Evidence for major genes influencing pulmonary function in the NHLBI Family Heart Study

Wilk, Jemma B.; Djoussé, Luc; Arnett, Donna K.; Rich, Stephen S.; Province, Michael A.; Hunt, Steven C.; Crapo, Robert O.; Higgins, Millicent; Myers, Richard H.

doi:10.1002/1098-2272(200007)19:1<81::aid-gepi6>3.0.co;2-8

Cited by 95 publications

(60 citation statements)

References 15 publications

(23 reference statements)

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“…Heritability estimates of lung function in the general population suggest that genetic factors explain 25 to 37% of between-subject variability in forced expiratory volume in 1 s (FEV1), forced vital capacity, and the ratio of FEV1/ forced vital capacity (Redline et al, 1989;Coultas et al, 1991;Wilk et al, 2000;Joost et al, 2002). Twin studies in subjects with asthma have suggested that within this susceptible population, genetic factors may explain a large proportion of altered lung function (77-91% for FEV1) even after accounting for smoking and the shared genetic effects of body size (Hankins et al, 1982;Hubert et al, 1982).…”

Section: Introductionmentioning

confidence: 99%

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Sh¹,

Fang²,

Hx³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. The Wnt signal pathway plays a role in lung development and in asthma pathogenesis. However, whether genetic polymorphisms of Wnt signal pathway are associated with lung function in asthma patients remain unclear. We genotyped 2 single nucleotide polymorphisms (SNPs, rs2929973 and rs6581612) involved in the Wnt signal pathway in a cohort of 560 Chinese Han asthmatic children. Associations between each SNP and lung function, in a baseline exam, were tested using multiple linear regression models. We found that rs2929973 of the WISP1 gene was significantly associated with forced expiratory volume in 1 s (FEV1), with the G allele conferring significantly lower FEV1 values. However, the rs6581612 SNP of the WIF1 gene was not associated with differences in FEV1 values. We conclude that genetic variants in Wnt are associated with lung function and suggest that Wnt participates in inflammatory pathways that have an impact on the level of lung function.

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Section: Introductionmentioning

confidence: 99%

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Sh¹,

Fang²,

Hx³

et al. 2013

Genet. Mol. Res.

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“…Thus, identifying those patients most likely to benefit from this treatment would be valuable. Because the intraindividual response to inhaled corticosteroid treatment in patients with asthma is highly repeatable (6) and because both FEV 1 and PC 20 are heritable traits (7,8), a genetic basis for the heterogeneity of this therapeutic response is plausible.…”

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confidence: 99%

TBX21 : A functional variant predicts improvement in asthma with the use of inhaled corticosteroids

Tantisira

Hwang

Raby

et al. 2004

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

173

112

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TBX21 encodes for the transcription factor T-bet (T-box expressed in T cells), which influences naïve T lymphocyte development and has been implicated in asthma pathogenesis. Specifically, the T-bet knockout mouse spontaneously develops airway hyperresponsiveness and other changes consistent with asthma. Because airway responsiveness is moderated by the use of inhaled corticosteroids in asthma, it is conceivable that genetic variation in TBX21 may alter asthma phenotypes in a treatment-specific fashion. Here we demonstrate that the nonsynonymous variation in TBX21 coding for replacement of histidine 33 with glutamine is associated with significant improvement in the PC 20 (a measure of airway responsiveness) of asthmatic children in a large clinical trial spanning 4 years. We note that this increase occurs only in the children randomized to inhaled corticosteroids and that it dramatically enhances the overall improvement in PC 20 associated with inhaled corticosteroid usage. The average PC20 at trial end for subjects on inhaled corticosteroids possessing a variant allele was in the normal range for nonasthmatics. In cellular models, we show that the TBX21 variant increases T helper 1 and decreases T helper 2 cytokine expression comparably with wild type. TBX21 may thus be an important determinant pharmacogenetic response to the therapy of asthma with inhaled corticosteroids. PC20 ͉ pharmacogenetics ͉ T-bet ͉ interaction C orticosteroids mediate a variety of immunological actions and are commonly used in the treatment of a diverse number of diseases. Inhaled corticosteroids are the most effective and commonly used therapy in the management of asthma (1, 2) but may be associated with serious adverse reactions (3). In evaluating asthma therapy response, measures of lung function, such as forced expiratory volume at 1 second (FEV 1 ), and of airway responsiveness, as measured by the provocative concentration of methacholine causing a 20% decrement in FEV 1 (PC 20 ) are commonly used. However, there is large interindividual variation in the FEV 1 and PC 20 responses to inhaled corticosteroids (4, 5). Thus, identifying those patients most likely to benefit from this treatment would be valuable. Because the intraindividual response to inhaled corticosteroid treatment in patients with asthma is highly repeatable (6) and because both FEV 1 and PC 20 are heritable traits (7, 8), a genetic basis for the heterogeneity of this therapeutic response is plausible.The gene TBX21 (GenBank accession no. NM 013351) encodes for transcription factor T-bet (T-box expressed in T cells), which is responsible for the induction of T helper (Th)1 cells and the repression of Th2 cells from naïve T lymphocytes (9). T-bet has been implicated in the pathogenesis of asthma (10, 11). Because the T-bet knockout mouse develops spontaneous airway hyperresponsiveness (10), a phenotype that is modulated by corticosteroids, we assessed the relationship of TBX21 with PC 20 outcomes in asthma. Only one common (estimated heterozygosity Ն 5%) nonsynonymo...

