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Published ahead of print on June 5, 2003, doi:10.1164/rccm.200303-410OC
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American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 556-561, (2003)
© 2003 American Thoracic Society

Original Article

Further Evidence for the Role of Genes on Chromosome 2 and Chromosome 5 in the Inheritance of Pulmonary Function

Alka Malhotra, Andy P. Peiffer, Darin T. Ryujin, Tami Elsner, Richard E. Kanner, Mark F. Leppert and Sandra J. Hasstedt

Department of Human Genetics, and Pulmonary Division, Department of Internal Medicine, University of Utah, Salt Lake City, Utah

Correspondence and requests for reprints should be addressed to Alka Malhotra, University of Utah, Department of Human Genetics, 15 North 2030 East, Room 2100, Salt Lake City, UT 84112–5330. E-mail: amalhotr{at}genetics.utah.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The spirometric measurements FEV1, FVC, and the ratio FEV1/FVC are used in the diagnosis of lung function disorders. Therefore, understanding the genetics underlying these spirometric measurements will increase our knowledge of the genetics of pulmonary function. FEV1 and FVC were measured on 264 members of 26 Utah Genetic Reference pedigrees, originally collected for the Centre d'Etude du Polymorphisme Humain genetic mapping project. Using segregation analysis, we inferred major locus inheritance of the FEV1/FVC ratio, although we could not distinguish between a dominant or recessive mode of inheritance. No evidence of major locus inheritance was found for either FEV1 or FVC. Suggestive evidence of linkage for the ratio FEV1/FVC was found on chromosome 2 (heterogeneity lod = 2.36, dominant model) and chromosome 5 (heterogeneity lod = 2.23, recessive model), replicating linkages from other studies. In addition, nonparametric variance component linkage analysis showed linkage of FEV1/FVC in both of these regions, providing further support to the results. No nonparametric lod scores over 1.5 were obtained for either FEV1 or FVC.

Key Words: spirometric measurements • segregation analysis • linkage analysis

Pulmonary function disorders are prevalent in the population. Diseases such as chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, and small airways disease have high morbidity and mortality (1). COPD is the fourth most common cause of death in the United States, and the prevalence is increasing worldwide (2). In addition, the number of asthma cases has increased by over 70% since the 1980s (3). These staggering statistics emphasize the impact that lung disorders have on the world population.

A number of factors contribute to lung disease. Cigarette smoking is one of the most important environmental factors, the risk increasing with the number of cigarettes smoked per day and the number of years of smoking. Air pollution and occupation have a smaller effect (4, 5).

Although smoking increases the risk of lung disease, only a small percentage (10–20% for COPD) of heavy cigarette smokers develop lung function abnormalities (5, 6). Therefore, other factors play a role in the development of lung dysfunctions. Heritability, the ratio of genetic variation relative to the total variation in the population, has been estimated in a number of pulmonary function studies to range from 41–47% (7–9). Givelber and colleagues (10) found a trimodal distribution of pulmonary function measurements obtained from the Framingham study, which could reflect the three genotypes possible at a biallelic locus.

Despite the evidence of involvement of genes, the genetic architecture underlying pulmonary function remains unknown. There might be a single gene with a large effect, several genes with large effects, or many genes each with small effects. To understand further the genetics underlying pulmonary function, we analyzed data from 264 individuals from 26 pedigrees. For this study, two pulmonary function measurements, FEV1 and FVC, were measured using spirometry. FEV1 is the maximum volume of air that can be exhaled in 1 second and FVC is the total volume of air exhaled using a forced expiratory maneuver. These spirometric measurements are reduced in patients suffering from lung disease (11, 12). Low FEVs are associated with an increase in mortality (13) and are age dependent (14). Reduced FEV1 and FEV1/FVC indicate airways obstruction (12), and low FVC levels are observed in restrictive disorders (15). Specifically, FEV1/FVC less than 70% is one of the criteria for the diagnosis of COPD (16). Therefore, understanding the genetics underlying these spirometric measurements will increase our knowledge of the genetics of pulmonary function. This in turn will allow further understanding of the etiology of diseases affecting pulmonary function. We performed segregation and linkage analyses of FEV1, FVC, and the FEV1/FVC ratio to infer the underlying mode of inheritance and locate the gene(s) of interest. Some of the results of this study have been previously reported in the form of abstracts (17–19).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Utah Centre d'Etude du Polymorphisme Humain Pedigrees
The family collection began as a collaborative effort to map genetic markers using pedigree data. For maximum informativeness, each pedigree collected consisted of 4 grandparents, 2 parents, and 6–11 offspring. Sixty-one pedigrees were collected without regard to any disease phenotypes (i.e., they were randomly ascertained) (20). Between 1997 and 2001, members of 26 Utah Centre d'Etude du Polymorphisme Humain (CEPH) pedigrees were measured for pulmonary function as part of the Utah Genetic Reference Project. The data obtained on these family members provided the basis for the dataset analyzed in this article. All Utah Genetic Reference Project study subjects gave informed consent under University of Utah Institutional Review Board–approved protocol number 6090–96.

