Arg753Gln polymorphism of the human Toll-like receptor 2 gene from infection to disease in pediatric tuberculosis

The aim of this study is to examine the occurrence of the Arg753Gln polymorphism of the Toll-like receptor 2 (TLR2) gene in Turkish children with pulmonary and/or extrapulmonary tuberculosis (TB) disease compared with that in healthy children with latent TB infection (LTBI) and to assess the risk of progression from LTBI to active TB disease in children. The Arg753Gln polymorphism of the TLR2 gene was studied in 198 TB patients compared with 200 ethnically and age-matched children with LTBI. The culture confirmed TB patients were more frequently Arg753Gln heterozygous [odds ratio (OR) 5.05, 95% confidence interval (95% CI) 2.61-9.76, p = 0.00], and Gln allele frequency was significantly higher in the patient group (13.86% vs 3.5%, OR 4.40, 95% CI 2.34-8.30, p = 0.00). We also showed that the frequencies of the heterozygous Arg753Gln genotype and the Gln allele were significantly higher in patients with pulmonary TB alone and in patients with definitive pulmonary plus extrapulmonary TB than in children with LTBI. Our data suggest that the Arg753Gln polymorphism of the TLR-2 gene influences the speed of progression from infection to TB disease in children. Further investigations are needed to clarify whether this polymorphism has a strong impact on susceptibility to TB in children.     

Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease

Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Different functional effective polymorphisms for the TLR 4 gene (Asp299Gly; Thr399Ile) and for the TLR 2 gene (Arg677Trp, Arg753Gln) have recently been described that are associated with impaired lipopolysaccharide signal transduction. A total of 122 patients with chronic periodontal disease and 122 healthy unrelated controls were genotyped for the Asp299Gly and Thr399Ile polymorphism of the TLR 4 gene and the Arg677Trp and Arg753Gln mutation of the TLR 2 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. The prevalence of the Asp299Gly and the Thr399Ile mutant allele was 4.1% (10/244) and 4.5% (11/244) among periodontitis patients. For the healthy controls the prevalence was 3.3% (8/244) for the Asp299Gly (P = 0.810) and 3.7% (9/244) for the Thr399Ile mutant allele (P = 0.819). The Arg753Gln mutant allele was found in 2.9% (7/244) of the periodontitis subjects as compared to 4.1% (10/244) in the control group (P = 0.622). The Arg677Trp mutant allele was not found in any of the study subjects. Unlike in ulcerative colitis there was not observed an association between chronic periodontitis and the various mutations of the TLR 2 and 4 gene.     

Toll‐like receptor‐2 Arg753Gln and Arg677Trp polymorphisms and susceptibility to pulmonary and peritoneal tuberculosis

Recent evidence suggests that toll‐like receptor‐2 (TLR2) is important for host defense against Mycobacterium tuberculosis (MTB). TLR2 polymorphisms have shown significant impact on susceptibility or resistance to tuberculosis (TB). This case–control study aims to determine the influence of TLR2 (Arg753Gln and Arg677Trp) polymorphisms on the susceptibility to develop pulmonary or peritoneal TB. Genotyping of TLR2 (Arg753Gln and Arg677Trp) polymorphisms was carried out on 52 patients with pulmonary TB, 44 patients with peritoneal TB, and 50 healthy controls using polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP). There was a significant association between the GA genotype (heterozygous mutant) of TLR2 Arg753Gln polymorphism and the risk of infection with pulmonary TB (p = 0.003, OR = 4.83) and TB peritonitis (p = 0.003, OR = 6.2). Differences in the genotype frequencies of TLR2 Arg677Trp polymorphisms between patients with pulmonary or peritoneal TB and healthy controls were not detected. GA753 TLR2 polymorphism may play a role in the susceptibility to pulmonary and peritoneal TB infection. Further studies on a large number of ethnically diverse patient cohorts may help to confirm the possible effect of these polymorphisms on the susceptibility to pulmonary and peritoneal TB.     

Lack of Toll-like receptor 4 and 2 polymorphisms in Korean patients with bacteremia

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in innate immune responses to bacterial infection. The purpose of this study is to describe the prevalence of TLRs genetic variations in the bacteremic patients in Korea. A total of 154 patients with bacteremia and 179 healthy volunteers were included. The Asp299Gly and Thr399Ile allele of the TLR4 gene and Arg753Gln and Arg677Trp allele of the TLR2 gene were tested by PCR-RFLP. The DNA sequences were determined to confirm the PCR-RFLP results. Contrary to the expectation, no genetic polymorphisms were detected in both groups of this study, suggesting that it is very rare in Korean.     

