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 1/19) 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. 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).

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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). Cystic fibrosis (CF) is a recessive monogenic disorder characterized by multi-organ involvement and clinical heterogeneity that is incompletely explained by mutations within the cystic fibrosis transmembrane conductance regulator ( CFTR) gene. Patients with CF, including those homozygous for DF508, exhibit a range of lung disease severity, and genetic variability in non- CFTR genes contributes to risk for severity of pulmonary disease. – Intrinsic abnormalities in the CF liver reflect loss of CFTR (Cl − channel) function on the apical membrane of cholangiocytes., This dysfunction is predicted to result in defective (sluggish) bile flow, and is associated with a cholangiocyte-induced inflammatory response with activation and proliferation of hepatic stellate cells, which results in cholangitis and fibrosis in focal portal tracts. – However, only a small fraction (~3–5%) of CF patients develops severe liver disease characterized by cirrhosis with portal hypertension (CFLD); thus, non- CFTR genetic variability may contribute to risk for severe liver disease. – To determine the association between non- CFTR genetic polymorphisms and severe liver disease in CF with portal hypertension (CFLD), we studied 9 functional variants in 5 genes previously studied in CF liver disease, including α1-antitrypsin (also known as α1-antiprotease, α1AP, SERPINA1), angiotensin-converting enzyme ( ACE), glutathione S-transferase ( GSTP1), mannose-binding lectin 2 ( MBL2) and transforming growth factor β1 ( TGFB1).

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Our initial study compared polymorphic genotypes in these candidate modifier genes in CF subjects with CFLD and “control” CF patients (without CFLD, who were at least 15 years of age). We tested our initial findings in a second study in different populations of CF patients with and without CFLD. Patients - Initial (First) Study Of the 158 CF patients evaluated for severe liver disease (CFLD; portal hypertension; enrolled 1/19), there were 128 patients who fulfilled criteria from 22 CF Centers in 10 countries (Australia, 8; Canada, 17; Czech Republic, 17; Germany, 3; Italy, 28; Netherlands, 1; Scotland, 2; Slovakia, 4; Turkey, 4; and U.S., 44). For patients without 2 defined mutations in CFTR, we tested further, using a panel of 70 mutations (Tm Bioscience/Luminex CFTR mutation detection assay). After genotyping was complete, >95% of CFLD patients with 2 defined mutations in CFTR had 2 pancreatic insufficient (PI) mutations ().

The 843 control patients (CF patients without CLFD) were enrolled from the U.S. (759 patients from 42 Centers) and Canada (84 patients from 32 Centers). The majority of the CF controls were ascertained from the GMS Lung Study population (DF508 homozygotes; 92.6%), Most of the other controls had biallelic PI mutations (see online supplement, Methods). These controls without CFLD were ≥ 15 years of age (1 SD above the mean age of diagnosis of CFLD), in order to exclude younger patients who might have occult liver disease. Patients - Replication (Second) Study Of the 191 CF patients evaluated for CFLD (portal hypertension; enrolled 1/2005–2/2007), there were 139 CF patients who fulfilled criteria from 35 CF Centers in 10 countries (Argentina, 5; Australia, 5; Canada, 24; Chile, 1; France, 9; Ireland, 8; Israel, 7; Italy, 14; United Kingdom, 4; and U.S., 62). The percentage of PI CFTR genotypes in CFLD subjects was similar to those in the initial study (). The 1088 control patients (CF patients ≥ 15 years without CFLD) were ascertained from five countries (Canada, 391 patients from 32 Centers; Czech Republic, 30 patients; Ireland, 6 patients; Italy, 71 patients; and U.S., 590 patients from 54 Centers).

The majority of the CF controls had 2 PI mutations (93.5%; mostly DF508/DF508 62.8%) (online supplement, Methods). Enrollment Criteria All patients had a diagnosis of CF, confirmed by sweat test and/or CFTR genotyping. CFLD was defined as cirrhosis in patients ≥ 2 years of age, confirmed by imaging (ultrasound, CT, MRI) showing hepatic parenchymal abnormalities of portal hypertension (esophageal varices, portal-systemic collaterals, splenomegaly) in the absence of another cause for liver disease. Data were independently reviewed by 2 hepatologists (P.R.D. And S.C. Disney Apprenticeship Program. L.) with experience in CFLD to ensure inclusion and exclusion criteria were met, using case report forms, radiology and endoscopy reports, and clinical notes.

When there was no consensus, the reviewers requested additional information to clarify the diagnosis of CFLD. No patient was excluded because of race or ethnic background, which were subject-defined. We excluded 30 (19%) and 52 (27%) subjects originally submitted for the initial and replication studies, respectively, with a presumed diagnosis of CFLD, because they had milder liver disease without portal hypertension, or inadequate documentation.

For the 47 patients with confirmed CFLD who had a liver transplant (26 in initial study; 21 in replication study), source documents were obtained from dates prior to transplant. Exclusion criteria for the CFLD group included portal vein thrombosis or other causes of liver disease (alcohol abuse, biliary atresia, clinically significant viral hepatitis, use of parenteral nutrition, and Wilson disease). The study was approved by the Institutional Review Boards of all participating institutions and written informed consent was obtained. Exclusion from Analysis Based on Age of Diagnosis of CFLD In common with previous reports, we found the mean age of diagnosis of CFLD (first documentation of portal hypertension) to be 10.6 (± 5.4) years ().,– The diagnosis of CFLD was first established after the age of 30 years in 7 subjects (ages of 32, 33, 35, 40, 43, 44, and 47 years), which is ≥ 4 SD above the mean of the normal distribution.

Therefore, these patients were excluded from the genetic analyses (4 from the initial study, and 3 from the replication study). Data Collection Patients received a unique identifier code, and data was stored in a secure database in the UNC Bioinformatics Center. Clinical data on standard case report forms included self-reported race/ethnicity, pancreatic exocrine status, medical history, physical examination, laboratory blood work values, and abdominal radiology reports. In addition, we reviewed the following procedure reports if available: liver explant pathology (from liver transplant), liver biopsy, endoscopy and colonoscopy. Histochemistry/Histopathology Immunohistochemistry with polyclonal rabbit anti-α-1 antitrypsin antibody and monoclonal mouse anti-CD68 (clone KP1) antibody (Dako Canada, Ontario, Canada), was performed on the Benchmark XT™ auto-immunostainer (Ventana Medical Systems, Tucson, AZ) at dilutions of 1:3000 and 1:5000, respectively.

Immunodetection was performed using the Ventana, i-VIEW DAB, LSAB kit. Tissue sections were dewaxed, enzyme pretreated for α-1 antitrypsin, heat epitope retrieved for CD68, peroxidase, and endogenous biotin blocked using Ventana proprietary reagents. Sections were hematoxylin counterstained for nuclear detail ().

Statistical Analysis Genotype distributions were tested for consistency with expected Hardy-Weinberg equilibrium (HWE) proportions for cases and controls in the initial, replication and combined studies, using all subjects and then restricted to Caucasian subjects, using the PLINK software package (version 1.03; ). For the initial study, the association between polymorphisms and CFLD was assessed using Cochran-Armitage trend tests. All tests were 2-sided and unadjusted P values are reported, along with P values that were significant (P.

Clinical Features - Initial Study Characteristics of the initial group of 124 CF patients with severe liver disease and 843 CF patients without CFLD are shown in. The CFLD group was younger at enrollment, had more males, and slightly fewer Caucasians. The CFTR mutations in CFLD patients were representative of PI mutations in North American and European CF patients (, ). The prevalence of meconium ileus at birth in CFLD patients (18.2%) is comparable to the control (no CFLD) group, and typical for the general CF population with pancreatic insufficient CFTR mutations. Initial study: Characteristics of cystic fibrosis patients with (CFLD) and without (CF no LD) severe liver disease Abnormalities in biochemical tests of the liver (AST, ALT and GGT) were not predictive of CFLD and showed no correlation with markers of hepatocellular synthetic dysfunction, such as international normalized ratio (INR) and serum albumin (). Preoperative assessment of data available from a subset of patients (n=22) who underwent liver transplant (n=43) showed a similar distribution of abnormal total bilirubin and, albumin values as the non-transplanted patients (, footnote “b” and “c”). Cochran-Armitage Trend Test of Association – Initial Study In the analysis of previously studied gene modifiers of liver disease in CF (), association was seen only for the SERPINA1 Z allele (P=3.3×10 −6; OR 4.72, CI 2.31–9.61) and TGFB1 codon 10 (P=2.8×10 −3; OR 1.53, CI 1.16–2.03).

The SERPINA1 Z allele displayed association for all CFLD patients, but was more prominent in females (). Similar results were seen when the analysis was restricted to Caucasians (data not shown). It is noteworthy that small effects for the non-significant polymorphisms would not be detected with sufficient power by this study (see online supplement Methods – Power Analysis; ). The genotypes and minor allele frequencies for genetic variants in patients without CFLD were similar to those previously reported. Logistic Regression for the Z Allele – Initial plus Replication Study We combined the initial and replication groups and performed logistic regression for the SERPINA1 Z allele to estimate the odds of CFLD, adjusting for the covariates of ethnicity, gender and CFTR genotype. Results remained consistent when using all subjects or Caucasian subjects only, with respect to both statistical significance estimates (P=1.5×10 −8 or P=6.3×10 −8, respectively) and odds ratio estimates (OR 5.04, CI 2.88–8.83 for all patients vs.

OR 4.87, CI 2.75–8.64 for Caucasians only). In addition, we saw no evidence for interactions between gender and the SERPINA1 Z allele in all subjects or only Caucasians. Similar results were obtained by logistic regression adjusting only for ethnicity in the complete sample, and models that additionally adjusted for the TGFB1 codon 10 genotype ().

Age of Diagnosis of CFLD The mean and median age of recognition (diagnosis) of portal hypertension in all CFLD patients was ~10–11 years () and 90% of patients had CFLD diagnosed before 20 years of age. Males had an earlier age of diagnosis of CFLD than females for all subjects (males=8.5 yrs, females=10.5 years; P=0.007), and for self-reported Caucasians (males=9.7 years, females=11.5 years; P=0.027). Age at diagnosis of CFLD was not associated with the presence of the SERPINA1 Z allele, CFTR genotype or self-reported ancestry. COMMENT Previous studies have suggested that genetic polymorphisms may act as modifiers of liver disease in cystic fibrosis, but these studies were small and phenotyping did not address the development of severe (biliary) cirrhosis associated with portal hypertension. – To increase the likelihood of identifying genetic modifiers that are relevant to the development of severe liver disease in CF, i.e., cirrhosis with portal hypertension, we performed 2 sequential studies in different groups of patients. The initial study involved 5 candidate genes that had previously been studied as modifiers of CF liver disease –, and the replication study tested for confirmation of SERPINA1 Z allele and TGFB1 codon 10 variant as modifiers of severe liver disease in CF.

This study had 3 key design features. First, we used rigorous criteria to identify CF patients with portal hypertension (“cases”), reflecting hepato-biliary cirrhosis, and key source documents were reviewed independently by 2 experts to confirm the CFLD phenotype. Second, for CF patients without CFLD (“controls”), we studied only patients who were ≥ 15 years of age, in order to exclude younger patients with predisposition to develop CFLD. Third, we enrolled a large number of CF patients with and without CFLD in order to improve statistical power.

