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1.  Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene 
Nature genetics  2013;45(10):10.1038/ng.2745.
Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation to clinical practice. Few of the almost 2,000 variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 cystic fibrosis patients in registries and clinics in North America and Europe. Among these patients, 159 CFTR variants had an allele frequency of ≥0.01%. These variants were evaluated for both clinical severity and functional consequence with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of cystic fibrosis patients enabled assignment of 12 of the remaining 32 variants as neutral while the other 20 variants remained indeterminate. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically-relevant genomic variation.
doi:10.1038/ng.2745
PMCID: PMC3874936  PMID: 23974870
2.  Genetic Dissection of Photoreceptor Subtype Specification by the Drosophila melanogaster Zinc Finger Proteins Elbow and No ocelli 
PLoS Genetics  2014;10(3):e1004210.
The elbow/no ocelli (elb/noc) complex of Drosophila melanogaster encodes two paralogs of the evolutionarily conserved NET family of zinc finger proteins. These transcriptional repressors share a conserved domain structure, including a single atypical C2H2 zinc finger. In flies, Elb and Noc are important for the development of legs, eyes and tracheae. Vertebrate NET proteins play an important role in the developing nervous system, and mutations in the homolog ZNF703 human promote luminal breast cancer. However, their interaction with transcriptional regulators is incompletely understood. Here we show that loss of both Elb and Noc causes mis-specification of polarization-sensitive photoreceptors in the ‘dorsal rim area’ (DRA) of the fly retina. This phenotype is identical to the loss of the homeodomain transcription factor Homothorax (Hth)/dMeis. Development of DRA ommatidia and expression of Hth are induced by the Wingless/Wnt pathway. Our data suggest that Elb/Noc genetically interact with Hth, and we identify two conserved domains crucial for this function. Furthermore, we show that Elb/Noc specifically interact with the transcription factor Orthodenticle (Otd)/Otx, a crucial regulator of rhodopsin gene transcription. Interestingly, different Elb/Noc domains are required to antagonize Otd functions in transcriptional activation, versus transcriptional repression. We propose that similar interactions between vertebrate NET proteins and Meis and Otx factors might play a role in development and disease.
Author Summary
The eyes of many animals contain groups of photoreceptor cells with different chromatic sensitivities that can be arranged in complex patterns. It is of great interest to identify the genes and pathways shaping these ‘retinal mosaics’ which include stochastically distributed groups of cells, versus highly localized ones. In many insect eyes, which are composed of large numbers of unit eyes, or ommatidia, specialized photoreceptors are found only in the dorsal periphery, where they face the sky. These ommatidia are responsible for detecting linearly polarized skylight, which serves as an important navigational cue for these animals. Here we describe how two closely related proteins called Elbow and No ocelli interact with the transcription factors Homothorax and Orthodenticle to correctly specify the polarization detectors at the dorsal rim of the retina of Drosophila melanogaster. Interestingly, all four proteins are evolutionarily conserved from worms to humans, and they appear to be involved in similar developmental processes across species. Furthermore, human homologs of Elbow and No ocelli have been identified as promoters of luminal breast cancer. The newly identified role of these two proteins within a regulatory network might therefore enable new approaches in a number of important processes.
doi:10.1371/journal.pgen.1004210
PMCID: PMC3953069  PMID: 24625735
3.  Application of personalized medicine to chronic disease: a feasibility assessment 
Personalized Medicine has the potential to improve health outcomes and reduce the cost of care; however its adoption has been slow in Canada. Bridgepoint Health is a complex continuous care provider striving to reduce the burden of polypharmacy in chronic patients. The main goal of the study was to explore the feasibility of utilizing personalized medicine in the treatment of chronic complex patients as a preliminary institutional health technology assessment. We analyzed stroke treatment optimization as a clinical indication that could serve as a “proof of concept” for the widespread implementation of pharmacogenetics. The objectives of the study were three-fold:
1. Review current practice in medication administration for stroke treatment at Bridgepoint Health
2. Critically analyze evidence that pharmacogenetic testing could (or could not) enhance drug selection and treatment efficacy for stroke patients;
3. Assess the cost-benefit potential of a pharmacogenetic intervention for stroke.
Review current practice in medication administration for stroke treatment at Bridgepoint Health
Critically analyze evidence that pharmacogenetic testing could (or could not) enhance drug selection and treatment efficacy for stroke patients;
Assess the cost-benefit potential of a pharmacogenetic intervention for stroke.