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“…The observation that pulmonary diseases cluster in families (1,2) and the substantial heritability of spirometric pulmonary function measures demonstrated in population-based samples (3)(4)(5)(6)(7)(8)(9)(10) support the hypothesis that genetic factors influence both variability in pulmonary function and risk of chronic obstructive pulmonary disease (COPD). The spirometric measurements of FEV 1 , FVC, and FEV 1 /FVC are estimated to be between 15 and 60% heritable in population-based samples (8,10).…”

mentioning

confidence: 77%

“…The spirometric measurements of FEV 1 , FVC, and FEV 1 /FVC are estimated to be between 15 and 60% heritable in population-based samples (8,10). Familial factors may influence lung size during development, as well as affect the response to environmental toxins such as cigarette smoke.…”

mentioning

confidence: 99%

Secreted Modular Calcium-binding Protein 2 Haplotypes Are Associated with Pulmonary Function

Wilk

Herbert²,

Shoemaker³

et al. 2007

Am J Respir Crit Care Med

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Rationale: Previously reported linkage to FEV 1 (LOD score ϭ 5.0) on 6q27 in the Framingham Heart Study (FHS) led us to explore a candidate gene, SMOC2, at 168.6 Mb. Objectives: We tested association between SMOC2 polymorphisms and FEV 1 and FVC in unrelated FHS participants. Methods: Twenty single-nucleotide polymorphisms (SNPs) around SMOC2 were genotyped in 1,734 subjects. Measurements and Main Results: SNP data were analyzed using multiple linear regression models incorporating sex, age, body mass index, height, and smoking history as covariates, and analyses were repeated within strata of ever-and never-smokers. The minor allele of SNP rs1402 was associated with higher mean FEV 1 (p ϭ 0.003) and FVC (p ϭ 0.02) measures. In never-smoking subjects, association with higher measures was observed with the minor allele of rs747995 (FEV 1 , p ϭ 0.0006; FVC, p ϭ 0.0008). These two SNPs lie in different haplotype blocks and reside in intron 4 of SMOC2. Haplotype analysis revealed a common G-T haplotype (rs747995-rs1402) with 77% frequency in never-smoking FHS subjects. The G-T haplotype was associated with reduction of 126 ml for FEV 1 (p ϭ 0.0002) and 157 ml for FVC (p ϭ 0.0002). The G-T haplotype was similarly associated in a set of never-smoking subjects from the Family Heart Study (FEV 1 , p ϭ 0.03; FVC, p ϭ 0.03). Conclusions:The replication of the association in two populations supports the possibility that SMOC2 might play an important role in the determination of FEV 1 and FVC.Keywords: FEV 1 ; FVC; genetics; single-nucleotide polymorphismThe observation that pulmonary diseases cluster in families (1, 2) and the substantial heritability of spirometric pulmonary function measures demonstrated in population-based samples (3-10) support the hypothesis that genetic factors influence both variability in pulmonary function and risk of chronic obstructive pulmonary disease (COPD). The spirometric measurements of FEV 1 , FVC, and FEV 1 /FVC are estimated to be between 15 and 60% heritable in population-based samples (8, 10). Familial factors may influence lung size during development, as well as affect the response to environmental toxins such as cigarette smoke.Today, ␣ 1 -antitrypsin deficiency is the only proven genetic determinant of COPD (11-16). The homozygous deficiency of the serine protease inhibitor ␣ 1 -antitrypsin is associated with early-onset emphysema in smokers in their fourth decade of life and nonsmokers in their fifth decade (17) and accounts for less What This Study Adds to the FieldThe study provides evidence for the implication of yet another gene, SMOC2, in lung function. SMOC2 was found to affect FEV 1 and FVC in two different populations, the NHLBI Framingham Heart Study and the NHLBI Family Heart Study.than 2% of all COPD (18). The heterozygous form of the mutation has been inconsistently associated with an increased risk of COPD. Mutations in alleles of ␣ 1 -antichymotrypsin, a highly homologous protease inhibitor (19), have also been associated with obstructive lung disease in case-contr...

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Evidence for major genes influencing pulmonary function in the NHLBI Family Heart Study

Cited by 95 publications

References 15 publications

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

Genetic variations in the Wnt signaling pathway affect lung function in asthma patients

TBX21 : A functional variant predicts improvement in asthma with the use of inhaled corticosteroids

Secreted Modular Calcium-binding Protein 2 Haplotypes Are Associated with Pulmonary Function

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