Cysteinyl leukotriene receptor 1 promoter polymorphism is associated with aspirin-intolerant asthma in males

BACKGROUND: Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA). METHODS: To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC). RESULTS: Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04). CONCLUSION: These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.     

Association between ADAM33 polymorphisms and adult asthma in the Japanese population

Background ADAM33, a member of the ADAM (a disintegrin and metalloprotease) family, is a putative asthma susceptibility gene recently identified by positional cloning. It is important to know whether the association exists in ethnically diverse populations. Objective To assess whether genetic functional variants of ADAM33 relate to the susceptibility or some phenotypes in adult patients with bronchial asthma in a Japanese population. Methods We searched for single nucleotide polymorphisms (SNPs) in ADAM33 by PCR‐directed sequencing and identified 48 SNPs. Fourteen SNPs were selected with regard to the LD pattern, and genotyped by Taq‐Man and PCR–RFLP methods. We conducted an association study of ADAM33 with 504 adult asthmatic patients and 651 controls, and haplotype analyses of related variants were performed. Results Significant associations with asthma were found for the SNPs T1 (Met764Thr), T2 (Pro774Ser), S2 and V?3 (with the lowest P‐value for T1, P=0.0015; OR 0.63). We analysed the haplotype using these four polymorphisms, and found a positive association with haplotype CCTG (P=0.0024). Conclusion Our results replicate associations reported recently in other ethnic populations, and suggest that the ADAM33 gene is involved in the development of asthma through genetic polymorphisms.     

eotaxin-3基因多态性与变应性哮喘的相关性

目的研究eotaxin-3基因多态性与变应性哮喘的相关性。方法用聚合酶链反应-单链构象多态性-四引物聚合酶链反应-限制性酶切的方法对湖北地区汉族成人eotaxin-3＋77C／T和＋2497T／G单核苷酸多态性与哮喘易感性、嗜酸性粒细胞（eosinophil，EOS）计数以及血浆总IgE水平的相关性进行了分析。结果eotaxin-3＋2497位哮喘组与对照组G等位基因的频率，哮喘组IgE浓度及EOS数量差异有统计学意义，P值分别为0．01l、0．021和0．029；＋77位哮喘组与对照组T等位基因的频率，哮喘组IgE浓度差异无统计学意义，P值分别为0．824和0．473；＋77位哮喘组EOS数量差异有统计学意义，P值为0．044。结论eotaxin-3＋2497T／G多态性与哮喘易感性、EOS数量及IgE水平相关，＋77位C／T基因多态性与哮喘EOS数量相关。     

Unraveling the Genetic Basis of Aspirin Hypersensitivity in Asthma Beyond Arachidonate Pathways

Although aspirin-exacerbated respiratory disease (AERD) has attracted a great deal of attention because of its association with severe asthma, it remains widely under-diagnosed in the asthmatic population. Oral aspirin challenge is the best method of diagnosing AERD, but this is a time-consuming procedure with serious complications in some cases. Thus, development of non-invasive methods for easy diagnosis is necessary to prevent unexpected complications of aspirin use in susceptible patients. For the past decade, many studies have attempted to elucidate the genetic variants responsible for risk of AERD. Several approaches have been applied in these genetic studies. To date, a limited number of biologically plausible candidate genes in the arachidonate and immune and inflammatory pathways have been studied. Recently, a genome-wide association study was performed. In this review, the results of these studies are summarized, and their limitations discussed. In addition to the genetic variants, changes in methylation patterns on CpG sites have recently been identified in a target tissue of aspirin hypersensitivity. Finally, perspectives on application of new genomic technologies are introduced; these will aid our understanding of the genetic pathogenesis of aspirin hypersensitivity in asthma.     

Efficacy of leukotriene receptor antagonist in bronchial hyperresponsiveness and hypersensitivity to analgesic in aspirin-intolerant asthma