We conducted a review of stroke treatment practices at Bridgepoint Health, scanned the literature for drug-gene and drug-outcome interactions, and evaluated the potential consequences of pharmacogenetic testing using the ACCE model.
There is a substantial body of evidence suggesting that pharmacogenetic stratification of stroke treatment can improve patient outcomes in the long-term, and provide substantial efficiencies for the healthcare system in the short-term. Specifically, pharmacogenetic stratification of antiplatelet and anticoagulant therapies for stroke patients may have a major impact on the risk of disease recurrence, and thus should be explored further for clinical application. Bridgepoint Health, and other healthcare institutions taking this path, should consider launching pilot projects to assess the practical impact of pharmacogenetics to optimize treatment for chronic continuous care.
doi:10.1186/2001-1326-2-16
PMCID: PMC3878365  PMID: 24351097
Stroke; Stroke treatment; TIA; Pharmacogenetics; Statins; Clopidogrel; Warfarin; Antihypertensive; Antidepressants; Patient outcomes
4.  Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis 
Liu, Jimmy Z. | Hov, Johannes Roksund | Folseraas, Trine | Ellinghaus, Eva | Rushbrook, Simon M. | Doncheva, Nadezhda T. | Andreassen, Ole A. | Weersma, Rinse K. | Weismüller, Tobias J. | Eksteen, Bertus | Invernizzi, Pietro | Hirschfield, Gideon M. | Gotthardt, Daniel Nils | Pares, Albert | Ellinghaus, David | Shah, Tejas | Juran, Brian D. | Milkiewicz, Piotr | Rust, Christian | Schramm, Christoph | Müller, Tobias | Srivastava, Brijesh | Dalekos, Georgios | Nöthen, Markus M. | Herms, Stefan | Winkelmann, Juliane | Mitrovic, Mitja | Braun, Felix | Ponsioen, Cyriel Y. | Croucher, Peter J. P. | Sterneck, Martina | Teufel, Andreas | Mason, Andrew L. | Saarela, Janna | Leppa, Virpi | Dorfman, Ruslan | Alvaro, Domenico | Floreani, Annarosa | Onengut-Gumuscu, Suna | Rich, Stephen S. | Thompson, Wesley K. | Schork, Andrew J. | Næss, Sigrid | Thomsen, Ingo | Mayr, Gabriele | König, Inke R. | Hveem, Kristian | Cleynen, Isabelle | Gutierrez-Achury, Javier | Ricaño-Ponce, Isis | van Heel, David | Björnsson, Einar | Sandford, Richard N. | Durie, Peter R. | Melum, Espen | Vatn, Morten H | Silverberg, Mark S. | Duerr, Richard H. | Padyukov, Leonid | Brand, Stephan | Sans, Miquel | Annese, Vito | Achkar, Jean-Paul | Boberg, Kirsten Muri | Marschall, Hanns-Ulrich | Chazouillères, Olivier | Bowlus, Christopher L. | Wijmenga, Cisca | Schrumpf, Erik | Vermeire, Severine | Albrecht, Mario | Rioux, John D. | Alexander, Graeme | Bergquist, Annika | Cho, Judy | Schreiber, Stefan | Manns, Michael P. | Färkkilä, Martti | Dale, Anders M. | Chapman, Roger W. | Lazaridis, Konstantinos N. | Franke, Andre | Anderson, Carl A. | Karlsen, Tom H.
