Biomedical subjects
Amos Pasternack
Publications and source records attributed to Amos Pasternack.
Immunoglobulin KM and GM gene polymorphisms modify the clinical presentation of primary Sjögren's syndrome.
OBJECTIVE: To investigate whether polymorphism of immunoglobulin (Ig) genes affects susceptibility to or severity of primary Sjogren's syndrome (pSS). METHODS: Ig gene kappa (KM) and gamma (GM) polymorphisms were analyzed by a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) based method in 65 Finnish Caucasian patients with pSS and in 66 healthy controls matched for sex, ethnic origin, and area of residence. Clinical and immunological data on the pSS patients were analyzed in relation to Ig genotypes. RESULTS: The genotype frequencies of Ig KM and GM genes did not differ between pSS patients and controls. Anti-SSB antibodies were encountered significantly more frequently in pSS patients carrying the KM1 allele than in those without (100% vs 48%, p = 0.016). The pSS patients with the KM1 allele had several signs of immunologically active disease: they had significantly higher erythrocyte sedimentation rate, serum IgA, serum beta2-microglobulin (beta2-m), and plasma IgG1 concentrations than patients without this allele. The pSS patients carrying the GM z allele had a milder form of pSS than those without this determinant. They had less severe labial salivary gland histological findings (grade 3-4 in 60% vs 93%, p = 0.004) and lower plasma IgG3 and serum beta2-m concentrations than those without GM z allele. CONCLUSIONS: Ig KM and GM genes do not contribute to susceptibility to pSS. The Ig KM1 allele is associated with several markers of immunologically active disease, whereas the Ig GM z allele is associated with milder pSS.
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Progression of atherosclerosis is associated with variation in the alpha1-antitrypsin gene.
OBJECTIVE: Alpha1-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials. METHODS AND RESULTS: We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3' UTR 11478G>A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n=14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n=8, -14.5% and n=16, -4.0%, respectively) than 11478GG men (n=107, -7.0% and n=108, -1.4%, respectively; overall, P=0.003). VV213 men treated with gemfibrozil (n=68) showed -4.8% progression, whereas A213 carriers (n=55) showed +1.4% regression of disease (P=0.001). No V213A effect was seen on placebo (P=0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the gemfibrozil-treated A213 association with regression, suggesting a pharmacogenetic difference. CONCLUSIONS: Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.
A novel functional polymorphism in the PECAM-1 gene (53G>A) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies.
A 53G>A polymorphism identified in the 5' untranslated region (5'UTR) of the platelet endothelial cell adhesion molecule-1 (PECAM-1) gene alters a putative shear stress responsive element (SSRE). PECAM-1 was shown to be responsive to shear stress and transient transfection of human umbilical vein endothelial cell (HUVECs) with two luciferase reporter constructs driven by the PECAM-1 promoter and 5'UTR showed a response of the 53G allele, not the 53A allele, to shear stress. Association between the 53G>A, and the previously published L125V polymorphism, and coronary atherosclerosis was examined in two angiographic studies. The frequencies of the rare alleles of the 53G>A and L125V polymorphisms were 0.01 and 0.49, respectively, in the Lopid Coronary Angiography Trial (LOCAT) study and 0.02 and 0.49, respectively, in the Regression Growth Evaluation Statin Study (REGRESS) study. Compared with 53G homozygotes, carriers of the 53A allele showed less focal progression of disease in the LOCAT study and a similar trend in the diffuse progression of disease in the REGRESS study, whereas no association between L125V and coronary atherosclerosis was observed in either study. These data demonstrate that the PECAM-1 gene is responsive to shear stress in vitro and that decreased PECAM-1 gene expression in 53A carriers may influence reduced progression of vessel stenosis in patients with coronary artery disease.
IgM nephropathy: clinical picture and long-term prognosis.
BACKGROUND: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis with mesangial hypercellularity and diffuse IgM deposits. METHODS: We studied clinical presentation, morphological findings, and prognostic factors in 110 patients with IgM nephropathy without systemic diseases. The series included both pediatric and adult patients with nephrotic syndrome (NS) or minor urinary abnormalities. RESULTS: Mean postbiopsy follow-up was 8 years. During 15 years of follow-up, 36% of patients developed renal insufficiency and 23% reached end-stage renal failure. In multivariate analysis, hypertension at the time of renal biopsy was the only significant risk factor for renal insufficiency. Of histological parameters, interstitial fibrosis had the strongest prognostic value. Hypertension was diagnosed in 50% of patients with a postbiopsy follow-up of 15 years. Twenty-nine percent of nephrotic patients had disease resistant to corticosteroids, whereas 80% of patients with steroid-sensitive disease were steroid dependent. Eleven patients, 8 patients with NS and 3 patients with asymptomatic proteinuria, underwent repeated renal biopsy. In five samples, typical morphological characteristics of focal and segmental glomerulosclerosis were seen. CONCLUSION: We propose that IgM nephropathy can be divided into two subgroups with similar renal biopsy findings, but differences in sex distribution and initial presentation.
