Heritability Estimates of Pulmonary Function

doi:10.1378/chest.96.4.743

Chest

Volume 96, Issue 4, October 1989, Pages 743-746

https://doi.org/10.1378/chest.96.4.743 Get rights and content

To test the hypothesis that there is genetic control of pulmonary function parameters independent of that influencing height, we evaluated 74 pairs of asymptomatic, nonsmoking twins. FVC, FEV₁, FEF25-75%, TLCsb, RVsb, Dsb, and D/VA were measured. Pulmonary function indices were adjusted for height using simple linear regression. Mean intrapair differences (unadjusted and adjusted for height) were compared using t tests of independent samples. Within pair, Holzinger's, and Falconer's heritability estimates were calculated using height-adjusted residual values. When total variances of a function parameter were statistically different between monozygotes and dizygotes, the among component heritability estimate was calculated and used as the best indicator of heritability. Following adjustment for height, no measure of pulmonary function which satisified the requirements of the analysis was found to be significantly heritable.

Section snippets

METHODS

Seventy-four pairs of same sex twins (47 sets of monozygotes and 27 sets of dizygotes) participated in the study. All were university students recruited through advertising. Each subject completed an extensive medical questionnaire modified from the epidemiology standardization project¹² to permit self-administration. Subjects were lifetime nonsmokers and free of cardiopulmonary symptoms.

Twins were classified as MZ or DZ on the basis of serologic analysis. Eighteen blood group markers from

RESULTS

Monozygotes made up 63.5 percent of the study population. Mean ages for MZ and DZ were 19.7 and 19.5 years, respectively (Table 1).

Evaluation of the assumptions required for genetic analysis revealed the following. All tested pulmonary function parameters, with the exception of FEV₁/FVC, met the Kolmogorov-Smirnov goodness of fit test for a Gaussian distribution. The FEV₁/FVC ratio was not tested further because it did not pass the test for a Gaussian distribution, even with logarithmic

DISCUSSION

Dizygotic twins are related only as full siblings and share an average of 50 percent of genes while MZ twins are genetically identical. Consequently, intrapair differences for genetically influenced traits will, on average, be smaller in monozygotes than in dizygotes. Several studies have investigated the heritability of spirometric indices by evaluating mean intrapair differences unadjusted for height and confirmed the presence of smaller intrapair differences in monozygotes. Our findings for

