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1.  Self-reported exercise and longitudinal outcomes in cystic fibrosis: a retrospective cohort study 
BMC Pulmonary Medicine  2014;14(1):159.
Background
Cystic fibrosis (CF) is characterized by recurrent respiratory infections and progressive lung disease. Whereas exercise may contribute to preserving lung function, its benefit is difficult to ascertain given the selection bias of healthier patients being more predisposed to exercise. Our objective was to examine the role of self-reported exercise with longitudinal lung function and body mass index (BMI) measures in CF.
Methods
A total of 1038 subjects with CF were recruited through the U.S. CF Twin-Sibling Study. Questionnaires were used to determine exercise habits. Questionnaires, chart review, and U.S. CF Foundation Patient Registry data were used to track outcomes.
Results
Within the study sample 75% of subjects self-reported regular exercise. Exercise was associated with an older age of diagnosis (p = 0.002), older age at the time of ascertainment (p < 0.001), and higher baseline FEV1 (p = 0.001), but not CFTR genotype (p = 0.64) or exocrine pancreatic function (p = 0.19). In adjusted mixed models, exercise was associated with both a reduced decline in FEV1 (p < 0.001) and BMI Z-score (p = 0.001) for adults, but not children aged 10–17 years old.
Conclusions
In our retrospective study, self-reported exercise was associated with improved longitudinal nutritional and pulmonary outcomes in cystic fibrosis for adults. Although prospective studies are needed to confirm these associations, programs to promote regular exercise among individuals with cystic fibrosis would be beneficial.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-159) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2466-14-159
PMCID: PMC4195986  PMID: 25287419
Cystic fibrosis; Lung function; FEV1; Body mass index; Exercise
2.  Genetic Modifiers of Cystic Fibrosis–Related Diabetes 
Diabetes  2013;62(10):3627-3635.
Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5′ to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10−8). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 × 10−10. SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 × 10−6), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population.
doi:10.2337/db13-0510
PMCID: PMC3781476  PMID: 23670970
3.  Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis 
The Journal of pediatrics  2012;161(2):290-5.e1.
Objective
To quantify the relative contribution of factors other than cystic fibrosis transmembrane conductance regulator genotype and environment on the acquisition of Pseudomonas aeruginosa (Pa) by patients with cystic fibrosis.
Study design
Lung infection with Pa and mucoid Pa was assessed using a co-twin study design of 44 monozygous (MZ) and 17 dizygous (DZ) twin pairs. Two definitions were used to establish infection: first positive culture and persistent positive culture. Genetic contribution to infection (ie, heritability) was estimated based on concordance analysis, logistic regression, and age at onset of infection through comparison of intraclass correlation coefficients.
Results
Concordance for persistent Pa infection was higher in MZ (0.83; 25 of 30 pairs) than DZ twins (0.45; 5 of 11 pairs), generating a heritability of 0.76. Logistic regression adjusted for age corroborated genetic control of persistent Pa infection. The correlation for age at persistent Pa infection was higher in MZ twins (0.589; 95% CI, 0.222-0.704) than in DZ twins (0.162; 95% CI, −0.352 to 0.607), generating a heritability of 0.85.
Conclusion
Genetic modifiers play a significant role in the establishment and timing of persistent Pa infection in individuals with cystic fibrosis.
doi:10.1016/j.jpeds.2012.01.042
PMCID: PMC3682831  PMID: 22364820
4.  A Novel Lung Disease Phenotype Adjusted for Mortality Attrition for Cystic Fibrosis Genetic Modifier Studies 
Pediatric pulmonology  2011;46(9):857-869.
SUMMARY
Genetic studies of lung disease in Cystic Fibrosis are hampered by the lack of a severity measure that accounts for chronic disease progression and mortality attrition. Further, combining analyses across studies requires common phenotypes that are robust to study design and patient ascertainment.
Using data from the North American Cystic Fibrosis Modifier Consortium (Canadian Consortium for CF Genetic Studies, Johns Hopkins University CF Twin and Sibling Study, and University of North Carolina/Case Western Reserve University Gene Modifier Study), the authors calculated age-specific CF percentile values of FEV1 which were adjusted for CF age-specific mortality data.
