Kathleen Naughton - Academia.edu (original) (raw)

Papers by Kathleen Naughton

Research paper thumbnail of A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

Diabetologia, Jul 8, 2009

Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (C... more Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

Research paper thumbnail of Patients with Mutations in Gsα Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G pro... more Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues.

Research paper thumbnail of Patients with Mutations in Gs Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G pro... more Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. Objective: The objective of the study was to gain insight into the downstream consequences

Research paper thumbnail of Combined daily therapy with intravenous ganciclovir and foscarnet for patients with recurrent cytomegalovirus retinitis

American journal of ophthalmology, Jan 15, 1994

We treated seven patients (nine eyes) who had cytomegalovirus retinitis with daily intravenous ga... more We treated seven patients (nine eyes) who had cytomegalovirus retinitis with daily intravenous ganciclovir plus foscarnet. All patients had demonstrated multiple progressions of retinitis on single-drug therapy, and some were intolerant to induction doses of one or both medications. Before combination therapy, the median number of progressions was five per patient. The mean interval between progressions was 11 weeks, and the mean interval before the final progression was four weeks. While taking combination therapy, two patients showed progression after 14 and 34 weeks. Two patients showed no progression after 17 and 36 weeks of follow-up. Three patients died after five, 14, and 23 weeks, respectively, without progression of retinitis. In every patient, the progression-free interval was longer during combination therapy than the previous progression-free interval during single-drug therapy. In no case was combination therapy stopped because of toxicity. Combination therapy was fairl...

Research paper thumbnail of Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis

PLoS genetics, 2012

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal prot... more 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...

Research paper thumbnail of Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients

Respiratory Research, 2010

Background: Lung infection by various organisms is a characteristic feature of cystic fibrosis (C... more 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.

Research paper thumbnail of A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis Genetic modifier studies

Pediatric Pulmonology, 2011

Research paper thumbnail of Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Research paper thumbnail of Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

Nature Genetics, 2011

A combined genome-wide association and linkage study was used to identify loci causing variation ... more A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10 −8 ) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del 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 quantitative trait locus on chromosome 20q13.2 (log 10 odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.

Research paper thumbnail of Quantification of the Relative Contribution of Environmental and Genetic Factors to Variation in Cystic Fibrosis Lung Function

The Journal of Pediatrics, 2010

Research paper thumbnail of Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis

The Journal of Pediatrics, 2012

OBJECTIVE: To quantify the relative contribution of factors other than cystic fibrosis transmembr... more 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.

Research paper thumbnail of Genetic Modifiers Play a Substantial Role in Diabetes Complicating Cystic Fibrosis

The Journal of Clinical Endocrinology & Metabolism, 2009

Insulin-requiring diabetes affects 7-15% of teens and young adults, and more than 25% of older ad... more Insulin-requiring diabetes affects 7-15% of teens and young adults, and more than 25% of older adults with cystic fibrosis (CF). Pancreatic exocrine disease caused by CF transmembrane conductance regulator (CFTR) dysfunction underlies the high rate of diabetes in CF patients; however, only a subset develops this complication, indicating that other factors are necessary. Our objective was to estimate the relative contribution of genetic and nongenetic modifiers to the development of diabetes in CF. This was a twin and sibling study involving 1366 individuals at 109 centers in the CF Twin and Sibling Study, from which were derived 68 monozygous twin pairs, 23 dizygous twin pairs, and 588 sibling pairs, all with CF. Chronic, insulin-requiring diabetes in the setting of CF, as established using longitudinal clinical and biochemical data, was studied. About 9% of this predominantly pediatric population (mean age = 15.8 yr) had diabetes. Key independent risk factors identified by regression modeling included having a twin or sibling with CF and diabetes, increasing age, pancreatic exocrine insufficiency or two mutations causing severe CFTR dysfunction, decreased lung function or decreased body mass index, and longer duration of glucocorticoid treatment. The concordance rate for diabetes was substantially higher in monozygous twins (0.73) than in dizygous twins and siblings with CF (0.18; P = 0.002). Heritability was estimated as near one (95% confidence interval 0.42-1.0). Diabetes is a frequent complication of CF that is associated with worse outcomes. Although a nongenetic factor (steroid treatment) contributes to risk, genetic modifiers (i.e. genes other than CFTR) are the primary cause of diabetes in CF.

