBJECTIVE: We intended to determine whether CTLA4 is associated with increased levels of total serum IgE or with the development of asthma or atopy. METHODS: We performed a case-control study involving 339 patients with asthma and 305 healthy control subjects, of whom 226 of the patients with asthma and 219 of the healthy control subjects had previously been genotyped for the -109C/T promoter polymorphism at FCER1B. In the current study, we genotyped 2 polymorphisms in the CTLA4 gene, one involving the promoter (-318C/T) and the other involving exon 1 (+49A/G), in addition to the FCER1B promoter polymorphism. RESULTS: Patients with asthma who were homozygous for the -318C allele at the CTLA4 promoter region had higher levels of total serum IgE than patients with asthma carrying the -318T allele (P =.00470). The analysis of -318C/T (at CTLA4) and -109C/T (at FCER1B) promoter polymorphisms showed a significant correlation between the combined genotypes and increased levels of total IgE in patients with asthma (P =.000014). In contrast, no correlation between total serum IgE levels and -318C/T or +49A/G genotypes was detected in 305 healthy control subjects. There was no evidence indicating an association between a putative allele for asthma or atopy and alleles at any of the CTLA4 polymorphic loci. CONCLUSION: Our findings suggest that promoter polymorphisms of both CTLA4 and FCER1B are genetic factors that influence total serum IgE levels in patients with asthma. This supports the theory that variance in total serum IgE levels in patients with asthma is determined by mutations in multiple genes, each of which has a relatively small effect on the phenotype.     

血管紧张素原基因的六种单核苷酸多态与原发性高血压的相关性

目的　研究血管紧张素原 (angiotensinogen,AGT)基因 6个位点的单核苷酸多态及其构成的单倍型与中国汉族人原发性高血压的相关性。方法　采用多重SNa Pshot反应 ,在 185例原发性高血压患者和185名健康对照者中 ,对 AGT基因启动子区域的 G- 2 17A、G- 15 2 A、A- 2 0 C、G- 6 A及第 2外显子的T174 M和 M2 35 T多态进行基因分型。结果　 6种单核苷酸多态的基因型分布及其等位基因频率在原发性高血压组和对照组中差异无显著性 (P>0 .0 5 )。单倍型分析提示由 - 15 2 A,- 2 0 C,- 6 A和 2 35 T等位基因构成的 H4单倍型在原发性高血压组中明显增加 ,与对照组相比差异有显著性 (P<0 .0 5 )。结论　AGT基因G- 15 2 A,A- 2 0 C,G- 6 A和 M2 35 T多态可能对中国汉族人原发性高血压的发病起了重要作用。     

Association between RANTES polymorphisms and asthma severity among Tunisian children

The chemokine known as RANTES (regulated upon activation, normal T cells expressed and secreted) is an important element for the chemotaxis at the site of allergic inflammation. Many studies have made an interesting link between RANTES polymorphisms and asthma, showing that the variant in the promoter region is associated with high risk of asthma and severe airway obstruction. We conducted a case-control and family study aiming at identifying the relationship between polymorphisms (-28 C/G and -403 G/A) and haplotypes in the RANTES gene with asthma and severity. The results of the case control study suggest an association between alleles level of -28 C/G and -403 G/A promoter polymorphism (p = 0.01) (p = 0.00175) and asthma. Univariate analysis of the RANTES polymorphisms show an increased prevalence of the AC and AG haplotypes in asthmatics (p = 0.014) and (p = 0.015) respectively. Our data suggest that -28 C/G and -403 G/A polymorphisms within the RANTES promoter region play an important role in asthma predisposition and in the severity of airway obstruction.     

