TBXA2R gene polymorphism and responsiveness to leukotriene receptor antagonist in children with asthma

Background Thromboxane A2 receptor (TBXA2R) gene polymorphism has been associated with atopy and asthma, but few studies have reported the effect of this gene polymorphism on asthma‐related phenotype or responsiveness to leukotriene receptor antagonist (LTRA) in asthmatic children. This study investigated associations between asthma‐related phenotypes and TBXA2R polymorphism, and also analysed whether the TBXA2R polymorphism has an effect on the efficacy of the LTRA, montelukast, in asthmatic children with exercise‐induced bronchoconstriction (EIB). Methods Asthmatic children (n=695) and control children (n=159) were evaluated for asthma‐related phenotypes including total IgE, pulmonary function test, and bronchial hyperresponsiveness to methacholine or exercise. Genotypes were detected by PCR‐RFLP. In the montelukast study, exercise challenge was performed before and after an 8‐week montelukast treatment. Results The TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma. However, asthmatic children with combinations of the TBXA2R+795T>C and +924T>C risk alleles had significantly higher total IgE levels (P=0.01), total eosinophil counts (P<0.01) and lower forced expiratory volume in 1 s (FEV₁) (P=0.02) and forced expiratory rates at 25–75% of vital capacity (P=0.02) than those carrying the common alleles. When compared with individuals with the common alleles, patients with the TBXA2R+924T>C TT homozygote and TBXA2R+795T>C hetero‐ or homozygote (CT or CC) had a 3.67‐fold poor response to 8‐week montelukast treatment with respect to maximum percent fall in FEV₁ after exercise (odds ratio, 3.67; 95% confidence interval, 1.15–11.15). Conclusions A combined effect of TBXA2R+795T>C and +924T>C risk alleles may be linked to IgE production, eosinophilic inflammation, and severity of asthma. In addition, the TBXA2R+795T>C genotype may be a predictive marker of a clinical response to the LTRA in Korean asthmatic children with EIB.     

Association of SLC6A12 variants with aspirin‐intolerant asthma in a Korean population

Aspirin‐intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin‐intolerant asthma (AIA) and 429 aspirin‐tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; P^corr= 0.03), rs557881 (non‐synonymous C10R, P= 0.007; P^corr= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; P^corr= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV₁ by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population.     

Association of thromboxane A2 receptor gene polymorphism with the phenotype of acetyl salicylic acid-intolerant asthma

BACKGROUND AND OBJECTIVE: The thromboxane A2 receptor (TBXA2R) is a receptor for a potent bronchoconstrictor, TBXA2 which is known to be related to bronchial asthma and myocardial infarction. TBXA2R antagonist and TBX synthase inhibitors have been found to be effective in the management of asthmatic patients. This study was aimed to evaluate whether genetic variants of TBXA2R may be related with development of acetyl salicylic acid (ASA)-intolerant asthma (AIA). METHODS: TBXA2R gene polymorphisms (TBXA2R+795T>C, TBXA2R+924T>C) were determined using a single-base extension method in 93 AIA patients compared with 172 patients with ASA-tolerant asthma (ATA) and 118 normal controls (NCs) recruited from the Korean population. HLA DPB1*0301 genotype was performed using a direct sequencing method. RESULTS: The rare C allele frequency of TBXA2R+795T>C was significantly higher in AIA than in ATA (P=0.03) and the TBXA2R+795T>C polymorphism was also associated with extent of percent fall in forced expiratory volume in 1 s (FEV1) after the inhalation of lysine-acetyl salicylic acid in AIA patients (P=0.009); AIA patients homozygous for the +795 C allele had a greater percent fall of FEV1 compared with individuals with TBXA2R+795 CT or TT genotypes. The frequency of patients carrying both the TBXA2R+795T>C rare allele and HLA DPB1(*)0301 was significantly higher in AIA patients (29.4%) than in ATA patients (7.3%) (P=0.008, odds ratio=5.3). CONCLUSION: These results suggest that the polymorphism of TBXA2R+795T>C may increase bronchoconstrictive response to ASA, which could contribute to the development of the AIA phenotype.     

Association of beta 2-adrenergic receptor polymorphism with the phenotype of aspirin-intolerant acute urticaria

The genetic mechanism of aspirin intolerant acute urticaria (AIAU) is unknown. To demonstrate an association between the beta 2 adrenergic receptor (ADRB2) polymorphism and the phenotype of AIAU, one hundred fourteen patients with AIAU, 110 patients with aspirin intolerant chronic urticaria (AICU), and 498 normal healthy controls (NC) based on a Korean population were enrolled. The genotype of ADRB2 at 46 A > G was analyzed using a direct sequencing method. The ADRB2 polymorphism at 46 A > G showed a significant difference between AIAU and NC; the frequency of the major genotype was significantly higher in the AIAU group (p= 0.017 in recessive model), while no differences were noted in allele and genotype frequencies between AICU and NC. In conclusion, the ADRB2 (46 A > G) gene polymorphism may contribute to the development of the phenotype of AIAU.     

Lack of association of serotonin‐2A receptor gene polymorphism (T102C) with suicidal ideation and suicide

Serotonergic dysfunction has been implicated in the pathophysiology of affective disorders and suicidality. Especially the density of the 5‐HT2A receptor was claimed as being increased in suicidality, proposed as an adaptive upregulation due to reduced serotonergic transmission. Recent studies have shown an association of allele C of the 5‐HT2A‐T102C polymorphism with suicidal ideation in patients with major depression. The purpose of this study was to test whether this proposed marker indicates susceptibility not only to suicidal ideation in depressed patients but also to suicidality as a syndrome. We investigated the 5‐HT2A‐T102C polymorphism in 131 suicide victims with unknown underlying psychiatric diagnoses, 84 patients with major depression with or without suicidal ideation, and 125 healthy controls. We were unable to find any association of genotype or allele frequencies to major depression, suicidal ideation, or suicide as a syndrome. Thus, our results suggest that this polymorphism may not commonly be involved in the susceptibility to suicidality. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:831–835, 2000. © 2000 Wiley‐Liss, Inc.     

Association between 5-hydroxytryptamine 2A receptor gene polymorphism and postoperative analgesic requirements after major abdominal surgery

Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women.     

多巴胺受体D2型基因启动区多态性与精神分裂症关联研究

目的探讨湖北武汉地区汉族人群中多巴胺受体D2型基因(dopamine receptor D2, DRD2)启动区-141位点胞嘧啶插入/缺失多态性与精神分裂症的关联关系.方法应用聚合酶链反应-限制性片段长度多态性方法,对120例精神分裂症患者、100名健康对照者进行基因分型.对精神分裂症患者的 DRD2 -141位点胞嘧啶插入/缺失多态性进行了相关分析.结果 DRD2型基因启动区-141位点的等位基因、基因型频率在精神分裂症组与对照组之间的分布差异有统计学意义(P<0.05).在精神分裂症组中,-141C缺失的等位基因频率为0.11,对照组为0.18(比值比为0.55,95%可信区间为0.30～0.96,P <0.05).结论 -141位点胞嘧啶插入/缺失多态性非独立性地对精神分裂症与 DRD2基因的相关性产生修饰作用.-141位点胞嘧啶缺失可能是湖北武汉汉族精神分裂症患者的保护因素之一.     

自杀未遂与5-羟色胺2A受体基因的关联分析

目的 探讨5-羟色胺（5-HT）2A受体基因A-1438G和T102C两种多态性与自杀未遂之间的关系。方法 以149例自杀未遂者为研究对象。190名正常人为对照,采用聚合酶链反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism,PCR-RFLP)方法,分析5-HT2A受体基因A-1438G和T102C多态性。结果 PCR-RFLP分析发现,男性自杀未遂与5-HT2A受体基因A-1438G多态性的基因型GG关联。结论 5-HT2A受体基因A-1438G多态性可能与男性的自杀易感性相关。     

血栓素合酶基因Pro1770Leu多态性与新疆维吾尔族心肌梗死的相关性研究

目的 探讨血栓素合酶基因CYP5A1 Pro1770Leu多态性与新疆维吾尔族心肌梗死的相关性.方法 采用聚合酶链反应-限制性片段长度多态性方法,对315例心肌梗死患者和218名健康受试者血栓素合酶基因第13外显子Pro1770Leu位点进行分析,同时进行血清血栓素B2(thromboxane B2,TXB2)水平测定.结果 血栓素合酶基因第13外显子Pro1770Leu在病例组和健康对照组中基因型频率分别为:CC型0.933和0.977,TC型0.067和0.023,病例组TC型高于对照组(P＜0.05),且T等位基因频率显著高于对照组(P＜0.05),血清TXB2水平病例组较对照组明显增高,差异具有统计学意义(P＜0.05);TC基因型携带者血清TXB2水平较CC基因型者增高,差异具有统计学意义(P＜0.05).结论 血栓素合酶基因第13外显子Pro1770Leu基因多态性和新疆维吾尔族心肌梗死的发生具有相关性,可能与基因变异导致的血清TXB2水平增高有关.     

