Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function

Artigas, María Soler; Wain, Louise V.; Repapi, Emmanouela; Obeidat, Ma’en; Sayers, Ian; Burton, Paul R.; Johnson, Toby; Zhao, Jing Hua; Albrecht, Eva; Dominiczak, Anna F.; Kerr, Shona M.; Smith, BH; Cadby, Gemma; Hui, Jennie; Palmer, Lyle J.; Hingorani, Aroon D.; Wannamethee, S. Goya; Whincup, Peter H.; Ebrahim, Shah; Smith, G. D.; Barroso, Inês; Loos, Ruth J.F.; Wareham, Nicholas J.; Cooper, Cyrus; Dennison, Elaine; Shaheen, Seif O.; Liu, J Z; Marchini, Jonathan; Dahgam, Santosh; Naluai, Åsa Torinsson; Olin, Anna‐Carin; Karrasch, Stefan; Heinrich, Joachim; Schulz, Holger; McKeever, Tricia M.; Pavord, Ian D.; Heliövaara, Markku; Ripatti, Samuli; Surakka, Ida; Blakey, John; Kähönen, Mika; Britton,; Nyberg, Fredrik; Holloway, John W.; Lawlor, Debbie A.; Morris, Richard W; James, Alan; Jackson, Catherine; Hall, Ian P.; Tobin, Martin D.

doi:10.1164/rccm.201102-0192oc

Cited by 129 publications

(110 citation statements)

References 30 publications

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“…22 The main hit rs2571445, a nonsynonymous coding SNP, has recently been reported to be associated with the presence of GOLD stage 2 to 4 COPD as well. 33 Our findings on the AGER SNP rs2070600 affecting the FEV 1 / FVC ratio are in line with the results from Hancock et al 26 The presence of 2 risk alleles of this nonsynonymous SNP in the gene coding for the receptor for advanced glycation end products (RAGE) has been reported to be strongly associated with higher levels of soluble forms of this protein in a Dutch population. 34 RAGE expression is most abundant in the lung, and the intensity of expression in respiratory epithelial cells varies during lung morphogenesis.…”

Section: Discussionsupporting

confidence: 91%

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Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Kerkhof

Boezen

Granell

et al. 2014

Journal of Allergy and Clinical Immunology

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Section: Discussionsupporting

confidence: 91%

“…Tensin 1 is involved in signal transduction and cell migration. 33 The TNS1 locus at 2q35 was initially discovered in a genome-wide association study on FEV 1 . 22 The main hit rs2571445, a nonsynonymous coding SNP, has recently been reported to be associated with the presence of GOLD stage 2 to 4 COPD as well.…”

Section: Discussionmentioning

confidence: 99%

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Kerkhof

Boezen

Granell

et al. 2014

Journal of Allergy and Clinical Immunology

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“…Mechanistic studies on novel susceptibility genes in complex traits, including COPD and pulmonary function levels, may provide insights into disease pathogenesis and thus highlight potential targets for therapy. Through GWAS, the chromosome 4q31 Hedgehog interacting protein (HHIP) locus has been consistently identified in COPD (8)(9)(10) and in spirometric measures, including the forced expiratory volume in 1 s (FEV 1 ) and ratio of FEV 1 to forced vital capacity in general population samples (11)(12)(13)(14). Hhip represses hedgehog signaling by competitive binding with three Hedgehog (HH) ligands: Sonic Hedgehog, Indian Hedgehog, and Desert Hedgehog (15).…”

mentioning

confidence: 99%

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Lao

Jiang

Yun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants in Hedgehog interacting protein (HHIP) have consistently been associated with the susceptibility to develop chronic obstructive pulmonary disease and pulmonary function levels, including the forced expiratory volume in 1 s (FEV1), in general population samples by genome-wide association studies. However, in vivo evidence connecting Hhip to age-related FEV1 decline and emphysema development is lacking. Herein, using Hhip heterozygous mice (Hhip+/−), we observed increased lung compliance and spontaneous emphysema in Hhip+/− mice starting at 10 mo of age. This increase was preceded by increases in oxidative stress levels in the lungs of Hhip+/− vs. Hhip+/+ mice. To our knowledge, these results provide the first line of evidence that HHIP is involved in maintaining normal lung function and alveolar structures. Interestingly, antioxidant N-acetyl cysteine treatment in mice starting at age of 5 mo improved lung function and prevented emphysema development in Hhip+/− mice, suggesting that N-acetyl cysteine treatment limits the progression of age-related emphysema in Hhip+/− mice. Therefore, reduced lung function and age-related spontaneous emphysema development in Hhip+/− mice may be caused by increased oxidative stress levels in murine lungs as a result of haploinsufficiency of Hhip.

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“…This finding was subsequently replicated in a population-based cohort including 742 cases with COPD 41 as well as with a different SNP near the HHIP locus in a candidate gene study. 42 Zhou and colleagues demonstrated a potential role for the HHIP locus in COPD pathogenesis through a series of functional analyses, integrating genetic and molecular biology techniques. 43 They first demonstrated a significant association between the previously identified upstream variant and severe COPD in a cohort of Caucasian smokers from Poland.…”

Section: Hhipmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

Hardin

Silverman

2014

J COPD F

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Abbreviations: single nucleotide polymorphism, SNP; genome-wide association studies, GWAS; forced expiratory volume in 1 second, FEV1; early-onset COPD, EOCOPD; National Emphysema Treatment Trial, NETT; Normative Aging Study, NAS; International COPD Genetics Network, ICGN; linkage disequilibrium, LD; Evaluation of COPD Longitudinally to Identify Surrogate Endpoints, ECLIPSE; cigarettes per day, CPD; forced volume capacity, FVC; Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium, CHARGE; messenger RNA, mRNA; body mass index, BMI; C-reactive protein, CRP; tumor necrosis factor-alpha, TNF-alpha; Clara cell secretory protein, CC16; surfactant protein D, SP-D; Funding: K12 HL120004, The Sheila J. Goodnight, MD, FCCP, Clinical Research Grant in Women's Lung Health, R01HL089856; P01HL105339; R01HL075478 Date of Acceptance: February 28, 2014 Citation: Hardin M, Silverman EK. Chronic obstructive pulmonary disease genetics: a review of the past and a look into the future.

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Effect of Five Genetic Variants Associated with Lung Function on the Risk of Chronic Obstructive Lung Disease, and Their Joint Effects on Lung Function

Abstract: Variants in TNS1, GSTCD, and HTR4 are associated with COPD. Our highest risk score category was associated with a 1.6-fold higher COPD risk than the population average score.

Cited by 129 publications

References 30 publications

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Hhip haploinsufficiency sensitizes mice to age-related emphysema

Chronic Obstructive Pulmonary Disease Genetics: A Review of the Past and a Look Into the Future

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