CD14 promoter polymorphism -159C>T is associated with susceptibility to chronic Chlamydia pneumoniae infection in peripheral blood monocytes

Chlamydia pneumoniae uses peripheral blood monocytes (PBMC) for systemic dissemination and has been linked to atherogenesis by inflammation mediated via TLR2/4 and CD14. We found 12.8% of 610 coronary artery disease (CAD) patients of Central European background to be chronically infected with C. pneumoniae based on the repeated detection of chlamydial DNA in PBMC. Among those the -159C>T CD14 promoter polymorphism was more frequent (OR 1.7, 95% CI 1.08-2.65, P=0.0224) than among C. pneumoniae-negative subjects matched for age and gender. The Arg753Gln TLR2 and Asp299Gly TLR4 polymorphisms were not related to chlamydial infection. Susceptibility for chronic chlamydial infection of PBMC in CAD patients appears associated with the CD14-159C>T promoter polymorphism encoding for enhanced CD14 expression.     

A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection

The toll-like receptor 2 (TLR2) has gained importance as a major mammalian receptor for lipoproteins derived from the cell wall of a variety of bacteria, such as Borrelia burgdorferi, Treponema pallidum, and Mycoplasma fermentans. We were interested in identifying mutations in the TLR2 gene that might prove to be associated with altered susceptibility to septic shock. We performed a mutation screen of the TLR2 gene using single-stranded conformational polymorphism in 110 normal, healthy study subjects and detected an Arg753Gln mutation in three individuals. No other missense mutations were detected in the TLR2 open reading frame. Functional studies demonstrate that the Arg753Gln polymorphism, in comparison to the wild-type TLR2 gene, is significantly less responsive to bacterial peptides derived from B. burgdorferi and T. pallidum. In a septic shock population, the Arg753Gln TLR2 polymorphism occurred in 2 out of 91 septic patients. More importantly, both of the subjects with the TLR2 Arg753Gln polymorphism had staphylococcal infections. These findings suggest that a mutation in the TLR2 gene may predispose individuals to life-threatening bacterial infections.     

Association between toll-like receptors/CD14 gene polymorphisms and inflammatory bowel disease in Korean population

The innate immune response in patients who develop inflammatory bowel disease (IBD) may be abnormal. However, the exact role of Toll-like receptors (TLRs) / CD14 gene in the pathogenesis of IBD has not been fully elucidated. We aimed to investigate the association between polymorphisms of TLR1, 2, 4, 6, and CD14 gene and susceptibility to IBD in Korean population. A total 144 patients of IBD (99 patients with ulcerative colitis, 45 patients with Crohn's disease) and 178 healthy controls were enrolled. Using a PCR-RFLP, we evaluated mutations of TLR1 (Arg80Thr), TLR2 (Arg753Gln and Arg677Trp), TLR4 (Asp299Gly and Thr399Ile), TLR6 (Ser249Pro) genes and the -159 C/T promoter polymorphism of CD14 gene. No TLR polymorphisms were detected in Korean subjects. T allele and TT genotype frequencies of CD14 gene were significantly higher in IBD patients than in healthy controls. In subgroup analysis, T allelic frequency was higher in pancolitis phenotype of ulcerative colitis. In Korean population, the promoter polymorphism at -159 C/T of the CD14 gene is positively associated with IBD, both ulcerative colitis and Crohn's disease.     

Genetic polymorphisms of viral infection-associated Toll-like receptors in Chinese population

Toll-like receptors (TLRs) play a pivotal role in an innate immunity system, which controls inflammation responses and further instructs development of adaptive immunity. We enrolled 250 Han Chinese in Taiwan screening for the single nucleotide polymorphisms (SNPs) in TLRs associated with viral infection, including TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9. The 6 SNPs not hitherto identified in Chinese populations, including TLR3 1377 C>T, TLR3 -7 C>A, TLR7 Gln11Leu, TLR7 IVS1+1817 G>T, TLR8 Met1Val, and TLR8 -129 G>C, had minor allele frequencies of 38%, 23%, 22.3%, 3%, 16.0%, and 16.0%, respectively. The frequencies of 2 common SNPs, TLR9, -1486 T>C and 2848 G>A, were 28% and 44%, respectively. As compared with other ethnic populations, Chinese displayed an opposite allele frequency of TLR8 Met1Val and TLR8 -129 G>C to Caucasians and African Americans. In addition, TLR2 Arg677Try, TLR2 Arg753Gln, TLR4 Asp299Gly, and TLR4 Thr399Ile that were apparent in approximately 10% of Caucasians were not detected in Chinese. In conclusion, obvious ethnic differences in TLR polymorphisms may in part reflect the ethnic diversity of host viral susceptibility.     