Cost analysis of renal replacement therapies in Finland.
BACKGROUND: Costs for treating patients with end-stage renal disease (ESRD) have grown noticeably. However, most of the cost estimates to date have taken the perspective of the payers. Hence, direct costs of treating ESRD are not accurately known. METHODS: Files of all adult patients with ESRD who entered dialysis therapy between January 1, 1991, and December 31, 1996, were studied retrospectively, and all use of health care resources and services was recorded. Follow-up continued until December 31, 1996. RESULTS: Two hundred fourteen patients fulfilled the study criteria, 138 patients started with in-center hemodialysis (HD) therapy, and 76 patients started with continuous ambulatory peritoneal dialysis (CAPD) therapy. Patients were followed up until death (72 patients) or treatment modality changed for more than 1 month. Fifty-five patients received a cadaveric transplant, and after transplantation (TX), they were examined as a separate group of TX patients. Direct health care costs for the first 6 months in the HD, CAPD, and TX groups were 32,566 US dollars, 25,504 dollars, and 38,265 dollars, and for the next 6 months, 26,272 dollars, 24,218 dollars, and 7,420 dollars, respectively. During subsequent years, annual costs were 54,140 US dollars and 54,490 dollars in the HD group, 45,262 dollars and 49,299 dollars in the CAPD group, and 11,446 dollars and 9,989 dollars in the TX group. Regression analyses showed 4 variables significantly associated with greater daily costs in dialysis patients: age, ischemic heart disease, nonprimary renal disease, and HD treatment. CONCLUSION: Compared with HD, CAPD may be associated with lower costs, yet the absolute difference is not striking. After the TX procedure is performed once, annual costs decline remarkably, and cadaveric TX is less costly than both dialysis modalities.
Plasma concentrations of asymmetric-dimethyl-arginine in type 2 diabetes associate with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased plasma levels of ADMA may indicate endothelial dysfunction and increased risk of angiopathy. The relation of ADMA to diabetes, glycemic control, and renal function, especially early diabetic hyperfiltration, remains unknown. We tried to evaluate whether there is an association between ADMA and glycosylated hemoglobin (GHbA(1c)) on the one hand and glomerular filtration rate (GFR) on the other hand in diabetic subjects with normal or slightly increased GFR. We also studied whether plasma ADMA is associated with some risk factors of vasculopathy (hypercholesterolemia and hypertension). The study subjects consisted of 86 patients with type 2 diabetes and 65 control subjects. Plasma ADMA levels were measured by high-pressure liquid chromatography as o-pthalaldehyde (OPA) derivatives and GFR was determined by the plasma clearance of chromium 51-EDTA. The diabetic patients had lower plasma ADMA levels than the nondiabetic control subjects (0.29 +/- 0.15 v 0.34 +/- 0.16 micromol/L, P <.03). In the diabetic subjects, plasma ADMA concentrations were inversely correlated with GHbA(1c) (R = -0.28, P =.01). In a multivariate linear model, significant predictors of ADMA were GFR (R = -0.32, P =.008) in diabetic subjects and GHbA(1c) (R = -0.19, P =.03) and GFR (R = -0.19, P =.02) in all subjects. Plasma ADMA was not associated with risk factors of vasculopathy. We conclude that diabetic patients with a normal or slightly increased GFR have lower circulating ADMA concentrations than nondiabetic control subjects. In type 2 diabetic patients high GFR and poor glycemic control were related to low plasma ADMA concentrations.
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Human leukocyte antigen-B8-DR3 is a more important risk factor for severe Puumala hantavirus infection than the tumor necrosis factor-alpha(-308) G/A polymorphism.
The tumor necrosis factor (TNF)-alpha(-308) G/A polymorphism (TNF-2) is in linkage disequilibrium with the human leukocyte antigen (HLA)-B8-DR3 haplotype. Both factors have been associated with severe Puumala hantavirus-induced nephropathia epidemica (NE). To examine which part of this extended haplotype might show the strongest association with the outcome of NE, the HLA-B, HLA-DRB1, and TNF-alpha(-308) alleles in 116 hospital-treated patients with NE were analyzed. The findings pointing to clinically severe NE were strongly associated with HLA-B8-DR3 haplotype. There was a trend toward severe disease in persons positive for TNF-2. This was probably due to strong linkage disequilibrium with HLA-B8-DR3, since there were no differences in the clinical severity of NE when TNF-2-positive/B8-DR3-negative persons were compared with TNF-2-negative/B8-DR3-negative persons. It is concluded that the HLA-B8-DR3 haplotype is an important contributor to the course of NE. The data indicate that the TNF-2 allele is not an independent risk factor for severe NE but a passive component in the extended haplotype.
Peroxisome proliferator-activated receptor alpha gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease.
BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD). METHODS AND RESULTS: We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism CONCLUSIONS: The PPARalpha gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall.