Research paper thumbnail of Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease

JAMA, 2008

Context Disease variation can be substantial even in conditions with a single gene etiology such ... more 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.

Research paper thumbnail of Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis

Human Molecular Genetics, 2008

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutati... more 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, '2509' and rs1982073, 'codon 10') in the 5 0 region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patientparent -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 2509 C and codon 10 T alleles along with the C allele of the 3 0 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.

Research paper thumbnail of Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency

The Journal of clinical endocrinology and metabolism, 2007

Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein sign... more Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues.

Research paper thumbnail of Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

Gastroenterology, 2006

Background & Aims-Neonatal intestinal obstruction (meconium ileus or MI) occurs in 15% of patient... more 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.

Research paper thumbnail of Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis

European Journal of Human Genetics, 2010

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspe... more 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 (P¼0.0034). 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 (P¼0.0003). 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.

Research paper thumbnail of A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

Diabetologia, 2009

Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (C... more Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

Research paper thumbnail of Cerebral Circulatory and Metabolic Responses to Intravenously Administered Lorazepam

Anesthesiology, 1980

Cerebral vascular and metabolic effects of lorazepam were evaluated in ten awake monkeys by use o... more Cerebral vascular and metabolic effects of lorazepam were evaluated in ten awake monkeys by use of a modification of the Kety-Schmidt technique. Five received ketamine, 10 mg/kg, im, five to eight hours prior to the study, but all animals were otherwise treated identically. Monkeys receiving ketamine had significantly greater (P < 0.05) cerebral blood flow (CBF) values before lorazepam was given (46 +/- 1 ml/100 g/min) than did monkeys not receiving ketamine (41 +/- 1 ml/100 g/min), but in all other respects, premedicated and unpremedicated animals did not differ. Lorazepam administration did not significantly alter systemic arterial blood pressure or blood-gas values. However, it did decrease CBF by 26 per cent and increase cerebral vascular resistance (CVR) by approximately 25 per cent (P < 0.01). The cerebral metabolic rate for glucose (CMRg) decreased 42 per cent (P < 0.05). Following lorazepam administration, the cerebral metabolic rate for oxygen (CMRO2) decreased by 21-30 per cent. When combined CMRO2 data for the two anesthetic groups are pooled, this decrease is significant (P < 0.05). This study indicates that sedative doses of lorazepam decrease cerebral blood flow and metabolism with minimal effects on blood pressure and blood-gas values. Lorazepam administration did not produce any change in cerebral metabolism indicative of brain hypoxia or ischemia.

Research paper thumbnail of Heritability of Lung Disease Severity in Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, 2007

Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correla... more Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing 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 FEV 1 within the last year was used for cross-sectional analysis. FEV 1 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 ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects.

Research paper thumbnail of A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

Diabetologia, Jul 8, 2009

Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (C... more Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

Research paper thumbnail of Patients with Mutations in Gsα Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

The Journal of Clinical Endocrinology Metabolism, Jul 2, 2013

Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G pro... more Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues.

Research paper thumbnail of Patients with Mutations in Gs Have Reduced Activation of a Downstream Target in Epithelial Tissues due to Haploinsufficiency

Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G pro... more Context: Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues. Objective: The objective of the study was to gain insight into the downstream consequences

Research paper thumbnail of Combined daily therapy with intravenous ganciclovir and foscarnet for patients with recurrent cytomegalovirus retinitis

American journal of ophthalmology, Jan 15, 1994

We treated seven patients (nine eyes) who had cytomegalovirus retinitis with daily intravenous ga... more We treated seven patients (nine eyes) who had cytomegalovirus retinitis with daily intravenous ganciclovir plus foscarnet. All patients had demonstrated multiple progressions of retinitis on single-drug therapy, and some were intolerant to induction doses of one or both medications. Before combination therapy, the median number of progressions was five per patient. The mean interval between progressions was 11 weeks, and the mean interval before the final progression was four weeks. While taking combination therapy, two patients showed progression after 14 and 34 weeks. Two patients showed no progression after 17 and 36 weeks of follow-up. Three patients died after five, 14, and 23 weeks, respectively, without progression of retinitis. In every patient, the progression-free interval was longer during combination therapy than the previous progression-free interval during single-drug therapy. In no case was combination therapy stopped because of toxicity. Combination therapy was fairl...

