Increased D allele frequency of the angiotensin-converting enzyme gene in pulmonary fibrosis

Morrison, Carl; Papp, Audrey C.; Hejmanowski, Ashley Q.; Addis, Victoria; Prior, Thomas W.

doi:10.1053/hupa.2001.24321

Cited by 38 publications

(27 citation statements)

References 35 publications

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“…Previous work in liver fibrosis has described a positive association between -6 AA gene variants and an advanced grade of fibrosis, although genotype frequencies were not different from those of the control population [22]. Studies of ANG system gene polymorphisms in lung diseases have revealed that there is an increase in the D allele of the ACE gene in pulmonary fibrosis and in noninfectious pulmonary dysfunction that leads to allogenic stem cell transplant [30,31]. Therefore, these results, together with the present findings, suggest that ANG system gene variants could be involved in interstitial lung fibrotic diseases.…”

Section: Discussionmentioning

confidence: 99%

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Molina-Molina¹,

Xaubet²,

Li³

et al. 2008

Eur Respir J

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Angiotensin II is a growth factor that plays a key role in the physiopathology of idiopathic pulmonary fibrosis (IPF). A nucleotide substitution of an adenine instead of a guanine (G-6A) in the proximal promoter region of angiotensinogen (AGT), the precursor of angiotensin II, has been associated with an increased gene transcription rate.In order to investigate whether the G-6A polymorphism of the AGT gene is associated with IPF development, severity and progression, the present study utilised a case-control study design and genotyped G-6A in 219 patients with IPF and 224 control subjects.The distribution of G-6A genotypes and alleles did not significantly differ between cases and controls. The G-6A polymorphism of the AGT gene was not associated with disease severity at diagnosis. The presence of the A allele was strongly associated with increased alveolar arterial oxygen tension difference during follow-up, after controlling for the confounding factors. Higher alveolar arterial oxygen tension changes over time were observed in patients with the AA genotype (0.37¡0.7 mmHg (0.049¡0.093 kPa) per month) compared to GA genotype (0.12¡1 mmHg (0.016¡0.133 kPa) per month) and GG genotype (0.2¡0.6 mmHg (0.027¡0.080 kPa) per month).G-6A polymorphism of the angiotensinogen gene is associated with idiopathic pulmonary fibrosis progression but not with disease predisposition. This polymorphism could have a predictive significance in idiopathic pulmonary fibrosis patients.

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Section: Discussionmentioning

confidence: 99%

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Molina-Molina¹,

Xaubet²,

Li³

et al. 2008

Eur Respir J

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“…The deletion allele, correlating with high serum ACE levels, has been shown to associate with systemic sclerosis, a disease showing a high propensity for lung fibrosis [69]. In addition, MORRISON et al [40] have detected an increased deletion allele frequency in a small cohort of mixed IIP cases (69 versus 54% in controls), which definitively requires further confirmation.…”

Section: Renin-angiotensin-aldosterone Systemmentioning

confidence: 94%

Genetics of fibrosing lung diseases

Grutters

Bois²

2005

Eur Respir J

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Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury. Remarkably, different histological patterns were observed in the affected subjects, suggesting the influence of modifier genes and/or environmental factors. Surfactant protein C gene variations have not, however, been associated with sporadic cases,i.e.idiopathic pulmonary fibrosis (IPF).Susceptibility to IPF probably involves a combination of polymorphisms related to epithelial cell injury and abnormal wound healing. To date, the genetic associations with IPF that have been reported in different cohorts include the genes encoding tumour necrosis factor (TNF; −308 adenine), interleukin-1 receptor antagonist (+2018 thymidine) and association with severity and progression (interleukin-6/TNF receptor II and transforming growth factor-β1 (TGFB1; +869 cytosine)), but none of these associations have been replicated by others.Unlike in IPF, immunological inflammation seems to be more prominent in the pathogenesis of scleroderma lung fibrosis, being an autoimmune disease with specific autoantibodies, such as antitopoisomerase antibodies, in patients with diffuse lung disease, and anticentromere antibodies, in patients with pulmonary vascular disease. Antitopoisomerase antibody positivity is associated with the carriage of human leukocyte antigen DRB1*11 and DPB1*1301 alleles, suggesting the recognition of a specific amino-acid motif. Extended haplotype analysis also supports the conclusion that TNF may be the primary association with anticentromere positivity. Intriguingly, associations with TGFB1 and genes involved in extracellular matrix homeostasis have been reported in this disease.In conclusion, significant steps forward have been taken in the understanding of the genetic contribution to fibrosing lung diseases, but major challenges lay ahead. It is the present authors' opinion that only a combined approach studying large numbers of familial and sporadic cases, all clinically well phenotyped, using multiple distinct cohorts, and genotyped according to relevant gene ontologies will be successful. It will be necessary to be particularly vigilant with regard to phenotype; the absence of very strong reproducible associations may be because of the rigidity of phenotype definition, coupled with the possibility that idiopathic pulmonary fibrosis may still be a heterogeneous group of diseases, despite the more rigid definition set out by the European Respiratory Society/American Thoracic Society statement.

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“…The latter may be involved in the fibrotic process because it acts as a proinflammatory cytokine, participating in various steps of the inflammatory response (Mezzano et al, 2001). Studies have also demonstrated that ACE insertion/deletion (I/D) polymorphism is associated with fibrotic and atherosclerotic cardiovascular disease (Mezzano et al, 2001;Morrison et al, 2001;Arkwright et al, 2003;Luther et al, 2003). Thus, ACE might be a candidate gene for OSF and OL.…”

mentioning

confidence: 99%

Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers

Yang

et al. 2005

Br J Cancer

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To investigate whether angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is related to the risk of oral precancerous lesions (OPL) in Taiwanese subjects who chew betel quid, a total of 61 betel quid chewers having OPL were compared with 61 asymptomatic betel quid chewers matched for betel quid chewing duration and dosage. The frequency of homozygote for ACE D variant is significantly higher in the case subjects than that of the controls (44.3 vs 24.6%; P ¼ 0.0108). The adjusted odds ratio of the D homozygous for the risk of OPL is 8.10 (95% confidence interval (CI) ¼ 2.04 -32.19, P ¼ 0.003). In the allelic base analysis, the D allele is also significantly associated with higher risk of OPL. When grouping the study subjects by smoking status, the association between ACE I/D polymorphism and risk of OPL was only observed in nonsmokers. Our results support the theory that genetic factors may contribute to the susceptibility of OPL and suggest that smoking and genetic factors may be differently involved in the development of OPL.

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Increased D allele frequency of the angiotensin-converting enzyme gene in pulmonary fibrosis

Cited by 38 publications

References 35 publications

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Angiotensinogen gene G-6A polymorphism influences idiopathic pulmonary fibrosis disease progression

Genetics of fibrosing lung diseases

Angiotensin-converting enzyme gene insertion/deletion polymorphism is associated with risk of oral precancerous lesion in betel quid chewers

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