Polymorphism of the cytokine genes and IgA nephropathy.
BACKGROUND: IgA nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Cytokine gene polymorphisms regulate cytokine production and play a role in immune and inflammatory responses; these immunological responses thus are possibly involved in the etiology and pathogenesis of IgAN. METHODS: We studied by polymerase chain reaction (PCR) polymorphisms of important cytokine genes of inflammation interleukin-1 (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) in 167 patients with IgAN and 400 healthy blood donor controls. IgAN patients had been followed up for 6 to 17 (median 11) years from renal biopsy. RESULTS: Carriage of the IL-1beta allele 2 (IL1beta2) or IL-1Ra allele 2 (IL1RN*2) was associated with an increased risk of IgAN. These alleles were highly linked and the odds ratio (OR) of IgAN for carriage of both alleles was 1.8 (95% confidence interval 1.2 to 2.6; P = 0.002). Carriage of the TNF-alpha allele 2 (TNF2) was associated with a decreased risk of IgAN (OR 0.5, range 0.3 to 0.7; P = 0.001). The risk of IgAN was found to be highest in those carrying IL1beta2 and IL1RN*2 but not TNF2 as compared to those who did not carry both of these IL-1 cluster genes and were carriers of TNF2 (OR 5.0 (2.4-10.3); P < 0.001). None of the polymorphisms studied was associated with poor prognosis. CONCLUSION: Carriage of IL1beta2 and IL1RN*2 together with non-carriage of TNF2 is associated with increased susceptibility, but not with a prognosis of IgAN.
Increased glomerular permeability in patients with nephropathia epidemica caused by Puumala hantavirus.
BACKGROUND: Nephropathia epidemica (NE) is the Scandinavian type of haemorrhagic fever with renal syndrome. Usually heavy transient proteinuria is present at the onset of the disease. METHODS: We investigated glomerular permeability in eight patients with acute NE and in eight healthy controls. Six patients were followed for 1 year. The glomerular filtration rate (GFR) was determined by inulin clearance and effective renal plasma flow (ERPF) by para-aminohippurate clearance. RESULTS: GFR and ERPF were significantly reduced in NE patients during the acute phase compared with those in controls (P<0.001 and P<0.001, respectively). The filtration fraction (FF) was thus high, 0.37. The fractional clearances of albumin, IgG, and IgG(4) were markedly increased. As a sign of tubular dysfunction, increased urinary excretion of alpha(1)-microglobulin was observed in all patients. After 1 year, the GFR of the patients no longer differed from that of the controls. ERPF was lower and FF higher than those in controls (P=0.014 and P=0.009, respectively). The fractional clearances of albumin, IgG, and IgG(4) remained increased. The high-molecular fractional dextran clearances in the patients were significantly increased compared with controls during the acute phase. Computed analysis of glomerular membrane-pore structure showed that the "shunt-flow" was increased in the patients during the acute phase compared with the controls. There was a positive correlation between the FF and the shunt (r=0.768, P=0.026). In addition, fractional clearances of albumin and IgG correlated significantly with the shunt (r=0.810, P=0.015 and r=0.762, P=0.028, respectively). CONCLUSIONS: Renal involvement in the acute phase of NE is characterized by a markedly decreased GFR and ERPF. Increased glomerular permeability is associated with impairment of both the size- and charge-selectivity properties of the glomerular filter.
Celiac disease and HLA DQ in patients with IgA nephropathy.
OBJECTIVES: Despite some reports on an association between celiac disease and IgA nephropathy, the evidence is still sparse. Celiac disease is strongly associated with the HLA DQ2 and DQ8 haplotypes, which might explain the potential risk of patients to contract various autoimmune conditions. In this study, we sought to establish how common celiac disease is in patients with IgA nephropathy, and whether the possible association can be explained by similar HLA DQ status. METHODS: A total of 223 consecutive adult patients with IgA nephropathy were studied; 95 cadaver organ transplant donors served as controls for HLA DQ analysis. The diagnosis of celiac disease was based on small bowel mucosal biopsy. All known celiac cases were recorded, and eligible patients (n = 168) underwent serological screening for celiac disease as well as HLA DQ2 and DQ8 analysis. Screening methods were serum endomysium and tissue transglutaminase antibodies; patients who tested positive underwent mucosal biopsy. RESULTS: Eight patients (3.6%, 95% CI = 1.6-7.0%) with IgA nephropathy were found to have celiac disease; three of them were identified by serological screening. All celiac cases had the HLA DQ2 or DQ8 haplotype, but these were not more common in patients with IgA nephropathy than in controls. As many as 14% of HLA DQ2 positive patients with IgA nephropathy had celiac disease. Gluten-free diet had no apparent influence on the course of nephropathy. CONCLUSIONS: Although there is no increase in celiac-type HLA DQ, patients with IgA nephropathy carry a risk of contracting celiac disease. It can be hypothesized that the increased intestinal permeability in IgA nephropathy may predispose genetically susceptible patients to celiac disease.
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