Association analysis of formyl peptide receptor 2 (FPR2) polymorphisms and aspirin exacerbated respiratory diseases

Aspirin-exacerbated respiratory diseases (AERD) are associated with the metabolism of arachidonic acid. FPR2 (formyl peptide receptor2) is a high-affinity ligand receptor for potent anti-inflammatory lipid metabolites: lipoxins. Thus, functional alterations of the FPR2 may contribute to AERD. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in the FPR2 and AERD. Asthmatics were categorized into AERD <15% decreases in forced expiratory volume in one second (FEV(1)), and/or naso-ocular reactions after oral aspirin challenge (n=170) and aspirin-tolerant asthma (ATA, n=268). In all, 11 SNPs were genotyped. FPR2 protein expressions on CD14-positive monocytes in peripheral blood were measured using flow cytometric analysis. We performed RT-PCR of the FPR2 mRNA expressed by peripheral blood mononuclear cells. Logistic regression analysis showed that the minor allele frequency of FPR2 -4209T>G (rs1769490) in intron 2 was significantly lower in the AERD group (n=170) than in the ATA group (n=268) (P=0.006, P(corr)=0.04, recessive model). The decline of FEV(1) after aspirin challenge was significantly lower in the subjects with GG homozygotes of FPR2 -4209T>G than those with the other genotypes (P=0.0002). Asthmatic homozygotes for FPR2 -4209T>G minor allele exhibited significantly higher FPR2 protein expression in CD14-positive monocytes than did those with the common allele of FPR2 -4209T>G allele (P=0.01). There was no difference in the expression of the wild form and the exon 2 deleted variant form of FPR2 gene according to the genotypes of FPR2 -4209T>G. The minor allele at FPR2 -4209T>G may have a protective role against the development of AERD, via increase of FPR2 protein expression in inflammatory cells.     

CCL5/RANTES chemokine gene promoter polymorphisms are not associated with atopic and nonatopic asthma in a Spanish population

CCL5/RANTES, a member of the C-C chemokine family, is a potent eosinophil, monocyte, basophile and lymphocyte chemo-attractant at the site of inflammation. Recent studies revealed that a functional mutation at the -403 position in the promoter may have significance for atopic dermatitis, bronchial asthma, sarcoidosis, rheumatoid arthritis and HIV infection, and others. Another polymorphism in the -28 position has been reported. Our objective was to investigate the possible influence of the CCL5/RANTES promoter polymorphisms in the different types of bronchial asthma. CCL5/RANTES genotyping was performed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) in 306 asthmatic patients with non-atopic (n = 145) and atopic (n = 161) asthma and 242 controls. The 81.9% of the atopic asthma patients for -403G/A had the G allele and the A allele frequency was 18%. Of the non-atopic asthma patients, the G allele frequency was 79.7% and the A allele was 20.3%. Concerning the -28C/G polymorphism, the frequency of the CCL5/RANTES -28G allele in our patients is 2.8%, which is similar to Spanish adult population. After comparing patients with asthma, atopic patients, non-atopic patients and control population, we found no significant deviation in the distribution of the alleles or genotypes of CCL5/RANTES promoter polymorphisms in any tested comparison. Therefore, human CCL5/RANTES gene promoter polymorphisms are not associated with the different types of bronchial asthma in Spanish population.     

Genetic association between interleukin-10 gene promoter region polymorphisms and type 1 diabetes age-at-onset

This study investigated whether interleukin-10 (IL-10) gene promoter region polymorphisms are associated with susceptibility to or clinical presentation of type 1 diabetes. The frequency of -1082G/A, -819C/T, and -592C/A polymorphisms was analyzed in 128 Japanese patients with type 1 diabetes and in 107 healthy control subjects in a case-controlled study. The allelic and haplotypic frequencies of the IL-10 gene promoter region polymorphisms were similar in patients with type 1 diabetes and in control subjects. However, the -819T and -592A allele were associated with adult-onset (>18 years) of the disease (p = 0.037). Furthermore, the frequency of ATA haplotype was increased in adult-onset patients than that in early-onset patients (< or =18 years; p = 0.037). Among the genotypes comprising ATA haplotype, the frequency of ATA/ATA was significantly higher in adult-onset patients than in early-onset patients (p = 0.004). These results suggest that the IL-10 gene promoter polymorphisms are associated with the age-at-onset in Japanese patients with type 1 diabetes.     

Preferential transmission and association of the -403 G --> A promoter RANTES polymorphism with atopic asthma

Asthma is a complex inherited disease. The study was undertaken to identify the association of RANTES promoter polymorphisms with atopy and asthma using family-based association tests (FBATs) and generation-specific case-control analyses. We identified 154 nuclear families (453 individuals) in whom we established RANTES promoter status using the RFLP-PCR method. Of the two known promoter polymorphisms -403G/A and -28C/G, only the former appeared with a clinically relevant frequency. A total of 61 families were eligible for assessment of transmission of the allele with asthma and atopy by the pedigree disequilibrium test (PDT). Overall, allele frequency for -403A was 38.3% and 84 of 89 (94.3%) alleles were transmitted with physician diagnosed asthma (PDA) (P=0.001). All 89 children with atopy received the mutant allele, which was more than expected following Mendelian Laws of transmission (P=0.0001). In 303 unrelated parents, significant associations of the mutant allele were for atopy with or without asthma (P=0.001). In 150 unrelated children, significant associations were for atopy alone (P=0.001) and asthma (P=0.001). No associations were found for bronchial hyper-responsiveness (BHR). The -403 G --> A is transmitted with atopy and atopic asthma, although its contribution appears to relate more to atopy than asthma and BHR.     

Probable role of Beta 2-adrenergic receptor gene haplotype in toluene diisocyanate-induced asthma

Purpose

A genetic polymorphism of the beta 2-adrenergic receptor is a major factor associated with the asthmatic phenotype. The association of this polymorphism with toluene diisocyanate (TDI)-induced asthma has not been investigated. We examined 103 TDI-induced asthma patients (TDI-OA), 60 asymptomatic exposed controls (AEC), and 263 unexposed healthy controls (NC) in order to identify beta 2-adrenergic receptor gene (ADRB2) polymorphisms and the possible association with TDI-induced asthma.

Methods

Single nucleotide polymorphisms (SNPs) of ADRB2 were genotyped by direct sequencing. Serum-specific IgE and IgG levels were measured using an enzyme-linked immunosorbent assay. Phenotypes and clinical patient parameters were compared.

Results

SNPs were identified (-47 T>C, -20 T>C, Arg16Gly A>G, Gln27Glu C>G, Leu134Leu G>A, Arg175Arg C>A) during ADRB2 screening (from -231 to 793 bp). No significant differences in allelic and genotypic frequencies were noted for any of the six ADRB2 SNPs. The Arg16Gly A>G, Leu134Leu G>A, and Arg175Arg C>A SNPs and haplotype 1 [TTACGC] were significantly associated with specific IgE antibodies to the TDI-human serum albumin (HSA) conjugate in TDI-exposed subjects (P<0.05). Exposed workers with the ADRB2 ht1/ht1 homozygote had a significantly higher TDI-HSA conjugate-specific IgE sensitization rate than did those with the null ht1 haplotype (odds ratio, 15.40; 95% confidence interval, 1.81-131.06).

Conclusions

ADRB2 polymorphisms may affect IgE-specific sensitization to TDI-HSA conjugate in TDI-exposed workers.     

Alleles -308A and -1031C in the TNF-alpha gene promoter do not increase the risk but associated with circulating levels of TNF-alpha and clinical features of vivax malaria in Indian patients

The biological significance of TNF promoter polymorphism and infectious disease association prompted us to investigate whether TNF-alpha -308 G/A and -1031 T/C promoter polymorphisms are associated with Plasmodium vivax infection, cellular TNF-alpha level and possibly with clinical symptoms by employing PCR-RFLP methods. An overall significant elevation of serum TNF-alpha, IL-6 content (p=0.0002, p=0.002, respectively), whereas highly significant depletion of IL-10 content (p=0.0001) was observed in vivax patients. In addition, TNF-alpha concentration in patients with and without fever were found to be significant (p=0.0001, p=0.0004, respectively). The genotypic distribution for -308 G/A and -1031 T/C positions were found non significant, but it was clinically potent to observe statistically significant distribution of genotypes (p=0.032) in patients with and without fever. Furthermore, the TNF-alpha level in TNF1 and TNF2 genotype for -308 position was significantly higher (p=0.010, p=0.006 respectively). In case of -1031 position TNF-alpha level was significant in ancestral (TT) genotype (p=0.0007) in patients compared to healthy subjects and significantly higher in rare (CC) genotype (p=0.021) as compared to ancestral genotype. In addition, the two polymorphisms 308G/A and -1031T/C were in highly significant LD (D'=0.7992, r(2)=0.6005, p=0.0001) in the patients as well as it is interesting to report that the distribution of novel 308A: 1031C alleles associated haplotypes are nearly the same in patients (0.2610) and in healthy subjects (0.2636). In view of present observation of promoter polymorphism with TNF-alpha level and other clinical parameters of vivax infection, we suggest that evaluation of TNF level and its polymorphisms in the promoter region may be considered to be reliable molecular and immunological markers, possess promising rational for diagnostic potential and immunotherapeutic interventions in clinical vivax malaria. Genetic variation in the promoter region is of biological significance and may play important roles in host defense mechanisms against vivax infection by enhancing cell-mediated immunity and stimulating the protective immunological cascade.     