Research paper thumbnail of Variation in MSRA modifies risk of neonatal intestinal obstruction in cystic fibrosis

PLoS genetics, 2012

Meconium ileus (MI), a life-threatening intestinal obstruction due to meconium with abnormal prot... more 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...

Research paper thumbnail of Mutations that permit residual CFTR function delay acquisition of multiple respiratory pathogens in CF patients

Respiratory Research, 2010

Background: Lung infection by various organisms is a characteristic feature of cystic fibrosis (C... more 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.

Research paper thumbnail of A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis Genetic modifier studies

Pediatric Pulmonology, 2011

Research paper thumbnail of Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis

Research paper thumbnail of Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2

Nature Genetics, 2011

A combined genome-wide association and linkage study was used to identify loci causing variation ... more A combined genome-wide association and linkage study was used to identify loci causing variation in cystic fibrosis lung disease severity. We identified a significant association (P = 3.34 × 10 −8 ) near EHF and APIP (chr11p13) in p.Phe508del homozygotes (n = 1,978). The association replicated in p.Phe508del 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 quantitative trait locus on chromosome 20q13.2 (log 10 odds = 5.03). Our findings provide insight into the causes of variation in lung disease severity in cystic fibrosis and suggest new therapeutic targets for this life-limiting disorder.

Research paper thumbnail of Quantification of the Relative Contribution of Environmental and Genetic Factors to Variation in Cystic Fibrosis Lung Function

The Journal of Pediatrics, 2010

Research paper thumbnail of Heritability of Respiratory Infection with Pseudomonas aeruginosa in Cystic Fibrosis

The Journal of Pediatrics, 2012

OBJECTIVE: To quantify the relative contribution of factors other than cystic fibrosis transmembr... more 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.

Research paper thumbnail of Genetic Modifiers Play a Substantial Role in Diabetes Complicating Cystic Fibrosis

The Journal of Clinical Endocrinology & Metabolism, 2009

Insulin-requiring diabetes affects 7-15% of teens and young adults, and more than 25% of older ad... more Insulin-requiring diabetes affects 7-15% of teens and young adults, and more than 25% of older adults with cystic fibrosis (CF). Pancreatic exocrine disease caused by CF transmembrane conductance regulator (CFTR) dysfunction underlies the high rate of diabetes in CF patients; however, only a subset develops this complication, indicating that other factors are necessary. Our objective was to estimate the relative contribution of genetic and nongenetic modifiers to the development of diabetes in CF. This was a twin and sibling study involving 1366 individuals at 109 centers in the CF Twin and Sibling Study, from which were derived 68 monozygous twin pairs, 23 dizygous twin pairs, and 588 sibling pairs, all with CF. Chronic, insulin-requiring diabetes in the setting of CF, as established using longitudinal clinical and biochemical data, was studied. About 9% of this predominantly pediatric population (mean age = 15.8 yr) had diabetes. Key independent risk factors identified by regression modeling included having a twin or sibling with CF and diabetes, increasing age, pancreatic exocrine insufficiency or two mutations causing severe CFTR dysfunction, decreased lung function or decreased body mass index, and longer duration of glucocorticoid treatment. The concordance rate for diabetes was substantially higher in monozygous twins (0.73) than in dizygous twins and siblings with CF (0.18; P = 0.002). Heritability was estimated as near one (95% confidence interval 0.42-1.0). Diabetes is a frequent complication of CF that is associated with worse outcomes. Although a nongenetic factor (steroid treatment) contributes to risk, genetic modifiers (i.e. genes other than CFTR) are the primary cause of diabetes in CF.

