We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cros... more We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metac...
Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterize... more Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 w...
American journal of respiratory cell and molecular biology, Dec 14, 2017
Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However... more Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability of clinical phenotype and survival, even among patients harboring the same genotype. We identified five CF patients with a homozygous F508del mutation in the CFTR gene living in their 5th or 6th decade of life, all with minimal change in lung function over longitudinal period of more than 20 years. Because of the rarity of this long-term non-progressive phenotype, we hypothesized those individuals may carry rare genetic variants in modifier genes that ameliorate disease severity. Individuals at the extremes of survival time and lung function trajectory underwent whole exome sequencing, and the data was filtered for missense, stopgain, indel, and splicing variants present with mean allele frequency <0.2%, and their potential impact on protein function was evaluated. The mutations in δ-ENaC were generated via site-directed mutagenesis, and expressed to carry...
GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly incr... more GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (...
Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, rena... more Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted &amp;amp;gt;2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.
We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cros... more We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study. We evaluated 368 p.C282Y homozygotes who underwent liver biopsy and compared characteristics of those with and without cirrhosis. We performed multivariable logistic regression on cirrhosis with: age; sex; race/ethnicity; diabetes; blood pints/units donated voluntarily; erythrocyte pints/units received; iron supplement use; alcohol intake, g/d; body mass index, kg/m2; swollen/tender 2nd/3rd metacarpophalangeal joints; elevated alanine aminotransferase; elevated aspartate aminotransferase; steatosis/fatty liver; iron removed by phlebotomy, g; and GNPAT p.D519G positivity. Mean age of 368 participants (73.6% men) was 47 ± 13 (standard deviation) y. Cirrhosis was diagnosed in 86 participants (23.4%). Participants with cirrhosis had significantly greater mean age, proportion of men, diabetes prevalence, mean daily alcohol intake, prevalence of swollen/ tender 2nd/3rd metac...
Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterize... more Cystic fibrosis, like primary ciliary dyskinesia, is an autosomal recessive disorder characterized by abnormal mucociliary clearance and obstructive lung disease. We hypothesized that genes underlying the development or function of cilia may modify lung disease severity in persons with cystic fibrosis. To test this hypothesis, we compared variants in 93 candidate genes in both upper and lower tertiles of lung function in a large cohort of children and adults with cystic fibrosis with those of a population control dataset. Variants within candidate genes were tested for association using the SKAT-O test, comparing cystic fibrosis cases defined by poor (n = 127) or preserved (n = 127) lung function with population controls (n = 3,269 or 3,148, respectively). Associated variants were then tested for association with related phenotypes in independent datasets. Variants in DNAH14 and DNAAF3 were associated with poor lung function in cystic fibrosis, whereas variants in DNAH14 and DNAH6 w...
American journal of respiratory cell and molecular biology, Dec 14, 2017
Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However... more Cystic Fibrosis (CF) remains the most lethal genetic disease in the Caucasian population. However, there is great variability of clinical phenotype and survival, even among patients harboring the same genotype. We identified five CF patients with a homozygous F508del mutation in the CFTR gene living in their 5th or 6th decade of life, all with minimal change in lung function over longitudinal period of more than 20 years. Because of the rarity of this long-term non-progressive phenotype, we hypothesized those individuals may carry rare genetic variants in modifier genes that ameliorate disease severity. Individuals at the extremes of survival time and lung function trajectory underwent whole exome sequencing, and the data was filtered for missense, stopgain, indel, and splicing variants present with mean allele frequency <0.2%, and their potential impact on protein function was evaluated. The mutations in δ-ENaC were generated via site-directed mutagenesis, and expressed to carry...
GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly incr... more GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores. We sought to determine associations of p.D519G and iron-related variables with iron stores in p.C282Y homozygotes. We defined markedly increased iron stores as serum ferritin >2247pmol/L (>1000μg/L) and either hepatic iron >236μmol/g dry weight or iron >10g by induction phlebotomy (men and women). We defined normal or mildly elevated iron stores as serum ferritin <674.1pmol/L (<300μg/L) or either age≥40y with iron ≤2.5g iron by induction phlebotomy or age≥50y with ≤3.0g iron by induction phlebotomy (men only). We compared participant subgroups using univariate methods. Using multivariable logistic regression, we evaluated associations of markedly increased iron stores with these variables: age; iron supplement use (dichotomous); whole blood units donated; erythrocyte units received as transfusion; daily alcohol consumption, g; and p.D519G positivity (...
Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, rena... more Glomerular abnormalities are frequent in patients undergoing liver transplantation; however, renal dysfunction following transplantation is mainly attributed to cyclosporine toxicity. Membranoproliferative glomerulonephritis (MPGN) is seen in patients infected with hepatitis C virus (HCV), the virus responsible for 30% of the end-stage liver disease leading to liver transplantation. To determine the incidence of renal abnormalities in liver transplant recipients and the association with HCV, we undertook a longitudinal study in HCV-positive (n=91) and HCV-negative (n=106) liver transplant recipients. Mean creatinine clearance before transplantation was 94 ml/min/1.73 m2 in HCV+ patients and 88 ml/min/1.73 m2 in HCV- patients. By 3 months after transplantation, the mean creatinine clearance decreased by approximately one third in both groups. A greater proportion of HCV+ patients excreted &amp;amp;gt;2 g protein/day after transplantation (P=0.05) and had renal biopsies showing MPGN than did HCV- recipients (4/10 HCV+ patients vs. 0/7 HCV- patients; P=0.1). In the HCV+ group, proteinuria was not associated with recurrent HCV hepatitis, DQ matching, posttransplant diabetes, or hypertension. Treatment of HCV-related MPGN with interferon-alpha2b appeared to stabilize proteinuria and renal function but did not reverse renal dysfunction nor cause liver allograft rejection. After transplantation, HCV+ patients had similar renal function over 3 years after transplantation, compared with HCV- patients, but they had an increased risk of proteinuria and occurrence of MPGN that was only partially responsive to interferon.
Uploads
Papers by Mary Emond