BACKGROUND: Albeit its exact pathogenesis is still ambiguous; aspirin-intolerant asthma is one of several types of asthma for which antileukotriene therapy is useful, because it is widely accepted that bronchial over-production of leukotrienes may be involved in its pathogenesis. Pranlukast (8-[p-(4-phenylbutyloxy) benzol] amino-2-(tetrazol-5-yl)-4-oxo-4H-1-benzopyran hemihydrate), a selective cysteinyl leukotriene receptor antagonist, is now widely used in the treatment of asthma. OBJECTIVE: This study was designed to investigate the protective effect of pranlukast on airway sensitivity to sulpyrine provocation testing, bronchial responsiveness to methacholine provocation testing, and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary LTE4 (uLTE4), a marker of the cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. METHODS: We assessed the effects of pretreatment with pranlukast on bronchoconstriction precipitated by inhalation of methacholine and sulpyrine in 16 adult patients with mild or moderate aspirin-intolerant asthma; those who were in stable clinical condition and were hypersensitive to sulpyrine provocation testing were allocated to this study. A double-blind, randomized, crossover design was used. uLTE4 was measured using combined reverse-phase high-performance liquid chromatography (rp-HPLC)/enzyme immunoassay. RESULTS: Pranlukast protected against analgesic-induced bronchoconstriction through mechanisms that were not related to the bronchodilator property, but were related to the improvement both of bronchial hyperresponsiveness and hypersensitivity to analgesic (P < 0.005 and P < 0.0001). Pranlukast showed little effect on excretion of uLTE4. CONCLUSION: These results support the hypothesis that cysteinyl leukotriene is one of the most important components in the pathogenesis of aspirin-intolerant asthma. Pranlukast improves not only hypersensitivity to analgesic, but also bronchial hyperresponsiveness in aspirin-intolerant asthma. It is also possible that pranlukast has another anti-asthmatic effect besides that of a leukotriene receptor antagonist.     

p53基因第72密码子多态性与中国人肝细胞癌遗传易感性的相关性

目的探讨在有无慢性乙型肝炎的不同背景下郦基因第72密码子多态性（R72P）与中国人肝细胞癌（hepatocellular carcinoma，HCC）遗传易感性的关系。方法采用聚合酶链反应-限制性片段长度多态方法，检测469例HCC（HBsAg阴性110例、HBsAg阳性359例）与567名对照（HBsAg阴性430例、HBsAg阳性137例）的郦R72P基因型分布及差异。结果全样本以及HBsAg阳性样本的HCC与对照问的基因型分布差异均无统计学意义。但在HBsAg阴性人群中，72P是HCC发生的危险因素（OR=1，69，95％CI=1，25～2．27）。与R／R基因型相比，R／P的HCC风险增加至1．73倍（95％CI=0．96～3．11），P／P的HCC风险显著增加至3．29倍（95％CI=1．58～6．86）。携带72P的男性个体、HCC家族史阳性个体的HCC风险分别进一步增加至9．39倍（95％CI=3，08～28．62）和11，14倍（95％CI=1，62～76．67）。结论皿形72P增加HBsAg阴性中国人的HCC风险，并与男性、HCC家族史在增加HCC风险中有协同作用。     

Generality of genomic findings on blood pressure traits and its usefulness in precision medicine in diverse populations: A systematic review

Remarkable findings from genome-wide association studies (GWAS) on blood pressure (BP) traits have made new insights for developing precision medicine toward more effective screening measures. However, generality of GWAS findings in diverse populations is hampered by some technical limitations. There is no comprehensive study to evaluate source(s) of the non-generality of GWAS results on BP traits, so to fill the gap, this systematic review study was carried out. Using MeSH terms, 1545 records were detected through searching in five databases and 49 relevant full-text articles were included in our review. Overall, 749 unique variants were reported, of those, majority of variants have been detected in Europeans and were associated to systolic and diastolic BP traits. Frequency of genetic variants with same position was low in European and non-European populations (n = 38). However, more than 200 (>25%) single nucleotide polymorphisms were found on same loci or linkage disequilibrium blocks (r² ≥ 80%). Investigating for locus position and linkage disequilibrium of infrequent unique variants showed modest to high reproducibility of findings in Europeans that in some extent was generalizable in other populations. Beyond theoretical limitations, our study addressed other possible sources of non-generality of GWAS findings for BP traits in the same and different origins.     

A polymorphism of MS4A2 (−109T>C) encoding the β-chain of the high-affinity immunoglobulin E receptor (FcɛR1β) is associated with a susceptibility to aspirin-intolerant asthma

BACKGROUND AND OBJECTIVE: The MS4A2 gene, the beta chain of the high-affinity receptor for immunoglobulin (Ig)E, has previously been linked to atopy and asthma. The beta-chain of FcepsilonR1 enhances receptor maturation and signal transduction capacity, leading to the release of proinflammatory mediators and cytokines that can exacerbate the symptom of asthma. This study was performed to evaluate whether two genetic polymorphisms of the FcepsilonR1beta gene (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) are associated with aspirin-intolerant asthma (AIA). The MS4A2 gene polymorphisms (FcepsilonR1beta-109T > C and FcepsilonR1beta E237G) were determined by SNP-IT assays in patients with AIA (N = 164), aspirin-tolerant asthma (ATA, N = 144) and normal controls (NC, N = 264) recruited from a Korean population. RESULTS: The genotype frequencies of FcepsilonR1beta-109T > C and E237G polymorphisms were not significantly associated with the pathogenesis of AIA. However, FcepsilonR1beta-109T > C polymorphism was significantly associated with the presence of specific IgE to Staphylococcal enterotoxin B (SEB); the number of subjects carrying both homozygous TT genotype of FcepsilonR1beta-109T > C and specific IgE to SEB was significantly higher in the AIA group when compared with the other control groups (P = 0.01, odds ratio (OR) = 7.723, 95% confidence interval (CI) = 1.327-39.860 for AIA vs. ATA; P = 0.02, OR = 6.364, 95% CI = 1.149 approximately 35.229 for AIA vs. NC). In addition, luciferase reporter assays also showed that the FcepsilonR1beta-109T allele was associated with higher promoter activity of MS4A2 in both RBL-2H3 and A549 cell lines. CONCLUSION: FcepsilonR1beta-109T > C polymorphism may increase expression of MS4A2 by mast cells, leading to enhanced release of proinflammatory mediators in the asthmatic airway, contributing to increased susceptibility to AIA.     

High throughput SNP and expression analyses of candidate genes for non-syndromic oral clefts

Background

Recent work suggests that multiple genes and several environmental risk factors influence risk for non‐syndromic oral clefts, one of the most common birth defects in humans. Advances in high‐throughput genotyping technology now make it possible to test multiple markers in many candidate genes simultaneously.

Methods

We present findings from family based association tests of single nucleotide polymorphism (SNP) markers in 64 candidate genes genotyped using the BeadArray approach in 58 case‐parent trios from Maryland (USA) to illustrate how multiple markers in multiple genes can be analysed. To assess whether these genes were expressed in human craniofacial structures relevant to palate and lip development, we also analysed data from the Craniofacial and Oral Gene Expression Network (COGENE) consortium, and searched public databases for expression profiles of these genes.

Results

Thirteen candidate genes showed significant evidence of linkage in the presence of disequilibrium, and ten of these were found to be expressed in relevant embryonic tissues: SP100, MLPH, HDAC4, LEF1, C6orf105, CD44, ALX4, ZNF202, CRHR1, and MAPT. Three other genes showing statistical evidence (ADH1C, SCN3B, and IMP5) were not expressed in the embryonic tissues examined here.

Conclusions

This approach demonstrates how statistical evidence on large numbers of SNP markers typed in case‐parent trios can be combined with expression data to identify candidate genes for complex disorders. Many of the genes reported here have not been previously studied as candidates for oral clefts and warrant further investigation.     

定位于12q24的腓骨肌萎缩症2L型10个候选基因的排除克隆

目的克隆定位于12号染色体微卫星标记D12S1720和D12S161l之间约6．8cM的区间内的腓骨肌萎缩症2L型的致病基因。方法应用生物信息学方法筛选10个候选基因，设计合成扩增10个基因外显子及外显子与内含子交界的引物，DNA直接测序法进行序列变异分析。结果在基因外显子及侧翼区共发现11个序列变异，其中杂合序列变异共5个，纯合序列变异共6个。上述序列变异与疾病表型无共分离现象。结论排除了10个候选基因（TAOK3、RAB35、RPLPO、PXN、RIVFl0、RHOF、VPS33A，RSN、DENR、RNP24）为腓骨肌萎缩症2L型致病基因的可能。发现了以上10个候选基因共11个单核苷酸多态，除镜影细胞（reed-steinberg cell，RS）细胞特异性中间丝相关蛋白基因的3207G→C在多态数据库已报道，其余均为新发现的单核苷酸多态。     

Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma

Background:  A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3 ) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans.
Objective:  We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like ( GSDML ) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population.
Methods:  We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4–17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens.
Results:  Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19–2.53, P  = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12–2.38, P  = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high ( r ² = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35–1.54, P  < 0.00001).
Conclusions:  Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma.     

Advances in asthma and allergy genetics in 2007

This review discusses the main advances in the genetics of asthma and allergy published in the Journal in 2007. The association studies discussed herein addressed 3 main topics: the effect of the environment and gene-environment interactions on asthma/allergy susceptibility, the contribution of T(H)2 immunity gene variants to allergic inflammation, and the role of filaggrin mutations in atopic dermatitis and associated phenotypes. Other articles revealed novel, potentially important candidate genes or confirmed known ones. Collectively, the works published in 2007 reiterate that allergy and asthma are typical complex diseases; that is, they are disorders in which intricate interactions among environmental and genetic factors modify disease susceptibility by altering the fundamental structural and functional properties of target organs at critical developmental windows.