Spirometric Measurements
Spirometric measurements were made on 264 individuals. Up to eight maneuvers were performed until three measurements of FEV1 and FVC within 0.2 L of each other were obtained. The spirometric measurements were made using a Morgan Scientific Spirometer in accordance to the American Thoracic Society standards (21). A volume–time curve was plotted from which FEV1 and FVC were inferred.

Marker Data
The Utah CEPH pedigrees have been extensively genotyped by multiple investigators. In addition, a set of 245 microsatellite markers spread across the genome was genotyped at the University of Utah using an automated hybridization imaging instrument (22). These markers and a set of 1,079 markers from the CEPH database (23) were used for this study. More details on the markers used are provided in the online supplement.

Statistical Analysis
Regression analysis, using the program Statistical Analysis System (24), showed a significant effect of age on FEV1/FVC, age, height, weight, and weight2 on FEV1 and on FVC. The data were adjusted for these variables separately in males and females. Smoking status was not accounted for, as there were only eight individuals who were current smokers. Data on age, height, and weight were obtained through a standard questionnaire, and smoking status was self-reported during the pulmonary function testing. Segregation analysis was then performed for each trait using the Pedigree Analysis Package (25). Segregation analysis tests for single gene inheritance and allows the inference of the mode of inheritance by the analysis of various genetic and nongenetic models. This provides statistical evidence for a genetic contribution to a trait (26). The assumptions made for the segregation analysis and the method used to infer the mode of inheritance are provided in an online data supplement.

To localize the gene(s) underlying the inheritance of these spirometric measurements, linkage analyses were performed using the program Genehunter (27, 28). Parametric linkage analysis was performed assuming the dominant and recessive models inferred from the segregation analysis of the ratio FEV1/FVC. Models could not be inferred for either FEV1 or FVC. For this reason, parametric linkage analysis was only performed for the ratio FEV1/FVC. In addition, nonparametric variance components linkage analysis was performed for the FEV1, FVC, and FEV1/FVC phenotypes. Residual values were used for all three phenotypes. The assumptions and methods used in the linkage analyses are described in the online supplement.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Table 1 shows the descriptive statistics for the participants in this study. Most of the grandparents are no longer alive. The sample included 13 members of the grandparental generation and 50 members of the parental generation, and the remaining 201 were from the offspring generation. Thirteen individuals, ranging in age from 23 to 80, had an FEV1/FVC ratio of less than 70% but were not diagnosed with COPD because they did not exhibit other conditions that are also required for the diagnosis (5). The sample contained 24 current and ex-smokers and 21 patients who had asthma; of these, one individual was both a smoker and had asthma.