The phenotype was computed for 2061 patients representing the Canadian CF population, 1137 extreme phenotype patients in the UNC/Case Western study, and 1323 patients from multiple CF sib families in the CF Twin and Sibling Study. Despite differences in ascertainment and median age, our phenotype score was distributed in all three samples in a manner consistent with ascertainment differences, reflecting the lung disease severity of each individual in the underlying population. The new phenotype score was highly correlated with the previously recommended complex phenotype, but the new phenotype is more robust for shorter follow-up and for extreme ages.
A disease progression and mortality adjusted phenotype reduces the need for stratification or additional covariates, increasing statistical power and avoiding possible distortions. This approach will facilitate large scale genetic and environmental epidemiological studies which will provide targeted therapeutic pathways for the clinical benefit of patients with CF.
doi:10.1002/ppul.21456
PMCID: PMC3130075  PMID: 21462361
Forced Expiratory Volume; Age Effects; Severity of Illness Index
5.  Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis 
Nature Genetics  2012;44(5):562-569.
Variants associated with meconium ileus in cystic fibrosis (CF) were identified in 3,763 patients by GWAS. Five SNPs at two loci near SLC6A14 (min P=1.28×10−12 at rs3788766), chr Xq23-24 and SLC26A9 (min P=9.88×10−9 at rs4077468), chr 1q32.1 accounted for ~5% of the phenotypic variability, and were replicated in an independent patient collection (n=2,372; P=0.001 and 0.0001 respectively). By incorporating that disease-causing mutations in CFTR alter electrolyte and fluid flux across epithelia into an hypothesis-driven genome-wide analysis (GWAS-HD), we identified the same SLC6A14 and SLC26A9 associated SNPs, while establishing evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple constituents of the apical plasma membrane where CFTR resides (P=0.0002, testing 155 apical genes jointly and replicated, P=0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis.
doi:10.1038/ng.2221
PMCID: PMC3371103  PMID: 22466613
6.  Variation in MSRA Modifies Risk of Neonatal Intestinal Obstruction in Cystic Fibrosis 
PLoS Genetics  2012;8(3):e1002580.
Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal protein content, occurs in approximately 15 percent of neonates with cystic fibrosis (CF). Analysis of twins with CF demonstrates that MI is a highly heritable trait, indicating that genetic modifiers are largely responsible for this complication. Here, we performed regional family-based association analysis of a locus that had previously been linked to MI and found that SNP haplotypes 5′ to and within the MSRA gene were associated with MI (P = 1.99×10−5 to 1.08×10−6; Bonferroni P = 0.057 to 3.1×10−3). The haplotype with the lowest P value showed association with MI in an independent sample of 1,335 unrelated CF patients (OR = 0.72, 95% CI [0.53–0.98], P = 0.04). Intestinal obstruction at the time of weaning was decreased in CF mice with Msra null alleles compared to those with wild-type Msra resulting in significant improvement in survival (P = 1.2×10−4). Similar levels of goblet cell hyperplasia were observed in the ilea of the Cftr−/− and Cftr−/−Msra−/− mice. Modulation of MSRA, an antioxidant shown to preserve the activity of enzymes, may influence proteolysis in the developing intestine of the CF fetus, thereby altering the incidence of obstruction in the newborn period. Identification of MSRA as a modifier of MI provides new insight into the biologic mechanism of neonatal intestinal obstruction caused by loss of CFTR function.
Author Summary
Cystic fibrosis (CF) is a monogenic disease with considerable phenotypic variability. About 15% of newborns with CF suffer from an intestinal obstruction called meconium ileus (MI), and studies in CF twins have shown that modifier genes play a substantial role in the development of this complication. We used a family-based study design to enrich for genetic modifiers of MI and found that variations in the MSRA gene, represented by combinations of SNPs, or haplotypes, were protective against this manifestation of CF. We investigated association between one of the MSRA haplotypes and MI in an independent sample of CF patients and showed that it had a similar protective effect. Furthermore, CF mice lacking Msra expression had lower mortality due to intestinal obstruction at the time of transitioning to solid food and lived longer than CF mice with normal Msra, thus supporting the protective effect of the haplotype we observed in human CF subjects. The identification of modifiers of MI such as MSRA offers new insight into the mechanism of this life-threatening complication of CF.
doi:10.1371/journal.pgen.1002580
PMCID: PMC3305406  PMID: 22438829
7.  Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2 
Nature Genetics  2011;43(6):539-546.
A combined genome-wide association and linkage study was used to identify loci causing variation in CF lung disease severity. A significant association (P=3. 34 × 10-8) near EHF and APIP (chr11p13) was identified in F508del homozygotes (n=1,978). The association replicated in F508del homozygotes (P=0.006) from a separate family-based study (n=557), with P=1.49 × 10-9 for the three-study joint meta-analysis. Linkage analysis of 486 sibling pairs from the family-based study identified a significant QTL on chromosome 20q13.2 (LOD=5.03). Our findings provide insight into the causes of variation in lung disease severity in CF and suggest new therapeutic targets for this life-limiting disorder.
doi:10.1038/ng.838
PMCID: PMC3296486  PMID: 21602797
8.  Understanding the Population Structure of North American Patients with Cystic Fibrosis 
Clinical genetics  2011;79(2):136-146.
Rationale
It is generally presumed that the Cystic Fibrosis (CF) population is relatively homogeneous, and predominantly of European origin. The complex ethnic make-up observed in the CF patients collected by the North American CF Modifier Gene Consortium has brought this assumption into question, and suggested the potential for population substructure in the three CF study samples collected from North America. It is well appreciated that population substructure can result in spurious genetic associations.
Objectives
To understand the ethnic composition of the North American CF population, and to assess the need for population structure adjustment in genetic association studies with North American CF patients.
Methods
Genome-wide single-nucleotide polymorphisms on 3076 unrelated North American CF patients were used to perform population structure analyses. We compared self-reported ethnicity to genotype-inferred ancestry, and also examined whether geographic distribution and CFTR mutation type could explain the structure observed.
Main Results
Although largely Caucasian, our analyses identified a considerable number of CF patients with admixed African-Caucasian, Mexican-Caucasian and Indian-Caucasian ancestries. Population substructure was present and comparable across the three studies of the consortium. Neither geographic distribution nor mutation type explained the population structure.
Conclusion
Given the ethnic diversity of the North American CF population, it is essential to carefully detect, estimate and adjust for population substructure to guard against potential spurious findings in CF genetic association studies. Other Mendelian diseases that are presumed to predominantly affect single ethnic groups may also benefit from careful analysis of population structure.
doi:10.1111/j.1399-0004.2010.01502.x
PMCID: PMC2995003  PMID: 20681990
ethnicity; principal component analysis; population substructure; population stratification
9.  Quantification of the Relative Contribution of Environmental and Genetic Factors to Variation in Cystic Fibrosis Lung Function 
The Journal of pediatrics  2010;157(5):802-807.e3.
Objective
To assess the relative contributions of environmental and genetic factors to variation in cystic fibrosis (CF) pulmonary disease.
Study design
Genetic and environmental contributions were quantified using intra-pair correlations and differences in CF-specific FEV1 measures from 134 monozygous twins and 272 dizygous twins and siblings while in different living environments (i.e. living with parents vs. living alone) as well as using intra-individual differences in lung function from a separate group of 80 siblings.
Results
Lung function among monozygous twins was more similar than among dizygous twin and sibling pairs, regardless of living environment, affirming the role of genetic modifiers in CF lung function. Regression modeling revealed that genetic factors account for 50% of lung function variation, unique environmental and stochastic factors 36%, and shared environmental factors, 14% (Model p: <0.0001). The intra-individual analysis produced similar estimates for the contributions of the unique and shared environment. The shared environment effects appeared primarily due to living with a sibling with CF (p: 0.003), rather than factors within the parental household (p: 0.310).