Nature genetics  2013;45(6):670-675.
doi:10.1038/ng.2616
PMCID: PMC3667736  PMID: 23603763
genetic association study; disease genetics; immunogenetics; liver
5.  GENETIC MODIFIERS OF LIVER DISEASE IN CYSTIC FIBROSIS 
Context
A subset (~3–5%) of patients with cystic fibrosis (CF) develops severe liver disease (CFLD) with portal hypertension.
Objective
To assess whether any of 9 polymorphisms in 5 candidate genes (SERPINA1, ACE, GSTP1, MBL2, and TGFB1) are associated with severe liver disease in CF patients.
Design, Setting, and Participants
A 2-stage design was used in this case–control study. CFLD subjects were enrolled from 63 U.S., 32 Canadian, and 18 CF centers outside of North America, with the University of North Carolina at Chapel Hill (UNC) as the coordinating site. In the initial study, we studied 124 CFLD patients (enrolled 1/1999–12/2004) and 843 CF controls (patients without CFLD) by genotyping 9 polymorphisms in 5 genes previously implicated as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 CFLD patients (enrolled 1/2005–2/2007) and 1088 CF controls.
Main Outcome Measures
We compared differences in distribution of genotypes in CF patients with severe liver disease versus CF patients without CFLD.
Results
The initial study showed CFLD to be associated with the SERPINA1 (also known as α1-antiprotease and α1-antitrypsin) Z allele (P value=3.3×10−6; odds ratio (OR) 4.72, 95% confidence interval (CI) 2.31–9.61), and with transforming growth factor β-1 (TGFB1) codon 10 CC genotype (P=2.8×10−3; OR 1.53, CI 1.16–2.03). In the replication study, CFLD was associated with the SERPINA1 Z allele (P=1.4×10−3; OR 3.42, CI 1.54–7.59), but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (P=1.5×10−8; OR 5.04, CI 2.88–8.83).
Conclusion
The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater odds (OR ~5) to develop severe liver disease with portal hypertension.
doi:10.1001/jama.2009.1295
PMCID: PMC3711243  PMID: 19738092
6.  Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity 
Nature medicine  2012;18(4):595-599.
Chronic pain is highly variable between individuals, as is the response to analgesics. Although much of the variability in chronic pain and analgesic response is heritable, an understanding of the genetic determinants underlying this variability is rudimentary1. Here we show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X7Rs, which are members of the family of ionotropic ATP-gated receptors, have two distinct modes of function: they can function through their intrinsic cationic channel or by forming nonselective pores that are permeable to molecules with a mass of up to 900 Da2,3. Using genome-wide linkage analyses, we discovered an association between nerve-injury–induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7 gene, such that mice in which P2X7Rs have impaired pore formation as a result of this mutation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Moreover, in two independent human chronic pain cohorts, a cohort with pain after mastectomy and a cohort with osteoarthritis, we observed a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2RX7. Our findings suggest that selectively targeting P2X7R pore formation may be a new strategy for individualizing the treatment of chronic pain.
doi:10.1038/nm.2710
PMCID: PMC3350463  PMID: 22447075
7.  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
8.  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
9.  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
10.  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
11.  Normalization of Obesity-Associated Insulin Resistance through Immunotherapy: CD4+ T Cells Control Glucose Homeostasis 
Nature medicine  2009;15(8):921-929.
Progressive obesity and its associated metabolic syndromes represent a globally growing challenge, yet mechanistic understanding and current therapeutics are unsatisfactory. We discovered that CD4+ T-lymphocytes, resident in visceral adipose tissue (VAT), control insulin-resistance in diet-induced obese (DIO) mice and likely humans. DIO VAT-associated T cells display biased TCR-Vα repertoires suggesting antigen-specific expansion. CD4+ T-lymphocyte control of glucose homeostasis is compromised in DIO when VAT accumulates pathogenic IFNγ-secreting Th1 cells, overwhelming static numbers of Th2 (CD4+GATA-3+) and regulatory Foxp3+ T cells. CD4+ T cell transfer into DIO, lymphocyte-free RAGnull mice reversed weight gain and insulin resistance predominately through Th2 cells. Brief systemic treatment with αCD3 antibody or its F(ab′)2 fragment, restores the Th1/Foxp3+ balance and reverses insulin resistance for months, despite continuing high-fat diet. The progression of obesity-associated metabolic abnormalities is physiologically under CD4+ T cell control, with expansion of adipose tissue-resident T cells that can be manipulated by immunotherapy.