Arg462Gln and Asp541Glu polymorphisms in ribonuclease L and prostate cancer risk: a meta-analysis

Objective

The association between ribonuclease L (RNASEL) gene polymorphisms and prostate cancer risk has been widely reported, but the results of these studies remained controversial and underpowered. We performed a meta-analysis of 28 studies to evaluate the association between Arg462Gln and Asp541Glu polymorphisms in the RNASEL gene and prostate cancer risk.

Methods

Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association between RNASEL polymorphisms and prostate cancer risk.

Results

A significantly increased prostate cancer risk was found for the Arg462Gln polymorphism in Africans (Gln/Gln vs Arg/Arg: OR = 2.50, 95%CI = 1.28-4.87; Gln/Gln vs Gln/Arg + Arg/Arg: OR = 2.54, 95%CI = 1.30-4.95), but not in Europeans and Asians. Additionally, the Asp541Glu polymorphism was associated with increased total prostate cancer risk (Glu-allele vs Asp-allele: OR = 1.04, 95%CI = 1.01-1.07; Glu/Glu vs Asp/Asp: OR = 1.22, 95%CI = 1.03-1.46; Glu/Glu vs Glu/Asp + Asp/Asp: OR = 1.09, 95%CI = 1.02-1.16). In the stratified analysis for the Asp541Glu polymorphism, there was a significantly increased prostate cancer risk in Africans and Europeans, and in hospital-based prostate cancer cases.

Conclusion

The meta-analysis results showed evidence that RNASEL Arg462Gln and Asp541Glu polymorphisms are associated with prostate cancer risk and could be low-penetrance prostate cancer susceptibility biomarkers.     

The association between the genetic polymorphisms of LMP2/LMP7 and the outcomes of HCV infection among drug users

Objective

To investigate a possible association of LMP2/LMP7 genes with chronic hepatitis C virus (HCV) infection, and to assess whether LMP2/LMP7 genes could influence the outcomes of HCV infection among drug users.

Methods

Genomic DNAs of 362 anti-HCV sero-positive drug users and 225 control drug users were extracted from the peripheral blood leukocytes. The sero-positive patients were divided into those who had persistent infection and those who had spontaneously cleared the infection. Polymorphisms of LMP genes were determined by PCR combined with restriction fragment length polymorphism (RFLP).

Results

The distribution of LMP2 genotypes among the control, persistent infection and spontaneous clearance groups were not different. However, the LMP7 codon 145 Gln/Lys, Lys/Lys, and Gln/Lys+Lys/Lys genotypes were found significantly more frequent in the persistent infection group than in control group (OR=1.75, 95%CI=1.06∼2.90; OR=3.16, 95%CI=1.23-8.12; OR = 1.94, 95%CI=1.21-3.12, respectively). Similarly, the frequencies of the codon 145 Gln/Lys, Lys/Lys, and Gln/Lys+Lys/Lys genotypes were found significantly more frequent in the persistent infection group than in the spontaneous clearance group (OR=1.64, 95%CI=1.04-2.57; OR=2.40, 95%CI=1.09-5.28; OR=1.76, 95%CI=1.15-2.69, respectively). Stratified analysis indicated that combined genotype Gln/Lys + Lys/Lys of the LMP7 gene was related to an increasing susceptibility to HCV infection (OR=1.91, 95%CI=1.02-3.55; OR=2.19, 95%CI=1.24-3.89; OR=1.91, 95%CI=1.05-3.48, OR=2.86, 95%CI=1.41-5.78, respectively) and the risk of persistent HCV infection (OR=1.94, 95%CI=1.12-3.34; OR=2.02, 95%CI=1.21-3.38; OR=1.78, 95%CI=1.12-2.85, OR=2.23, 95%CI=1.09-4.58, respectively) among > 30-year-old, males, the injection drug user (IDU) subjects and/or the shorter duration drug users (≤5 y).

Conclusion

These results suggest that polymorphism of the LMP7 gene may have an influence on the outcomes of HCV infection, and is one of the factors accounting for the genetic susceptibility to HCV infection among drug users.     

Lack of association between Toll-like receptor 2 polymorphisms and susceptibility to severe disease caused by Staphylococcus aureus

To investigate a putative link between genetically determined variations in Toll-like receptor 2 (TLR2) and the occurrence of severe Staphylococcus aureus infection, the functional Arg753Gln single-nucleotide polymorphism and the GT repeat microsatellite in the TLR2 gene were examined in a large case-control study. No associations with disease or mortality attributable to these features were found.     

<Emphasis Type="Italic">TOPBP1</Emphasis> missense variant Arg309Cys and breast cancer in a German hospital-based case-control study

The DNA double strand break repair gene TOPBP1 has been suggested as a breast cancer susceptibility gene and a missense variant Arg309Cys was observed at elevated frequency in familial breast cancer cases compared to healthy controls from Finland. We found the Arg309Cys allele at a 13% carrier frequency in a hospital-based series of 1064 German breast cancer patients and at a 14% carrier frequency in 1014 population controls (OR 0.89, 95%CI 0.69-1.15; p = 0.4). Arg309Cys carriers were not enriched among patients with a family history of breast cancer (OR = 0.87, 95%CI 0.53-1.43, p = 0.6) and were slightly underrepresented in patients with bilateral disease (OR = 0.49, 95%CI = 0.24-0.99; p = 0.047). In the latter group, the mean age at diagnosis was 62 years in carriers and 54 years in non-carriers (p = 0.004). We conclude that there is no evidence for the TOPBP1*Arg309Cys variant to confer an increased risk for breast cancer in the German population.     

eNOS基因和FⅦ基因多态性与冠心病的相关性研究

目的 探讨内皮型一氧化氮合酶(endothelial nitric oxide synthase,eNOS)基因外显子7的Glu298Asp和凝血因子Ⅶ(coagulation factor VH,FVH)基因外显子8的Arg353Gin多态性与汉族人群冠心病(CHD)及老年人CHD发病的关系.方法 选取147例CHD患者和116例正常对照组人群,应用聚合酶链反瘟-限制性片段长度多态性(PCR-RFLP)分析技术检测eNOS基因Glu298Asp和FⅦ基因Arg353G1n多态性.结果 ①eNOS基因Glu/Glu、Glu/Asp、Asp/Asp基因型频率CHD组分别为78.9%、20.4%、0.68%和对照组分别为89.7%、10.3%和0.0%;FⅦ基因型频率CHD组和对照组之间差异无统计学意义(P＞0.05);②Glu/Asp+Asp/Asp型和Asp等位基因频率CHD组(21.1%和10.9%)显著高于对照组(10.3%和5.2%)(P＜0.05),Asp等位基因对≥60岁老年人发生CHD的风险增高,OR=2.43,95%CI:1.22～4.86(P＜0.05);③携带FⅦ基因Arg/Gln+Gln/Gln型和Gin等位基因个体发生CHD的风险降低,OR=0.77,95%CI:0.33～0.56和OR=0.85,95%CI:0.38～0.53(P＞0.05).结论 eNOS基因Asp等位基因可能是汉族老年人CHD发病的遗传易感因素之一;FⅦ基因Arg353Gln多态性与CHD发病无关.     

Lack of Association between Toll-Like Receptor 2 Polymorphisms and Susceptibility to Severe Disease Caused by Staphylococcus aureus

To investigate a putative link between genetically determined variations in Toll-like receptor 2 (TLR2) and the occurrence of severe Staphylococcus aureus infection, the functional Arg753Gln single-nucleotide polymorphism and the GT repeat microsatellite in the TLR2 gene were examined in a large case-control study. No associations with disease or mortality attributable to these features were found.     

Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus

Human toll-like receptors (TLRs) participate in the innate response and signal the activation of adaptive immunity. Therefore, these TLRs may be important in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We investigated, by using a polymerase chain reaction restriction-fragment length polymorphism method, the possible association between the polymorphisms of TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes with the susceptibility or severity of RA and SLE. Our study population consisted of 122 patients with SLE, 224 patients with RA, and a control group of 199 healthy individuals. The TLR2 polymorphisms were very rare in our population; no individual carrying the TLR2-Arg677Trp polymorphism was observed, whereas the TLR2-Arg753Gln polymorphism was present in only 1% of the total population. We found no statistically significant differences in the TLR4-Asp299Gly and the TLR4-Thr399Ile genotype or allele distribution between SLE patients, RA patients, and control individuals. Similarly, no association was found with any of the demographic and clinical parameters tested either in RA or in SLE patients. In conclusion, a case-control study was used to analyze, for the first time, the influence of TLR2 and TLR4 gene polymorphism on the predisposition and clinical characteristics of SLE and RA but provided no evidence for association of TLR2 or TLR4 gene polymorphism with either disease in the population under study.     

青海省妊娠高血压综合征患者血清瘦素水平及瘦素受体的基因多态性

目的 探讨瘦素受体（LEPR）Gln223Arg（rs1137101）基因多态性与青海省妊娠高血压综合征之间的相关性。 方法 选取妊娠高血压综合征（PIH）患者107例,正常妊娠组116例,用ELISA法检测血清瘦素水平。以外周静脉血DNA为模板,采用聚合酶链反应 限制性内切酶长度片段多态性（PCR-RFLP）对LEPR 基因Gln223Arg位点基因型进行分析。 结果 PIH组血清瘦素水平高于对照组（P<0.05）。PIH组基因型频率GG型、GA型和AA型分别为49.5%、43.9%和6.5%,对照组分别为63.8%、32.8%和3.4%。PIH组和对照组LEPR基因Gln223Arg 位点等位基因G和A频率分布具有差异性。PIH组A等位基因频率高于正常妊娠组（χ²=4.60,P<0.05,OR=0.62,95%CI=0.40～0.96）。 结论 LEPR基因Gln223Arg的A等位基因是PIH遗传易感基因之一,可能是PIH的潜在危险因素。     

ABCG1基因两个单核苷酸多态位点与冠状动脉粥样硬化性心脏病易感性及病情严重程度的相关性分析

目的 应用基于群体的病例-对照关联研究方法探讨ABCG1基因上的遗传多态性与冠状动脉粥样硬化性心脏病(简称冠心病)及病情严重程度的相关性.方法 在山东汉族人群中收集541例冠心病患者和649名正常对照,采用聚合酶链反应-限制性片段长度多态方法对ABCG1基因内两个单核甘酸多态位点进行基因分型,统计学分析.结果 rs225374等位基因C在病例组中的频率显著高于对照组(OR=1.186,95%CI:1.009～1.394,P=O.039),在男性病例组与对照组中的差异同样具有统计学意义(OR=1.236,95%CI:1.014～1.506,P=O.036).rs1044317等位基因A在病例组中的频率显著高于对照组(OR=1.187,95%CI:1.009～1.397,P=0.039).单独在病例组内的分析结果显示,rs225374等位基因C频率在高Gensini积分组中显著高于低Gensini积分组(OR=1.303,95%CI:1.024～1.657,P=O.031).结论 ABCG1基因上两个单核苷酸多态位点与冠心病易感性及病情严重程度具有一定相关性.     

Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer

Factors underlying genetic predisposition for development of sporadic colorectal cancer are largely unknown. The fact that this cancer is more common in patients suffering from inflammatory bowel disease raises the question of the relationship between chronic inflammation and cancer. Toll-like receptors 2 (TLR2) and 4 (TLR4) are critical in initiating innate immune response and inflammation toward various bacteria commonly found in the intestine. Recent evidence about the association of polymorphisms in these genes with ulcerative colitis and Crohn's disease, as well as other inflammatory conditions, was the basis for our investigation of their role in sporadic colorectal cancer. We assessed genotype and allele frequencies of TLR2 GT microsatelite polymorphism, TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms in 89 colorectal cancer patients and 88 age- and sex-matched controls. The frequency of TLR2 GT microsatelite alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p = 0.001, respectively), while the frequency of the allele with 31 GT repeats was increased (p = 0.0147) in patients. The mutant allele Asp299Gly of TLR4 gene was slightly more frequent in colorectal cancer patients (p = 0.0269). In conclusion, we report an association of microsatelite GT polymorphisms of TLR2 gene and Asp299Gly polymorphism of the TLR4 gene with sporadic colorectal cancer among Croatians.     