The RANTES promoter polymorphism: a genetic risk factor for near-fatal asthma in Chinese children

BACKGROUND: RANTES promoter polymorphisms were found associated with asthma/atopy in some studies but not others, possibly reflecting the genetic heterogeneity among different ethnicities and different asthma severity. OBJECTIVE: The purpose of this investigation was to test the genetic association between the RANTES -28C/G and -403G/A polymorphisms and asthma/atopy in a cohort of Chinese children, with particular emphasis on those patients who had experienced life-threatening asthma attacks. METHODS: Forty-eight children with near-fatal asthma, 134 children with mild-to-moderate asthma, 69 children with allergic disorders but no asthma, and 107 nonasthmatic nonatopic control children were genotyped through use of a PCR-based assay. RESULTS: No significant difference was demonstrated for frequency of the RANTES -28C/G polymorphism when the mild-to-moderate asthma, atopic/nonasthmatic, and normal control groups were compared. The RANTES -28G allele was present in a significantly higher proportion of the children with near-fatal asthma compared with the nonasthmatic nonatopic controls (odds ratio, 2.93 [1.41-6.06]; P =.006) and the children with mild-to-moderate asthma (odds ratio, 3.52 [1.73-7.16]; P =.001). The frequency of -28G allele carriage correlated with asthma severity. The RANTES -28G allele was also associated with an increased blood eosinophil count and a higher degree of bronchial hyperresponsiveness. The RANTES -403G/A polymorphism did not influence asthma/atopy susceptibility, blood eosinophil count, or bronchial hyperresponsiveness. Interestingly, a higher frequency of -403A allele carriage was observed in the moderate asthma subgroup compared with the mild asthma analog. CONCLUSIONS: We conclude that the RANTES -28C/G polymorphism exacerbates asthma severity, representing a genetic risk factor for life-threatening asthma attacks in Chinese children. In addition, the linkage disequilibrium between these 2 polymorphisms is a potential confounder that must be considered in the design and interpretation of RANTES gene association studies.     

The effects of RANTES/CCR5 promoter polymorphisms on HIV disease progression in HIV-infected Koreans

Recent studies have reported that two single nucleotide polymorphisms (SNPs) in the RANTES gene promoter region, -403G/A and -28C/G, are associated with a slower rate of decline in CD4(+) T-cell number, whereas genetic polymorphisms within the CCR5 promoter are linked to acceleration of AIDS progression. In this study, we investigated the distribution of SNPs in the RANTES and CCR5 promoters and the association between these SNPs and HIV-1 disease progression in HIV-infected Koreans. Twenty-seven long-term non-progressors (LTNPs), 29 AIDS patients and 39 HIV-uninfected persons were enrolled in this study. SNPs for the RANTES and CCR5 promoters were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and a direct sequencing method. In the analysis of RANTES promoter polymorphisms, the genotypic and allelic frequencies of the RANTES -28G mutation were significantly lower in HIV-infected patients than in HIV-uninfected persons (P = 0.005 and P = 0.001, respectively). The genotypic frequencies of RANTES -28G and -403A mutations did not differ significantly between LTNPs and AIDS patients. The frequencies of three CCR5 promoter polymorphisms, designated 59029 G/A, 59353T/C, and 59402G/A, did not differ significantly between HIV-uninfected and HIV-infected patients. However, the allelic frequency of CCR559353C was significantly higher in AIDS patients than in LTNPs (P = 0.003). These results suggest that RANTES-28G and CCR5 59353C mutations might be associated with HIV infection or pathogenesis in the Korean population.