doi:10.1038/nm.2001
PMCID: PMC3063199  PMID: 19633657 CAMSID: cams1704
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.  Centrotemporal sharp wave EEG trait in Rolandic epilepsy maps to Elongator Protein Complex 4 
Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome; are a feature of several related childhood epilepsies; and are freqently observed in common developmental disorders (e.g. speech dyspraxia, attention deficit hyperactivity disorder (ADHD) and developmental coordination disorder (DCD)). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genomewide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine-mapping CTS to variants in Elongator Protein Complex 4 (hELP4) in two independent datasets; the strongest evidence was with rs986527 in intron 9 of hELP4, providing a Likelihood Ratio of 629:1 (p=0.0002) in favor of an association. Resequencing of hELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of hELP4. hELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in hELP4 impairs brain-specific Elongator mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.
doi:10.1038/ejhg.2008.267
PMCID: PMC2729813  PMID: 19172991
linkage; neurodevelopmental traits; centrotemporal spikes; attention deficit hyperactivity disorder; speech dyspraxia; developmental coordination disorder; association
14.  Centrotemporal sharp wave EEG trait in rolandic epilepsy maps to Elongator Protein Complex 4 (ELP4) 
European Journal of Human Genetics  2009;17(9):1171-1181.
Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder). Here we report the first genome-wide linkage scan in RE for the EEG trait, centrotemporal sharp waves (CTS), with genome-wide linkage of CTS to 11p13 (HLOD 4.30). Pure likelihood statistical analysis refined our linkage peak by fine mapping CTS to variants in Elongator Protein Complex 4 (ELP4) in two independent data sets; the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. Resequencing of ELP4 coding, flanking and promoter regions revealed no significant exonic polymorphisms. This is the first report of a gene implicated in a common focal epilepsy and the first human disease association of ELP4. ELP4 is a component of the Elongator complex, involved in transcription and tRNA modification. Elongator depletion results in the brain-specific downregulation of genes implicated in cell motility and migration. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders.
doi:10.1038/ejhg.2008.267
PMCID: PMC2729813  PMID: 19172991
linkage; neurodevelopmental traits; centrotemporal spikes; idiopathic partial epilepsy; association
15.  Complex two-gene modulation of lung disease severity in children with cystic fibrosis 
The Journal of Clinical Investigation  2008;118(3):1040-1049.
Although cystic fibrosis (CF) is a monogenic disease, its clinical manifestations are influenced in a complex manner. Severity of lung disease, the main cause of mortality among CF patients, is likely modulated by several genes. The mannose-binding lectin 2 (MBL2) gene encodes an innate immune response protein and has been implicated as a pulmonary modifier in CF. However, reports have been conflicting, and interactions with other modifiers have not been investigated. We therefore evaluated the association of MBL2 with CF pulmonary phenotype in a cohort of 1,019 Canadian pediatric CF patients. MBL2 genotypes were combined into low-, intermediate-, and high-expression groups based on MBL2 levels in plasma. Analysis of age at first infection with Pseudomonas aeruginosa demonstrated that MBL2 deficiency was significantly associated with earlier onset of infection. This MBL2 effect was amplified in patients with high-producing genotypes of transforming growth factor beta 1 (TGFB1). Similarly, MBL2 deficiency was associated with more rapid decline of pulmonary function, most significantly in those carrying the high-producing TGFB1 genotype. These findings provide evidence of gene-gene interaction in the pathogenesis of CF lung disease, whereby high TGF-β1 production enhances the modulatory effect of MBL2 on the age of first bacterial infection and the rate of decline of pulmonary function.
doi:10.1172/JCI33754
PMCID: PMC2248329  PMID: 18292811

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