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  		TABLE 1. Descriptive statistics of the covariates and spirometric measurements for the individuals participating in this study

 
Major loci could not be inferred from the segregation analysis of FEV1 and FVC (results not shown). Heritability estimates of 46% and 52% were obtained for FEV1 and FVC, respectively. The results from the segregation analysis of the ratio FEV1/FVC are summarized in Table 2 . In the polygenic model, we estimated a heritability of 67%, which suggests a stronger genetic effect on FEV1/FVC inheritance in comparison to FEV1 and FVC. The general model estimated transmission probabilities of {tau}(AA) = 0.3456 ± 0.2934 (SEM), {tau}(AB) = 0.6070 ± 0.0693, and {tau}(BB) = 0.0133 ± 0.0172. The poor estimate of {tau}(AA) is often observed in situations in which the genotype is rare. Both the environmental model ({chi}2[3] = 11.40, p = 0.0097) and the polygenic model ({chi}2[6] = 24.70, p = 0.0004) were rejected but not the major locus model ({chi}2[3] = 4.99, p = 0.1725), evidence that a major gene underlies the inheritance of FEV1/FVC. However, neither the dominant ({chi}2[3] = 0; p approximately 1) nor the recessive ({chi}2[3] = 2.55, p = 0.1103) models could be rejected, leaving the mode of inheritance uncertain. Removal of those who smoked, had asthma, or both reduced significance levels and made the results inconclusive. This is because seven individuals from these groups (two with asthma and five who were current/ex-smokers) were from the parental generation, which reduced the amount of genetic information that could be extracted from these pedigrees. In addition, two-locus models did not fit better than single gene models (results not shown).


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  		TABLE 2. Results from the segregation analysis of the ratio fev1/fvc

 
The linkage analysis results for the ratio FEV1/FVC are summarized in Figure 1 . Parametric and variance component linkage analysis for these traits suggested linkage to several regions. Multipoint parametric heterogeneity lod scores of 2.36 (1-lod drop: 216–251 cM) on chromosome 2 (dominant model) and 2.23 (1-lod drop: 290–304 cM) on chromosome 5 (recessive model) were obtained. Nonparametric variance component linkage lod scores of 1.12 and 1.08 were observed in these regions of chromosomes 2 and 5, respectively. A parametric lod score of 2.02 was observed in the region suggesting linkage on chromosome 2 without taking heterogeneity into account. In addition, two-point lod scores provided support of linkage in these regions (Table 3) . The highest variance component multipoint lod score for FEV1/FVC was 1.24 (331–340 cM, lod of more than 1) on chromosome 2, 1.28 (52–55 cM, lod of more than 1) for FEV1 on chromosome 8 and 1.10 (88–99 cM, lod of more than 1) for FVC on chromosome 19.




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  		Figure 1. Linkage analysis results (heterogeneity lod scores) for a genome scan for the ratio FEV1/FVC (dominant; recessive; variance components).

 

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  		TABLE 3. Two-point lod scores for the regions suggesting linkage in the analysis of the ratio fev1/fvc

 
We corrected the results for multiple testing as three separate genome scans were performed for the linkage analysis of the ratio FEV1/FVC. To account for the number of tests performed, we used a previously described method of correction (30). This method uses principles similar to those applied by Lander and Kruglyak (31), with the addition of an estimate of the number of "independent" genome scans performed for a trait. For our study, we estimated the number of scans to be 2.39, which gave a lod threshold of 2.29 for suggestive linkage. This threshold is conservative based on simulation studies (30). Therefore, both the heterogeneity lod scores of 2.36 on chromosome 2 and 2.23 on chromosome 5 provide suggestive evidence of linkage.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Our study identified two previously reported regions of linkage in the analysis of FEV1/FVC. A parametric heterogeneity lod score of 2.36, with a 1-lod drop ranging from 216–251 cM, was observed on chromosome 2 with two-point (lod = 1.55) and variance component (lod = 1.12) linkage support. This region was also observed in a study performed by Silverman and colleagues, analyzing data from patients with early-onset COPD. This group observed a significant lod score of 4.12 on chromosome 2 (222 cM) for the FEV1/FVC ratio (32).

In addition to chromosome 2, a heterogeneity lod score of 2.23, with a 1-lod drop ranging from 290–304 cM, was observed on chromosome 5 in the analysis of the Utah CEPH pedigrees. Three markers gave two-point lod scores above 1 in this region and four markers had lod scores above 1 using variance components linkage, with a maximum two-point score of 2.64 at D5S422. Ober and colleagues studied an isolated population and identified a region on chromosome 5, overlapping the region identified in our study with a lod score of 1.55 at D5S820, which might play a role in the inheritance of the FEV1/FVC (33). These replications provide further evidence for susceptibility loci in these regions.