For the initial study, ~50% of the CFLD patients were from outside North America and 93% were self-described as Caucasian, and all control CF patients were from North America. For the replication (second) study, a slightly greater percentage of CFLD patients were from North America (63% versus 50%), and there were some control CF patients (10%) from outside North America. Genetic analyses of the initial cohort showed that a single copy of the SERPINA1 Z allele and each additional copy of the TGFB1 codon 10 C allele were associated with significantly increased odds of CFLD. In the replication study, the SERPINA1 Z allele was confirmed as a modifier of liver disease in CF, whereas the TGFB1 codon 10 variant was not confirmed. It is noteworthy that small effects of the non-significant polymorphisms in other genes would not be detected with sufficient power by this study. The association of the SERPINA1 Z allele with CFLD contrasts to a previous “negative” study, which used less stringent phenotypic markers of CF liver disease, such as liver function tests, which do not correlate with severity of CFLD (portal hypertension). When the initial and replication study populations were combined for joint analysis by multivariable logistic regression, the magnitude of the effect of the SERPINA1 Z allele was large compared to most genetic association studies (odds ratio ~5) when gender, ethnicity and CFTR genotype were included as covariates.

The strength of the association of the SERPINA1 Z allele with CFLD varied by gender for the initial versus the replication studies, but the overall odds were not statistically different for females and males when all subjects were analyzed. Population stratification is unlikely to account for the results for the SERPINA1 Z allele; the prevalence of the Z allele (1.14%) in our CF patients without CFLD (controls) is similar to that reported for >85,000 individuals genotyped in pertinent regions of the world (1.20%)., (). The mechanism of the SERPINA1 Z allele as an adverse modifier of liver disease in CF patients likely reflects the dual stimulation of hepatic stellate cells by inflammatory mediators from both CFTR-deficient cholangiocytes and hepatocytes containing the misfolded SERPINA1 protein, i.e., these inflammatory stimuli induce hepatic stellate cells to migrate and proliferate in the bile duct regions in a pro-fibrogenic manner. –,,– Bile duct ligation with resultant cholestasis induces more activated stellate cells and fibrosis in the liver of homozygous transgenic PiZ versus wild-type mice, which is compatible with this proposed mechanism of the Z allele as an adverse modifier in CF.

How To Install Wba Themes In Windows 7. Further studies are necessary to better define the pathogenesis of the Z allele in CFLD. The Z allele variant causes misfolding of the SERPINA1 protein, which results in an accumulation of protein in hepatocytes. The most prevalent CFTR mutation, DF508, is also a misfolding mutation, expressed predominantly in cholangiocytes in the liver.

Author Contributions: Dr Knowles had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bartlett, Friedman, Ling, Pace, Zou, Silverman, Wright, Lange, Durie, Knowles. Acquisition of data: Bartlett, Friedman, Ling, Pace, Bell, Bourke, Castaldo, Castellani, Cipolli, C. Colombo, Debray, Fernandez, Lacaille, Macek, Rowland, Salvatore, Taylor, Wainwright, Wilschanski, Zemkova, Hannah, Phillips, Corey, Zielenski, Dorfman, Silverman, Drumm, Durie, Knowles.

Analysis and interpretation of data: Bartlett, Friedman, Ling, Pace, Corey, Zielenski, Wang, Zou, Silverman, Wright, Lange, Durie, Knowles. Drafting of the manuscript: Bartlett, Friedman, Wright, Lange, Durie, Knowles.

Critical revision of the manuscript for important intellectual content: Bartlett, Friedman, Ling, Pace, Bell, Bourke, Castaldo, Cipolli, C. Colombo, Debray, Lacaille, Macek, Rowland, Salvatore, Wainwright, Wilschanski, Corey, Zielenski, Dorfman, Drumm, Wright, Lange, Durie, Knowles. Statistical Analysis: Wang, Zou, Wright, Lange. Obtained funding: Bartlett, Friedman, Bell, Bourke, Castaldo, Castellani, Cipolli, C. Colombo, Macek, Rowland, Salvatore, Taylor, Wainwright, Corey, Zielenski, Dorfman, Zou, Silverman, Drumm, Wright, Lange, Durie, Knowles. Administrative, technical, or material support: Bartlett, Friedman, Pace, Hannah, Phillips, Silverman.

Study supervision: Bartlett, Friedman, Ling, Pace, Hannah, Durie, Knowles. Financial Disclosures: No financial conflicts were disclosed.

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