Effect of heme oxygenase-1 polymorphisms on lung function and gene expression

Goh Tanaka; Farzian Aminuddin; Loubna Akhabir; Jian Qing He; Karey Shumansky; John E. Connett; Nicholas R. Anthonisen; Raja T. Abboud; Peter D. Paré; Andrew J. Sandford

doi:10.1186/1471-2350-12-117

Effect of heme oxygenase-1 polymorphisms on lung function and gene expression

Goh Tanaka, Farzian Aminuddin, Loubna Akhabir, Jian Qing He, Karey Shumansky, John E. Connett, Nicholas R. Anthonisen, Raja T. Abboud, Peter D. Paré, Andrew J. Sandford

Biostatistics

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Background: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.Methods: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV₁% predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H₂O₂and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.Results: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)_npolymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.Conclusions: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.

Original language	English (US)
Article number	117
Journal	BMC medical genetics
Volume	12
DOIs	https://doi.org/10.1186/1471-2350-12-117
State	Published - Sep 8 2011

Bibliographical note

Funding Information:
The authors sincerely appreciate the significant contribution from Alison Wallace, Takeo Ishii, John English, Hong Li, Richard Finley, Nestor Müller, and Harvey Coxson in the development of the alveolar macrophage cohort. This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant 5R01HL064068-04. The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute. LA is the recipient of a UBC Four Year Doctoral Fellowship and an AllerGen NCE Inc. Canadian Allergy and Immune Diseases Training Award. J-QH is the recipient of a Michael Smith Foundation for Health Research Fellowship and an Izaak Walton Killam Memorial Scholarship Award. AJS is the recipient of a Canada Research Chair in genetics and a Michael Smith Foundation for Health Research Senior Scholar Award.

Keywords

Chronic obstructive pulmonary disease
Heme oxygenase
Polymorphism

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10.1186/1471-2350-12-117

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title = "Effect of heme oxygenase-1 polymorphisms on lung function and gene expression",

abstract = "Background: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.Methods: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.Results: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.Conclusions: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.",

keywords = "Chronic obstructive pulmonary disease, Heme oxygenase, Polymorphism",

author = "Goh Tanaka and Farzian Aminuddin and Loubna Akhabir and He, {Jian Qing} and Karey Shumansky and Connett, {John E.} and Anthonisen, {Nicholas R.} and Abboud, {Raja T.} and Par{\'e}, {Peter D.} and Sandford, {Andrew J.}",

note = "Funding Information: The authors sincerely appreciate the significant contribution from Alison Wallace, Takeo Ishii, John English, Hong Li, Richard Finley, Nestor M{\"u}ller, and Harvey Coxson in the development of the alveolar macrophage cohort. This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant 5R01HL064068-04. The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute. LA is the recipient of a UBC Four Year Doctoral Fellowship and an AllerGen NCE Inc. Canadian Allergy and Immune Diseases Training Award. J-QH is the recipient of a Michael Smith Foundation for Health Research Fellowship and an Izaak Walton Killam Memorial Scholarship Award. AJS is the recipient of a Canada Research Chair in genetics and a Michael Smith Foundation for Health Research Senior Scholar Award.",

year = "2011",

month = sep,

day = "8",

doi = "10.1186/1471-2350-12-117",

language = "English (US)",

volume = "12",

journal = "BMC medical genetics",

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T1 - Effect of heme oxygenase-1 polymorphisms on lung function and gene expression

AU - Tanaka, Goh

AU - Aminuddin, Farzian

AU - Akhabir, Loubna

AU - He, Jian Qing

AU - Shumansky, Karey

AU - Connett, John E.

AU - Anthonisen, Nicholas R.

AU - Abboud, Raja T.

AU - Paré, Peter D.

AU - Sandford, Andrew J.

N1 - Funding Information: The authors sincerely appreciate the significant contribution from Alison Wallace, Takeo Ishii, John English, Hong Li, Richard Finley, Nestor Müller, and Harvey Coxson in the development of the alveolar macrophage cohort. This work was supported by grants from the Canadian Institutes of Health Research and National Institutes of Health Grant 5R01HL064068-04. The Lung Health Study was supported by contract N01-HR-46002 from the Division of Lung Diseases of the National Heart, Lung, and Blood Institute. LA is the recipient of a UBC Four Year Doctoral Fellowship and an AllerGen NCE Inc. Canadian Allergy and Immune Diseases Training Award. J-QH is the recipient of a Michael Smith Foundation for Health Research Fellowship and an Izaak Walton Killam Memorial Scholarship Award. AJS is the recipient of a Canada Research Chair in genetics and a Michael Smith Foundation for Health Research Senior Scholar Award.

PY - 2011/9/8

Y1 - 2011/9/8

N2 - Background: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.Methods: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.Results: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.Conclusions: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.

AB - Background: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.Methods: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1 % predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2 and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.Results: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)n polymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.Conclusions: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene.

KW - Chronic obstructive pulmonary disease

KW - Heme oxygenase

KW - Polymorphism

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ER -

Effect of heme oxygenase-1 polymorphisms on lung function and gene expression

Abstract

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