白细胞介素6受体基因单核苷酸多态性与2型糖尿病的关联性

目的探讨甘肃地区汉族人中白细胞介素6受体基因（interleukin 6 receptor gene，IL6R）启动子-183（G→A）和第9外显子D358A的变异与2型糖尿病（type 2 diabetes mellitus，T2DM）的关联。方法随机选取无亲缘关系甘肃地区汉族人183名，其中T2DM患者87例、正常对照96名，应用聚合酶链反应-限制性片段长度多态性（polymerase chain reaction-restriction fragment length polymorphism，PCR-RFLP）方法进行-183（G→A）和D358A变异的检测。结果正常对照组D358A的3种基因型频率和等位基因频率分别为AA31．2％、AC41．7％、CC27．1％、A52．1％、C47．9％，2型糖尿病组相应为AA44．8％、AC41．4％、CC13．8％、A65．5％、C34．5％，正常对照组CC基因型频率和C等位基因频率高于2型糖尿病组（χ^2=4．900，P〈0．05；χ^2=6．784，P〈0．01）。-183（G→A）3种基因型频率和等位基因频率差异无统计学意义。结论提示该基因D358A多态可能与中国人2型糖尿病关联。     

血栓素受体参与子痫前期的发病

目的 探讨血栓素受体(TPr)与子痫前期发病机制的关系.方法 用免疫组化和实时荧光定量PCR(real-time PCR)的方法检测36例子痫前期孕妇(病例组)和34例正常妊娠孕妇(对照组)胎盘中血栓素合酶(TXS)、血栓素受体(TPr)和非吞噬细胞氧化酶1(NOX1)的表达,用酶联免疫吸附试验(ELISA)检测胎盘TXA2的表达.结果 TXS和TPr蛋白主要表达在细胞滋养细胞、合体滋养细胞和绒毛血管内皮细胞的胞质中,NOX1蛋白主要表达在细胞滋养细胞、合体滋养细胞、绒毛血管内皮细胞及间质细胞的胞质中.子痫前期组胎盘TXS和NOX1蛋白、mRNA表达和TXA2表达均强于对照组(P＜0.05).子痫前期TXA2表达与新生儿体质量呈负相关(P＜0.01).TXA2表达与NOX1 mRNA表达呈正相关(P＜0.05).结论 TXA2可能通过TPr通路导致胎盘产生过量ROS并向母体血液循环释放,参与子痫前期的发病过程.     

Association of polymorphisms in the melanocortin receptor type 2 (MC2R, ACTH receptor) gene with heroin addiction

The melanocortin receptor type 2 (MC2R or adrenocorticotropic hormone, ACTH receptor) gene (MC2R) encodes a protein involved in regulation of adrenal cortisol secretion, important in the physiological response to stressors. A variant of MC2R, -179A>G, results in reduction of promoter activity and less adrenal action. We hypothesize that altered stress responsivity plays a key role in the initiation of substance abuse. By direct resequencing of the promoter region and exons 1 and 2 of the MC2R gene in 272 subjects including Caucasians, Hispanics and African Americans with approximately equal numbers of former heroin addicts and normal volunteers, we identified five novel variants each with allele frequency <2%. Previously reported polymorphisms -184G>A (rs2186944), -179A>G, 833A>C (rs28926182), 952T>C (rs4797825), 1005C>T (rs4797824) and 1579T>C (rs4308014) were each in allelic frequency >/=2% in one or more ethnic groups. These polymorphisms were genotyped in 632 subjects (260 Caucasians, 168 Hispanics, 183 African Americans and 21 Asians) using TaqMan assays. Significant differences in genotype frequency among ethnic groups studied were found for each of the six variants analyzed. We found a significant association (p=0.0004, experiment-wise p=0.0072) of the allele -184A with a protective effect from heroin addiction in Hispanics. Also, in Hispanics only we found the haplotype GACT consisting of four variants (-184G>A, -179A>G, 833A>C and 1005C>T) to be significantly associated with heroin addiction (p=0.0014, experiment-wise p=0.0168), whereas another haplotype, AACT, consisting of the same variants, was associated with a protective effect from heroin addiction (p=0.0039, experiment-wise p=0.0468).     