Research paper thumbnail of Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease

JAMA, 2008

Context Disease variation can be substantial even in conditions with a single gene etiology such ... more 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.

Research paper thumbnail of Interaction between a novel TGFB1 haplotype and CFTR genotype is associated with improved lung function in cystic fibrosis

Human Molecular Genetics, 2008

Cystic fibrosis (CF), the most common lethal single gene disorder in Caucasians, is due to mutati... more 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, '2509' and rs1982073, 'codon 10') in the 5 0 region of transforming growth factor-beta1 (TGFB1), a putative CF modifier gene. Quantitative transmission disequilibrium testing of 472 CF patientparent -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 2509 C and codon 10 T alleles along with the C allele of the 3 0 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.

Research paper thumbnail of Patients with mutations in Gsalpha have reduced activation of a downstream target in epithelial tissues due to haploinsufficiency

The Journal of clinical endocrinology and metabolism, 2007

Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein sign... more Patients with Albright hereditary osteodystrophy (AHO) have defects in stimulatory G protein signaling due to loss of function mutations in GNAS. The mechanism by which these mutations lead to the AHO phenotype has been difficult to establish due to the inaccessibility of the affected tissues.

Research paper thumbnail of Relative Contribution of Genetic and Nongenetic Modifiers to Intestinal Obstruction in Cystic Fibrosis

Gastroenterology, 2006

Background & Aims-Neonatal intestinal obstruction (meconium ileus or MI) occurs in 15% of patient... more 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.

Research paper thumbnail of Use of a modeling framework to evaluate the effect of a modifier gene (MBL2) on variation in cystic fibrosis

European Journal of Human Genetics, 2010

Variants in mannose-binding lectin (MBL2; protein MBL) have shown association with different aspe... more 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 (P¼0.0034). 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 (P¼0.0003). 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.

Research paper thumbnail of A susceptibility gene for type 2 diabetes confers substantial risk for diabetes complicating cystic fibrosis

Diabetologia, 2009

Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (C... more Aims/hypothesis-Insulin-requiring diabetes affects 25-50% of young adults with cystic fibrosis (CF). Although the cause of diabetes in CF is unknown, recent heritability studies in CF twins and siblings indicate that genetic modifiers play a substantial role. We sought to assess whether genes conferring risk for diabetes in the general population may play a risk modifying role in CF.

Research paper thumbnail of Cerebral Circulatory and Metabolic Responses to Intravenously Administered Lorazepam

Anesthesiology, 1980

Cerebral vascular and metabolic effects of lorazepam were evaluated in ten awake monkeys by use o... more Cerebral vascular and metabolic effects of lorazepam were evaluated in ten awake monkeys by use of a modification of the Kety-Schmidt technique. Five received ketamine, 10 mg/kg, im, five to eight hours prior to the study, but all animals were otherwise treated identically. Monkeys receiving ketamine had significantly greater (P < 0.05) cerebral blood flow (CBF) values before lorazepam was given (46 +/- 1 ml/100 g/min) than did monkeys not receiving ketamine (41 +/- 1 ml/100 g/min), but in all other respects, premedicated and unpremedicated animals did not differ. Lorazepam administration did not significantly alter systemic arterial blood pressure or blood-gas values. However, it did decrease CBF by 26 per cent and increase cerebral vascular resistance (CVR) by approximately 25 per cent (P < 0.01). The cerebral metabolic rate for glucose (CMRg) decreased 42 per cent (P < 0.05). Following lorazepam administration, the cerebral metabolic rate for oxygen (CMRO2) decreased by 21-30 per cent. When combined CMRO2 data for the two anesthetic groups are pooled, this decrease is significant (P < 0.05). This study indicates that sedative doses of lorazepam decrease cerebral blood flow and metabolism with minimal effects on blood pressure and blood-gas values. Lorazepam administration did not produce any change in cerebral metabolism indicative of brain hypoxia or ischemia.

Research paper thumbnail of Heritability of Lung Disease Severity in Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, 2007

Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correla... more Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing 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 FEV 1 within the last year was used for cross-sectional analysis. FEV 1 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 ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects.