<i>EPHX1</i>polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis

Lee, J; Nordestgaard, Børge G.; Dahl, Morten

doi:10.1183/09031936.00012110

Cited by 27 publications

(21 citation statements)

References 42 publications

(86 reference statements)

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“…To validate our findings, we genotyped an additional 53,777 individuals from the Copenhagen General Population Study for the Thr164Ile polymorphism. These two cohorts have been successfully used in previous genetic epidemiological studies, where positive associations between variants and disease have been found [16][17][18] and in others where possible associations have been excluded [19][20][21].…”

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confidence: 99%

β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

Thomsen¹,

Nordestgaard²,

Sethi³

et al. 2011

Eur Respir J

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The b 2 -adrenergic receptor (ADRB2) is an important regulator of airway smooth muscle tone. We tested the hypothesis that three functional polymorphisms in the ADRB2 gene (Thr164Ile, Gly16Arg and Gln27Glu) are associated with reduced lung function, asthma or chronic obstructive pulmonary disease (COPD).We first genotyped 8,971 individuals from the Copenhagen City Heart Study for all three polymorphisms. To validate our findings, we genotyped an additional 53,777 individuals from the Copenhagen General Population Study for the Thr164Ile polymorphism.We identified 60,910 Thr164Ile noncarriers, 1,822 heterozygotes and 16 homozygotes. In the Copenhagen City Heart Study, the Thr164Ile genotype was associated with reduced forced expiratory volume in 1 s (FEV1) % predicted (trend p50.01) and FEV1/forced vital capacity (FVC) (p50.001): Thr164Ile heterozygotes had 3% and 2% reduced FEV1 % pred and FEV1/FVC, respectively, compared with noncarriers. The odds ratio for COPD in Thr164Ile heterozygotes was 1.46 (95% CI 1.05-2.02). In the Copenhagen General Population Study, the Thr164 genotype associated with reduced FEV1 % pred (p50.04) and FEV1/FVC (p,0.001): Thr164Ile homozygotes and heterozygotes had 7% and 1% reduced FEV1 % pred and 6% and 1% reduced FEV1/FVC, respectively, compared with noncarriers. The odds ratios for COPD in Thr164Ile homozygotes and heterozygotes were 4.53 (95% CI 1.54-13.3) and 1.07 (95% CI 0.92-1.25), respectively.Our results suggest that ADRB2 Thr164Ile is associated with reduced lung function and increased risk of COPD in the general population.

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confidence: 99%

β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

Thomsen¹,

Nordestgaard²,

Sethi³

et al. 2011

Eur Respir J

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“…For individual genotypes, this tendency was reflected in that the codon 113C "slow allele" was associated with higher risk of developing tobacco-related cancer, whereas the codon 139G "fast allele" showed a statistically insignificant trend toward lowered risk. A similar phenomenon has been shown for the genotypes and chronic obstructive pulmonary disease (COPD) in meta-analyses where the 113C "slow allele" is associated with higher risk for developing COPD whereas the 139G "fast allele" shows a statistically insignificant trend toward lowered risk (30). Among tobacco-related cancers, lung cancer is the most common.…”

Section: Tobacco-related Cancermentioning

confidence: 60%

“…30). These 2 single-nucleotide polymorphisms (SNP) were chosen because they are functional and have previously been investigated in relation to the endpoints under investigation in the current study.…”

Section: Genotypingmentioning

confidence: 99%

Genetically Lowered Microsomal Epoxide Hydrolase Activity and Tobacco-Related Cancer in 47,000 Individuals

Lee¹,

Dahl²,

Nordestgaard³

2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Two functional polymorphisms of the microsomal epoxide hydrolase (mEH) gene (EPHX1), Tyr113His (rs1051740) and His139Arg (rs2234922), have variably been found to influence susceptibility to various cancer forms. We tested whether genetically lowered mEH activity affects risk of developing cancer in the general population.Methods: We genotyped 47,089 individuals from the Danish general population for the Tyr113His and His139Arg polymorphisms in the EPHX1 gene and divided them into groups with predicted fast, intermediate, and slow mEH activity. Using Cox proportional hazards models, we calculated HRs for 26 individual cancer diagnoses and for groups of any cancer, tobacco-related cancers, estrogen-related female cancers, and other cancers.Results: Of the 47,089 individuals, 7,590 experienced a cancer event, and of these, 1,466 were tobaccorelated. After multifactorial adjustment, the HRs (95% CI) for tobacco-related cancer were 1.1 (0.8-1.5) and 1.5 (1.1-2.0) in individuals with intermediate and slow mEH activity versus individuals with the fast phenotype (P trend ¼ 0.003). The corresponding HRs among ever-smokers were 1.1 (0.8-1.5) and 1.5 (1.1-2.0; P trend ¼ 0.003), whereas HRs among never-smokers did not differ from 1.0.Conclusions: Our results indicate that genetically lowered mEH activity is associated with increased risk of developing tobacco-related cancer among smokers in the general population; however, additional studies are needed to confirm our findings.Impact: To our knowledge, this is the largest study to investigate the association of mEH phenotype and genotype with tobacco-related cancers combined in the general population. Cancer Epidemiol Biomarkers Prev; 20(8); 1673-82. Ó2011 AACR.

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“…Genetic variants of this enzyme have been widely studied for their role in the genetic susceptibility to COPD. EPHX1 is strongly expressed in the lung, but down-regulated in COPD (Tomaki et al, 2007;Lee et al, 2011). However, genetic associations with COPD identified in EPHX1 studies have been inconsistent.…”

Section: Introductionmentioning

confidence: 99%

“…These studies included 9 Caucasian populations (Rodriguez et al, 2002;Korytina et al, 2003;Hersh et al, 2005;Park et al, 2005;Brøgger et al, 2006;Chappell et al, 2008;Židzik et al, 2008;Penyige et al, 2010;Lee et al, 2011) and 10 Eastern Asian populations (Takeyabu et al, 2000;Yim et al, 2000;Yoshikawa et al, 2000;Zhang et al, 2002;Budhi et al, 2003;Park et al, 2003;Cheng et al, 2004;Xiao et al, 2004;Fu et al, 2007;Hua et al, 2012) ( Table 1). The total number of samples in the Caucasian and Eastern Asian populations were 47,048 (6471 cases vs 40,577 controls) and 2586 (1228 cases vs 1358 controls), respectively.…”

Section: Literature Searchmentioning

confidence: 99%

Exploration of association between EPHX1 and chronic obstructive pulmonary disease on the basis of combined data mining

Liu¹,

Xia²,

Zhou³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Chronic obstructive pulmonary disease (COPD) is an important respiratory disease with high mortality. Although smoking is the major environmental risk factor for the development of COPD, only 10% of heavy smokers develop symptomatic disease, suggesting association between genetic susceptibilities and environmental influences. In recent years, as one of the most widely studied genes including tests for associations between a genetic variant and COPD, epoxide hydrolase 1 (EPHX1) was found to be involved in the metabolism of tobacco smoke, an important risk factor of COPD. However, genetic associations with COPD identified in studies on EPHX1 are controversial. To address this issue, except for performing the meta-analysis, which specially added our current study on two polymorphisms (T337C and A416G) of EPHX1, we performed combined data mining based on functional prediction algorithms of nonsynonymous single-nucleotide polymorphisms and gene-based variable threshold testing. Genetic variations in EPHX1 did not affect COPD in Caucasian and Eastern Asian population, which is supported by recent evidence. We found no association between EPHX1 and COPD; however, a minor effect of EPHX1 on COPD risk was not completely excluded; further replication studies with large samples are needed to confirm our findings.

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EPHX1polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis

Cited by 27 publications

References 42 publications

β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

Genetically Lowered Microsomal Epoxide Hydrolase Activity and Tobacco-Related Cancer in 47,000 Individuals

Exploration of association between EPHX1 and chronic obstructive pulmonary disease on the basis of combined data mining

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EPHX1polymorphisms, COPD and asthma in 47,000 individuals and in meta-analysis

Cited by 27 publications

References 42 publications

β2-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

β2-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

Genetically Lowered Microsomal Epoxide Hydrolase Activity and Tobacco-Related Cancer in 47,000 Individuals

Exploration of association between EPHX1 and chronic obstructive pulmonary disease on the basis of combined data mining

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β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies

β₂-adrenergic receptor polymorphisms, asthma and COPD: two large population-based studies