Gene–gene interaction between interleukin-4 and interleukin-4 receptor α in Korean children with asthma

BACKGROUND: Interleukin-4 receptor alpha (IL-4Ralpha), which binds IL-4 and IL-13, is involved in signal transduction of those cytokines that lead to IgE production, and is also a key functional component of the Th2 lymphocyte phenotype. OBJECTIVE: To determine whether IL-4 and IL-4Ralpha polymorphisms are associated with susceptibility to asthma and whether there are gene-gene interactions between IL-4 and IL-4Ralpha polymorphisms. METHODS: We genotyped three groups of Korean children, consisting of 196 atopic asthmatics, 60 non-atopic asthmatics, and 100 healthy children, for an IL-4 promoter polymorphism (C-590T) and three IL-4Ralpha polymorphisms (Ile50Val, Pro478Ser, and Arg551Gln) using PCR-RFLP (restriction fragment length polymorphism) assays. RESULTS: The allele frequencies of the IL-4 (C/T) polymorphism and the Ile50Val and Pro478Ser polymorphisms of IL-4Ralpha did not differ statistically among the three groups of children. For the Arg551Gln polymorphism, the combined genotype frequency of the Arg/Gln heterozygote and the Arg/Arg homozygote was significantly higher in atopic asthmatics (27.6%) than in healthy children (16.0%) (odds ratio (OR) = 1.97, 95% CI (confidence interval) = 1.07-3.71). The eosinophil fraction (%) and bronchial responsiveness were higher in children with the Arg/Gln and Arg/Arg genotype than in those with the Gln/Gln genotype (P = 0.036 and 0.024, respectively). In asthmatic children, combinations of the IL-4 CT/TT genotype and the IL-4Ralpha Arg/Gln and Arg/Arg genotypes were associated with significantly increased risk for development of asthma (OR = 3.70, 95% CI = 1.07-12.78, P = 0.038). CONCLUSIONS: In Korean children, the IL-4Ralpha Arg551 allele may play a role in susceptibility to atopic asthma and correlate with markers of asthma pathogenesis, including increased eosinophil fraction and enhanced bronchial hyper-responsiveness. In addition, a significant gene-gene interaction between the IL-4-590C and the IL-4Ralpha Arg551 allele significantly increases an individual's susceptibility to asthma.     

Meta-analysis of the association of beta2-adrenergic receptor polymorphisms with asthma phenotypes

BACKGROUND: Two common polymorphisms of the beta2-adrenergic receptor gene (Arg16Gly and Gln27Glu ) have been extensively studied for their possible association with asthma-related phenotypes, but the results of individual studies have been inconclusive. OBJECTIVE: We aimed to integrate quantitatively the available evidence on the association of the Arg16Gly and the Gln27Glu polymorphisms with asthma, nocturnal asthma, asthma severity, and bronchial hyperresponsiveness. METHODS: Meta-analysis of case-control and cohort studies using random effects models. RESULTS: A total of 28 studies were included in the meta-analysis. The summary estimates suggested that neither the Gly16 nor the Glu27 allele contributes to asthma susceptibility overall (odds ratio [OR], 1.01; 95% CI, 0.90-1.13; and OR, 0.95; 95% CI, 0.83-1.09, respectively) or to bronchial hyperresponsiveness (OR, 0.90; 95% CI, 0.77-1.05; and OR, 1.07; 95% CI, 0.94-1.22, respectively). There was a strong association of Gly16 with nocturnal asthma (OR, 2.20; 95% CI, 1.56-3.11) and a less strong association with severe or moderate rather than milder asthma (OR, 1.42; 95% CI, 1.04-1.94). No such effects were seen for the Glu27 allele (OR, 1.02; 95% CI, 0.74-1.40; and OR, 0.82; 95% CI, 0.59-1.14, respectively). Moreover, there was evidence that Gly16 homozygotes had a much higher risk for nocturnal asthma (OR, 5.15; 95% CI, 2.44-10.84) and asthma severity (OR, 2.84; 95% CI, 1.62-4.96) than the Arg16 homozygotes. CONCLUSION: The Gly16 allele of the beta2-adrenergic receptor gene predisposes to nocturnal asthma, and this may also explain the association with asthma severity. Neither polymorphism modulates the risk for bronchial hyperresponsiveness or mild asthma.