Association of toll‐like receptor 4 polymorphisms with type 2 diabetes mellitus

Toll‐like receptor 4 (TLR4) plays important roles in modulating innate immunity. Type 2 diabetes mellitus (T2DM) is a chronic and complex disease that is characterized by impaired insulin resistance and dysregulated immune response. In the current study, we investigated whether TLR4 polymorphisms were correlated with susceptibility to T2DM in the Chinese population. Four TLR4 polymorphisms (?2431T/C, Asp299Gly, Thr399Il3, and +3725G/C) were genotyped in 936 T2DM patients and 978 healthy controls. Results showed that the prevalence of TLR4 +3725GC and CC genotypes was significantly decreased in T2DM cases than those in controls [odds ratio (OR) = 0.68, 95% confidence interval (CI) = 0.55–0.84, p = 0.0003, and OR=0.46, 95% CI = 0.32–0.67, p = 3.71 × 10^?5, respectively). Also, the frequency of TLR4 +3725C allele was significantly lower in T2DM patients (p = 2.50 × 10^?8). The ?2431T/C did not reveal any significant differences between cases and controls. We did not detect Asp299Gly and Thr399Il3 polymorphisms in our study group. Stratification analysis of the clinical features in the patients demonstrated that frequency of +3725CC genotype was lower in patients older than 50 years old (p = 0.047). In conclusion, these results indicate that TLR4 +3725G/C polymorphism may be a novel protective factor against T2DM in the Chinese population.     

Association of the IL‐10 receptor A536G (S138G) loss‐of‐function variant with multiple sclerosis in Tunisian patients

Interleukin‐10 (IL‐10), a potent anti‐inflammatory T‐cell cytokine, has been shown to be a regulatory cytokine that is associated with disease remission in multiple sclerosis (MS) and exerts its activity through its cognate cell surface receptor complex, IL‐10 receptor 1 (IL‐10R1) and IL‐10R2. The purpose of this study was to investigate the IL‐10R1 S138G loss‐of‐function polymorphism (A536G: rs3135932) for possible influence on susceptibility and outcome of MS in Tunisian patients. A total of 103 Tunisian MS patients and 160 control subjects were studied. Genomic DNA samples were extracted from leukocytes and used to investigate S138G polymorphism in IL‐10R1 gene by multiplex allele‐specific polymerase chain reaction. Associations between G allele [odds ratio (OR) = 5.57; 95% confidence intervals (CI) = 3.26–9.54; p = 10^?7], GG genotypes [OR = 10.41; 95% CI = 2.28–47.58; p = 0.0007] and AG genotype [OR = 4.14; 95% CI = 2.16–7.93; p = 0.000016] with the risk development of MS were found. In contrast, the AA genotype seemed to be associated with protection against MS [OR = 0.17; 95% CI = 0.09–0.30; p = 10^?7]. No association was found between S138G SNP and clinical features or disease activity of MS patients. In conclusion, our results suggest that S138G loss‐of‐function polymorphism of the IL‐10R1 may be important risk factor in increasing susceptibility to MS.     

Association of interleukin-1 receptor antagonist gene polymorphism and susceptibility to human brucellosis

The aim of this study was to determine the influence of the polymorphism within the intron 2 of the interleukin-1 receptor antagonist gene (IL-1Ra) on the susceptibility to or development of brucellosis. A total of 255 patients with brucellosis and 162 healthy volunteers were genotyped for polymorphisms in intron 2 of the IL-1Ra gene. The frequency of allele 2 of the IL-1Ra gene was significantly higher in patients with brucellosis compared with the controls (24.5% vs 18.5%, P = 0.03). Although the heterozygosity was more prevalent in patients than in control individuals, it did not have any statistical significance (P = 0.1). Alleles 3, 4, and 5 were absent in our study population. This work is the first that verifies a significant association between genetic polymorphism of IL-1Ra and susceptibility to brucellosis.     

The 5‐HT2A receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients

Several lines of evidence suggest that genetic factors constitute an important determinant of suicidal behavior. A significant association between the 5‐HT_2A‐C allele and suicidality has recently been reported. The aim of this study was to investigate whether the proposed association between 5‐HT_2A‐102T/C polymorphism and suicidality could be replicated in a larger and independent sample of Spanish patients with major depression. The 102T/C polymorphism of the 5‐HT_2A receptor gene was analyzed in 159 patients with major depression (DSM‐IV criteria) and 164 unrelated and healthy controls using a case control design. All individuals were subjects of Spanish origin. Significant differences in allele (chi‐square = 4.13, df = 1, P = 0.04) and genotype (chi‐square = 6.19, df = 2, P = 0.04) distributions were found between non–suicide attempters and suicide attempters. Moreover, those patients carrying 5‐HT_2A‐C allele had more than five times the risk for attempting suicide than noncarriers (OR = 5.50, 95% CI = 1.18–35.20, P = 0.01). Our results replicate the proposed association between 5HT_2A‐C allele and suicidality in major depression. Moreover, no overall associations are detected when patients with major depression and controls are compared for 102T/C frequencies, suggesting that the increased risk for suicidality conferred by 5‐HT_2A‐C allele is primarily associated with suicidal behavior and not with the diagnosis of major depression itself. © 2001 Wiley‐Liss, Inc.