A number of other linkage analyses have been performed for the identification of loci underlying the inheritance of FEV1, FVC, and FEV1/FVC. A Framingham study of these traits showed several regions suggesting linkage (chromosomes 4 and 6 for FEV1, chromosome 21 for FVC, and chromosome 6 for the ratio) (34). Similarly, a genome scan of data from patients with asthma suggested several regions of linkage with chromosomes 10 and 22 for FEV1 and chromosome 16 for FVC (35).

From the segregation analysis of the Utah CEPH pedigrees, we were unable to infer a major locus for either FEV1 or FVC, but a Mendelian major gene inheritance pattern was observed for the ratio FEV1/FVC. In contrast, the National Heart, Lung, and Blood Institute Family Heart Study found evidence for a genetic model underlying the inheritance of FEV1, but not FEV1/FVC or FVC (36). A segregation analysis of the Framingham study concluded that a polygenic or environmental model was most likely to explain FEV1 inheritance (10). Rybicki and colleagues (12) inferred major locus inheritance of FEV1 in families ascertained for COPD, although not in non-COPD families. The differences in the conclusions of these studies could be attributed to the heterogeneity present in the different populations for some of the phenotypes analyzed in each study. For example, the National Heart, Lung, and Blood Institute Family Heart Study involved collection of data for subjects from four geographical regions. The lack of evidence of Mendelian inheritance could be due to higher heterogeneity present in their study population.

In summary, the segregation analysis and linkage analysis of the ratio FEV1/FVC suggest a role of genetic factors in the inheritance of this trait. As observed, neither the dominant nor the recessive models could be rejected in the segregation analysis. The parametric linkage analysis supports this with suggestive linkage at two regions, one under a dominant model (chromosome 2) and the second under a recessive model (chromosome 5). Despite the fact that the inability to reject either the dominant or recessive model weakens the evidence of major locus inheritance, the consistency between the parametric and variance components methods for the linkage analysis of the FEV1/FVC ratio suggests the presence of a susceptibility gene(s) involved in lung function in the regions identified on chromosomes 2 and 5. Multiple testing corrections for the linkage analysis still provided evidence for linkage at these loci (30). In addition, these results replicate previous linkage findings in these regions (32, 33).

The next step in this study would be to identify candidate genes in the regions on chromosomes 2 and 5 localized in the analysis of the Utah CEPH pedigrees. Although a few genetic factors are associated with COPD (37) and asthma (38), the genetics of these conditions are still not understood to a significant degree. Because FEV1/FVC is reduced in patients with COPD, analysis of the candidate genes on chromosomes 2 and 5 will allow further elucidation into the etiology of pulmonary diseases such as COPD.


   Acknowledgments
 
The authors extend sincere thanks to all family members who participated in the Utah Genetics Reference Project. They also thank Melissa M. Dixon, Utah Genetic Reference Project Study Coordinator; Lisa Baird, who genotyped the markers used in the initial stages of the map construction; and Hilary Coon, for her comments on an initial draft of the article.


   FOOTNOTES
 
Supported by National Center for Research grant M01-RR00064, National Institutes of Health grant HL67496, and gifts from the W. M. Keck Foundation and the George Delores Doré Eccles Foundation.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: A.M. has no declared conflict of interest; A.P.P. has no declared conflict of interest; D.T.R. has no declared conflict of interest; T.E. has no declared conflict of interest; R.E.K. has no declared conflict of interest; M.F.L. has no declared conflict of interest; S.J.H. has no declared conflict of interest.

Received in original form March 21, 2003; accepted in final form June 4, 2003


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{alpha}1-Antitrypsin deficiency {middle dot} 2: Genetic aspects of {alpha}1-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk
Thorax, March 1, 2004; 59(3): 259 - 264.
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M. J. Tobin
Sleep-Disordered Breathing, Control of Breathing, Respiratory Muscles, Pulmonary Function Testing in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 254 - 264.
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