Conclusions
Genetic and environmental factors contribute equally to lung function variation in CF. Environmental effects are dominated by unique and stochastic effects rather than common exposures.
doi:10.1016/j.jpeds.2010.05.018
PMCID: PMC2948620  PMID: 20580019
cystic fibrosis; heritability, lung disease, genetics; FEV1
10.  Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease 
Context
Disease variation can be substantial even in conditions with a single gene etiology such as cystic fibrosis (CF). Simultaneously studying the effects of genes and environment may provide insight into the causes of variation.
Objective
To determine whether secondhand smoke exposure is associated with lung function and other outcomes in individuals with CF, whether socioeconomic status affects the relationship between secondhand smoke exposure and lung disease severity, and whether specific gene-environment interactions influence the effect of secondhand smoke exposure on lung function.
Design, Setting, and Participants
Retrospective assessment of lung function, stratified by environmental and genetic factors. Data were collected by the US Cystic Fibrosis Twin and Sibling Study with missing data supplemented by the Cystic Fibrosis Foundation Data Registry. All participants were diagnosed with CF, were recruited between October 2000 and October 2006, and were primarily from the United States.
Main Outcome Measures
Disease-specific cross-sectional and longitudinal measures of lung function.
Results
Of 812 participants with data on secondhand smoke in the home, 188 (23.2%) were exposed. Of 780 participants with data on active maternal smoking during gestation, 129 (16.5%) were exposed. Secondhand smoke exposure in the home was associated with significantly lower cross-sectional (9.8 percentile point decrease; P<.001) and longitudinal lung function (6.1 percentile point decrease; P=.007) compared with those not exposed. Regression analysis demonstrated that socioeconomic status did not confound the adverse effect of secondhand smoke exposure on lung function. Interaction between gene variants and secondhand smoke exposure resulted in significant percentile point decreases in lung function, namely in CFTR non-ΔF508 homozygotes (12.8 percentile point decrease; P=.001), TGFβ1-509 TT homozygotes (22.7 percentile point decrease; P=.006), and TGFβ1 codon 10 CC homozygotes (20.3 percentile point decrease; P=.005).
Conclusions
Any exposure to secondhand smoke adversely affects both cross-sectional and longitudinal measures of lung function in individuals with CF. Variations in the gene that causes CF (CFTR) and a CF-modifier gene (TGFβ1) amplify the negative effects of secondhand smoke exposure.
doi:10.1001/jama.299.4.417
PMCID: PMC3139475  PMID: 18230779
11.  Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis 
Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.
doi:10.1038/ejhg.2009.226
PMCID: PMC2874654  PMID: 20068595
infection; confounding; immunity
12.  Modifier gene study of meconium ileus in cystic fibrosis: statistical considerations and gene mapping results 
Human genetics  2009;126(6):763-778.
Cystic fibrosis (CF) is a monogenic disease due to mutations in the CFTR gene. Yet, variability in CF disease presentation is presumed to be affected by modifier genes, such as those recently demonstrated for the pulmonary aspect. Here, we conduct a modifier gene study for meconium ileus (MI), an intestinal obstruction that occurs in 16–20% of CF newborns, providing linkage and association results from large family and case–control samples. Linkage analysis of modifier traits is different than linkage analysis of primary traits on which a sample was ascertained. Here, we articulate a source of confounding unique to modifier gene studies and provide an example of how one might overcome the confounding in the context of linkage studies. Our linkage analysis provided evidence of a MI locus on chromosome 12p13.3, which was segregating in up to 80% of MI families with at least one affected offspring (HLOD = 2.9). Fine mapping of the 12p13.3 region in a large case–control sample of pancreatic insufficient Canadian CF patients with and without MI pointed to the involvement of ADIPOR2 in MI (p = 0.002). This marker was substantially out of Hardy–Weinberg equilibrium in the cases only, and provided evidence of a cohort effect. The association with rs9300298 in the ADIPOR2 gene at the 12p13.3 locus was replicated in an independent sample of CF families. A protective locus, using the phenotype of no-MI, mapped to 4q13.3 (HLOD = 3.19), with substantial heterogeneity. A candidate gene in the region, SLC4A4, provided preliminary evidence of association (p = 0.002), warranting further follow-up studies. Our linkage approach was used to direct our fine-mapping studies, which uncovered two potential modifier genes worthy of follow-up.