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Genome-wide association study of lung function phenotypes in a founder population
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Lung function is a long-term predictor of mortality and morbidity.
We sought to identify single nucleotide polymorphisms (SNPs) associated with lung function.
We performed a genome-wide association study (GWAS) of FEV₁, forced vital capacity (FVC), and FEV₁/FVC in 1144 Hutterites aged 6 to 89 years, who are members of a founder population of European descent. We performed least absolute shrinkage and selection operation regression to select the minimum set of SNPs that best predict FEV₁/FVC in the Hutterites and used the GRAIL algorithm to mine the Gene Ontology database for evidence of functional connections between genes near the predictive SNPs.
Our GWAS identified significant associations between FEV₁/FVC and SNPs at the THSD4-UACA-TLE3 locus on chromosome 15q23 (P = 5.7 × 10⁻⁸ to 3.4 × 10⁻⁹). Nine SNPs at or near 4 additional loci had P < 10⁻⁵ with FEV₁/FVC. Only 2 SNPs were found with P < 10⁻⁵ for FEV₁ or FVC. We found nominal levels of significance with SNPs at 9 of the 27 previously reported loci associated with lung function measures. Among a predictive set of 80 SNPs, 6 loci were identified that had a significant degree of functional connectivity (GRAIL P < .05), including 3 clusters of β-defensin genes, 2 chemokine genes (CCL18 and CXCL12), and TNFRSF13B.
This study identifies genome-wide significant associations and replicates results of previous GWASs. Multimarker modeling implicated for the first time common variation in genes involved in antimicrobial immunity in airway mucosa that influences lung function.
Genetics of maximally attained lung function: A role for leptin?
2012, Respiratory Medicine
Citation Excerpt :
In our sample, 69% and 63% of the total variation in maximally attained FEV1 and FVC was explained by genetic factors, respectively. One study in a younger twin sample (mean age 19 years) failed to identify significant heritabilities for FEV1 and FVC,31 which might be due to their relatively small sample size (74 twin pairs). Conversely, twin studies in older samples revealed heritability estimates for FEV1 and FVC between 32 and 91%.8–13
To estimate the heritabilities of maximally attained lung function in young adult twins, and to examine whether circulating leptin, leptin (LEP) and leptin receptor (LEPR) gene polymorphisms are associated with maximally attained lung function.
Measures on forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC) were available of 578 twins recruited from the East Flanders Prospective Twin Survey (165 monozygotic (MZ) and 73 dizygotic (DZ) complete pairs and 102 single twins). Twin model fitting and (genetic) association analyses were performed.
Intra-pair correlations of FEV₁ and FVC did not differ significantly between MZ monochorionic and MZ dichorionic pairs. Heritability estimates of FEV₁ and FVC were 69% and 63%, respectively. The A allele of the LEP 19G>A SNP was significantly associated with a lower FEV₁ (p_Additive = 0.01) and FVC (p_Dominant = 0.047), while the LEPR K109R and Q223R SNPs showed no associations. Accounting for body mass index, serum leptin was negatively associated with FVC (p = 0.02) in men, but not in women.
More than 60% of variation in maximally attained FEV₁ and FVC is explained by genetic factors. Moreover, these results suggest that leptin may be important in the determination of maximally attainable lung function.
The role of genetic research in sport
2011, Science and Sports
Citation Excerpt :
Molecular studies of inherited cardiomyopathies have to led to the identification of several genetic loci contributing to cardiac structures and functions; Na+/K+ transporting ATPase beta-1 (ATP1B1, the enzyme responsible for regulating the number of sodium pumps transported to the plasma membrane) [22], angiotensinogen (AGT) [23], neuropeptide Y Y1 receptor (NPYY1R) [24]. Studies on twins also generally show higher intrapair correlations for pulmonary measurements in MZ twins than DZ twins, suggesting a significant genetic effect [25–28]. The results of these studies, often based however on just a small number of twins, provided a wide range of heritability estimates [3], ranging from 0% [26] to 77% [22] for the Forced Expiratory Volume in the first second (FEV-1).
This study describes the history of the application of genetics in sport and present achievements in this field.
It reviews the main directions in genetics with regard to sport: population genetics, popular in the second half of the 20th century, based on studies of the phenotypic characteristics without genotype pattern recognition; the beginnings of research on genotype characteristics with genotype pattern recognition; and recent achievements in molecular biology after the completion of ‘The Human Genome Project’ in 2003. The first section of the paper presents the significance, role and the most important achievements of early genetic researches based on the comparison of twins and parents with children. Thus developed heritability indices for individual traits are still a very precious source of information for people responsible for planning training. The next part of the paper presents a gradual development of molecular research in sport. The analysis concerned the first of a few dozen currently examined genetic markers (ACE, ACTN3, MSTN) and genetic conditions of individual functional traits of the human body, with the emphasis on the potential application of this knowledge. We also present the increasing ethical concerns with regard to the use of molecular techniques in sport and related threats, such as the use of the genetic doping in sport. The last part of the paper attempts to determine the role and range of genetics in sport in the future, for example in traumatology, rehabilitation, and sport medicine.
Présenter le rôle et l’importance de la génétique dans le sport contemporain.