doi:10.1007/s00439-009-0724-8
PMCID: PMC2888886  PMID: 19662435
13.  Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis 
Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspects (eg, lung function, infection, survival) of cystic fibrosis (CF) in some studies but not others. Inconsistent results may be due to confounding among disease variables that were not fully accounted for in each study. To account for these relationships, we derived a modeling framework incorporating CFTR genotype, age, Pseudomonas aeruginosa (Pa) infection, and lung function from 788 patients in the US CF Twin and Sibling Study. This framework was then used to identify confounding variables when testing the effect of MBL2 variation on specific CF traits. MBL2 genotypes corresponding to low levels of MBL associated with Pa infection 1.94 years earlier than did MBL2 genotypes corresponding to high levels of MBL (P=0.0034). In addition, Pa-infected patients with MBL2 genotypes corresponding to low levels of MBL underwent conversion to mucoid Pa 2.72 years earlier than did patients with genotypes corresponding to high levels of MBL (P=0.0003). MBL2 was not associated with the time to transition from infection to conversion or with lung function. Thus, use of a modeling framework that identified confounding among disease variables revealed that variation in MBL2 associates with age at infection with Pa and age at conversion to mucoid Pa in CF.
doi:10.1038/ejhg.2009.226
PMCID: PMC2874654  PMID: 20068595
infection; confounding; immunity
14.  Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients 
Respiratory Research  2010;11(1):140.
Background
Lung infection by various organisms is a characteristic feature of cystic fibrosis (CF). CFTR genotype effects acquisition of Pseudomonas aeruginosa (Pa), however the effect on acquisition of other infectious organisms that frequently precede Pa is relatively unknown. Understanding the role of CFTR in the acquisition of organisms first detected in patients may help guide symptomatic and molecular-based treatment for CF.
Methods
Lung infection, defined as a single positive respiratory tract culture, was assessed for 13 organisms in 1,381 individuals with CF. Subjects were divided by predicted CFTR function: 'Residual': carrying at least one partial function CFTR mutation (class IV or V) and 'Minimal' those who do not carry a partial function mutation. Kaplan-Meier estimates were created to assess CFTR effect on age of acquisition for each organism. Cox proportional hazard models were performed to control for possible cofactors. A separate Cox regression was used to determine whether defining infection with Pa, mucoid Pa or Aspergillus (Asp) using alternative criteria affected the results. The influence of severity of lung disease at the time of acquisition was evaluated using stratified Cox regression methods by lung disease categories.
Results
Subjects with 'Minimal' CFTR function had a higher hazard than patients with 'Residual' function for acquisition of 9 of 13 organisms studied (HR ranging from 1.7 to 3.78 based on the organism studied). Subjects with minimal CFTR function acquired infection at a younger age than those with residual function for 12 of 13 organisms (p-values ranging: < 0.001 to 0.017). Minimal CFTR function also associated with younger age of infection when 3 alternative definitions of infection with Pa, mucoid Pa or Asp were employed. Risk of infection is correlated with CFTR function for 8 of 9 organisms in patients with good lung function (>90%ile) but only 1 of 9 organisms in those with poorer lung function (<50%ile).
Conclusions
Residual CFTR function correlates with later onset of respiratory tract infection by a wide spectrum of organisms frequently cultured from CF patients. The protective effect conferred by residual CFTR function is diminished in CF patients with more advanced lung disease.
doi:10.1186/1465-9921-11-140
PMCID: PMC2964615  PMID: 20932301
15.  Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis 
Human Molecular Genetics  2008;17(14):2228-2237.
Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutations in the CFTR gene. Twin and sibling analysis indicates that modifier genes, rather than allelic variation in CFTR, are responsible for most of the variability in severity of lung disease, the major cause of mortality in CF patients. We used a family-based approach to test for association between lung function and two functional SNPs (rs1800469, ‘−509’ and rs1982073, ‘codon 10’) in the 5′ region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patient–parent–parent trios revealed that both TGFB1 SNPs showed significant transmission distortion when patients were stratified by CFTR genotype. Although lung function and nutritional status are correlated in CF patients, there was no evidence of association between the TGFB1 SNPs and variation in nutritional status. Additional tagging SNPs (rs8179181, rs2278422, rs8110090, rs4803455 and rs1982072) that capture most of the diversity in TGFB1 were also typed but none showed association with variation in lung function. However, a haplotype composed of the −509 C and codon 10 T alleles along with the C allele of the 3′ SNP rs8179181 was highly associated with increased lung function in patients grouped by CFTR genotype. These results demonstrate that TGFB1 is a modifier of CF lung disease and reveal a previously unrecognized beneficial effect of TGFB1 variants upon the pulmonary phenotype.
doi:10.1093/hmg/ddn123
PMCID: PMC2902288  PMID: 18424453
16.  Heritability of Lung Disease Severity in Cystic Fibrosis 
Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the disease-causing gene, indicating that other factors determine severity of lung disease.
Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity.
Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV1 within the last year was used for cross-sectional analysis. FEV1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins (∼ 100% gene sharing) with that of dizygous (DZ) twins/siblings (∼ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects.
Measurements and Main Results: Forty-seven MZ twin pairs, 10 DZ twin pairs, and 231 sibling pairs (of a total of 526 patients) with CF were studied. Correlations for all measures of lung function for MZ twins (0.82–0.91, p < 0.0001) were higher than for DZ twins and siblings (0.50–0.64, p < 0.001). Heritability estimates from both methods were consistent for each measure of lung function and ranged from 0.54 to 1.0. Heritability estimates generally increased after adjustment for differences in nutritional status (measured as body mass index z-score).
Conclusions: Our heritability estimates indicate substantial genetic control of variation in CF lung disease severity, independent of CFTR genotype.
doi:10.1164/rccm.200608-1164OC
PMCID: PMC1899267  PMID: 17332481
genetics; pulmonary function
17.  Relative Contribution of Genetic and Non-genetic Modifiers to Intestinal Obstruction in Cystic Fibrosis 
Gastroenterology  2006;131(4):1030-1039.
Background & Aims
Neonatal intestinal obstruction (meconium ileus or MI) occurs in 15% of patients with cystic fibrosis (CF). Our aim was to determine the relative contribution of genetic and non-genetic modifiers to the development of this major complication of CF.
Methods
Using clinical data and DNA collected by the CF Twin and Sibling Study, 65 monozygous twin pairs, 23 dizygous twin/triplet sets, and 349 sets of siblings with CF were analyzed for MI status, significant covariates, and genome-wide linkage.
Results
Specific mutations in CFTR, the gene responsible for CF, correlated with MI indicating a role for CFTR genotype. Monozygous twins showed substantially greater concordance for MI than dizygous twins and siblings (p=1×10−5) demonstrating that modifier genes independent of CFTR contribute substantially to this trait. Regression analysis revealed that MI was correlated with distal intestinal obstruction syndrome (DIOS; p=8×10−4). Unlike MI, concordance analysis indicated that the risk for development of DIOS in CF patients is primarily due to non-genetic factors. Regions of suggestive linkage (logarithm of the odds of linkage >2.0) for modifier genes that cause MI (chromosomes 4q35.1, 8p23.1, and 11q25) or protect from MI (chromosomes 20p11.22 and 21q22.3) were identified by genome-wide analyses. These analyses did not support the existence of a major modifier gene within the CFM1 region on chromosome 19 that had previously been linked to MI.
Conclusions
The CFTR gene along with two or more modifier genes are the major determinants of intestinal obstruction in newborn CF patients, while intestinal obstruction in older CF patients is primarily due to non-genetic factors.
doi:10.1053/j.gastro.2006.07.016
PMCID: PMC1764617  PMID: 17030173
Twins; siblings; linkage; association; intestinal obstruction; CFM-1

Results 1-17 (17)