Les auteurs ont effectué une évaluation des tendances principales des recherches en génétique réalisées dans le sport : génétique des populations dans la seconde moitié du xx^e siècle, basée sur une étude des caractéristiques des phénotypes sans identification des patterns du génotype; démarrages des recherches sur les caractéristiques du génotype avec reconnaissance des patterns du génotype ; et les récents progrès en biologie moléculaire après l’achèvement après l’achèvement « The Human Genome Project » en 2003. La première partie du papier présente la signification, le rôle et les plus importants résultats des premiers travaux de génétique fondés sur la comparaison de jumeaux ainsi que les parents et leurs enfants. Les indicateurs d’hérédité élaborées sur cette base sont jusqu’à aujourd’hui une très précieuse source d’informations pour les personnes responsables des programmes d’entraînement. La partie suivante de l’article expose la progression dans le développement des recherches moléculaires dans le sport. Les analyses ont porté sur plusieurs dizaines de marqueurs génétiques (ACE, ACTN3, MSTN) ainsi que la prédétermination génétique des traits fonctionnels de l’organisme humain, l’accent étant mis sur les applications potentielles pour la connaissance. Nous avons aussi parlé des problèmes éthiques soulevés par l’utilisation des techniques moléculaires dans le sport et du risque lié éventuellement à un usage de dopage génétique. La dernière partie du papier essaie de déterminer le rôle de la génétique dans le sport à court et moyen termes, notamment dans les domaines de la traumatologie, la réadaptation et la médicine du sport.
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Pharmacogenetic studies of drug response in asthma assume that patients respond consistently to a treatment but that treatment response varies across patients; however, no formal studies have demonstrated this.
To determine the repeatability of commonly used outcomes for treatment response to asthma medications: bronchodilator response, FEV₁, and PC₂₀.
The Childhood Asthma Management Program was a multicenter clinical trial of children randomized to receiving budesonide, nedocromil, or placebo. We determined the intraclass correlation coefficient (ICC) for each outcome over repeated visits over a period of 4 years in the Childhood Asthma Management Program by using mixed-effects regression models. We adjusted for the covariates age, race/ethnicity, height, family income, parental education, and symptom score. We incorporated each outcome for each child as repeated outcome measurements and stratified by treatment group.
The ICC for bronchodilator response was 0.31 in the budesonide group, 0.35 in the nedocromil group, and 0.40 in the placebo group, after adjusting for covariates. The ICC for FEV₁ was 0.71 in the budesonide group, 0.60 in the nedocromil group, and 0.69 in the placebo group, after adjusting for covariates. The ICC for PC₂₀ was 0.67 in the budesonide and placebo groups and 0.73 in the nedocromil group, after adjusting for covariates.
The within–treatment group repeatability of FEV₁ and PC₂₀ is high; thus, these phenotypes are heritable. FEV₁ and PC₂₀ may be better phenotypes than bronchodilator response for studies of treatment response in asthma.
The interaction of genes and smoking on forced expiratory volume: A classic twin study
2007, Chest
Citation Excerpt :
Some previous studies8910 have reported a significant genetic influence on FEV1 after adjustment for body habitus and other factors. In contrast, Ghio et al21 found in 74 university student pairs of twins with an average age of 20 years, that heritability was not significant after adjustment for height. Small sample sizes and a relatively young sample are a likely explanation for this discrepancy.
Genetic influences on lung function as measured by FEV₁ have been reported from twin and family studies. The aims of this study were to estimate heritability of the ratio of measured FEV₁ (mFEV₁) to expected FEV₁ (eFEV₁) in a white population, and to examine the interaction between genetic factors and smoking on this ratio.
The sample consisted of unselected monozygotic (MZ) and dizygotic (DZ) twin pairs from the TwinsUK registry. FEV₁ was measured with a spirometer, and mFEV₁/eFEV₁ ratio was calculated.
A total of 475 MZ and 1,054 DZ twin pairs participated (mean age, 47 years; range, 18 to 84 years). mFEV₁/eFEV₁ ratio was 0.057 lower in smokers than nonsmokers (p < 0.0001). The difference in the correlation for mFEV₁/eFEV₁ ratio between MZ and DZ twin pairs was 0.32 in nonsmokers and 0.19 in current smokers, suggesting a significant genetic influence on lung function that was modified in current smokers. Using structural equation modeling, the heritability estimate for mFEV₁/eFEV₁ ratio was found to be 66% (95% confidence interval [CI], 59 to 72%) in nonsmokers but significantly reduced to 32% (95% CI, 12 to 53%) in current smokers. However, there was no clear difference in the heritability of mFEV₁/eFEV₁ ratio between nonsmokers and ex-smokers.
Genes are the major influence on the variability of mFEV₁/eFEV₁ ratio in nonsmokers. However, this strong genetic influence is strongly modified by an interaction with cigarettes.
Genetic and Environmental Influences on Pulmonary Function and Muscle Strength: The Chinese Twin Study of Aging
2017, Twin Research and Human Genetics

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Chest

Clinical InvestigationsHeritability Estimates of Pulmonary Function

Section snippets

METHODS

RESULTS

DISCUSSION

J Chronic Dis

J Chronic Dis

Genetic influence on normal variability of maximum expiratory flow-volume curve

J Appl Physiol

Pattern of genetic influence on pulmonary function

Chest

Genetic and environmental determinants of level of pulmonary function

Am J Epidemiol

The NHLBI twin study of cardiovascular disease risk factors: methodology and summary of results

Am J Epidemiol

Familial aggregation of pulmonary function measurements

Am Rev Respir Dis

Genetic and environmental influences on pulmonary function in adult twins

Am Rev Respir Dis

Lung function, respiratory disease, and smoking in families

Am J Epidemiol

Variance components analysis of forced expiration in families

Am J Med Genet

Household aggregation of pulmonary function and chronic bronchitis

Am Rev Respir Dis

Assessment of genetic and nongenetic influences on pulmonary function: a twin study

Am Rev Respir Dis

Clinical Investigations
Heritability Estimates of Pulmonary Function