SLC11A1 promoter gene polymorphisms and fibrosis progression in chronic hepatitis C

BACKGROUND AND AIMS: The solute carrier family 11 member 1 (SLC11A1) gene (formerly Nramp1) encodes for the protein solute carrier family 11, member 1. It affects susceptibility and clinical outcome of autoimmune and infectious diseases. We investigated the possible role of the functional polymorphism located in the promoter region of SLC11A1 and tumour necrosis factor (TNF) genes in the progression of fibrosis in chronic hepatitis C. METHODS: A total of 242 Caucasian Spanish patients with biopsy proven chronic hepatitis C and 194 healthy control subjects were genotyped for SLC11A1 and TNF promoter polymorphisms. RESULTS: No significant differences in the distribution of frequencies among patient and control groups were observed. The SCL11A1 homozygous 2/2 genotype was rarely detected among patients showing advanced fibrosis (2/82; 2.4%) but was highly represented in those with mild fibrosis (29/160; 18.1%; odds ratio (OR) 8.85 (95% confidence interval (CI) 1.9-55.2, p(c) = 0.002). In patients carrying allele 3 of SLC11A1, the presence of -238 TNF A/G was associated with advanced fibrosis (14/26 (53.8%) v 68/216 (31.4%); OR 2.53 (95% CI 1.03-6.23); p = 0.02). CONCLUSIONS: SLC11A1 gene promoter polymorphism could influence fibrosis progression in chronic hepatitis C in that the homozygous genotype 2/2 exerts a protective effect against cirrhosis development. Also, the combination of TNF -238 A/G and the presence of allele 3 is conducive to progression to pre-cirrhotic or cirrhotic stages of the disease.     

Macrophage migration inhibitory factor gene polymorphism is associated with sarcoidosis in biopsy proven erythema nodosum

OBJECTIVE: To assess whether polymorphism of the macrophage migration inhibitory factor (MIF) gene at the position -173 is implicated in the development of sarcoidosis. METHODS: Twenty-eight patients with biopsy proven erythema nodosum (EN) associated with sarcoidosis, 70 patients with biopsy proven EN related to other etiologies, and 122 healthy matched controls from the Lugo region of Northwest Spain were studied. Patients and controls were genotyped for a single nucleotide polymorphism in the 5'-flanking region at position -173 of the MIF gene, using SNapshot ddNTP primer extension, followed by capillary electrophoresis (ABI 3100). RESULTS: A significantly increased frequency of the C mutant allele was observed in patients with EN secondary to sarcoidosis compared to controls (p = 0.0016; p(corr) = 0.0032; OR 2.78, 95% CI 1.45, 5.35) and also compared to patients with EN unrelated to sarcoidosis (p = 0.0004; p(corr) = 0.0008; OR 3.72, 95% CI 1.75, 7.87). Patients with EN carrying an MIF 173 C allele were found to have an increased risk of sarcoidosis (57% in EN secondary to sarcoidosis vs 24% in patients with EN related to other etiologies; p = 0.002; p(corr) = 0.004; OR 4.16, 95% CI 1.64, 10.50). CONCLUSION: This is the first attempt to assess the influence of MIF genetic polymorphism at position -173 in the development of sarcoidosis. The MIF 173 C allele is associated with a significantly increased risk of developing sarcoidosis in patients with EN.     

C-C chemokine receptor 5 gene variants in relation to lung disease in sarcoidosis

RATIONALE: Genetic factors are likely to influence the clinical course and pattern of sarcoidosis, a granulomatous disease of unknown origin. OBJECTIVES: We tested this hypothesis for C-C chemokine receptor 5 (CCR5), a molecule involved in recruitment and activation of mononuclear cells. METHODS: In addition to the known CCR5 Delta 32 insertion/deletion, we evaluated a further eight single-nucleotide polymorphisms in 106 British patients and 142 British unaffected subjects, and second-setted the results in 112 Dutch patients and 169 healthy Dutch control subjects. MEASUREMENTS AND MAIN RESULTS: In the British population, the frequency of one of the identified haplotypes (HHC) was strongly associated with the presence of parenchymal disease (radiographic stage >or= II versus stages 0 and I) at presentation (odds ratio [OR], 5.2; 95% confidence interval [CI], 1.96-13.7; corrected p = 0.02), at 2 (OR, 6.6; 95% CI, 2.5-17.6; corrected p = 0.006), and at 4 years follow-up (OR, 6.8; 95% CI, 2.5-18.0; corrected p = 0.0045). In the Dutch population, the same association was seen at 2 (OR, 6.7; 95% CI, 2.8-16.4; corrected p = 0.002), and 4 years follow-up (OR, 9.0; 95% CI, 3.5-23.1; corrected p = 0.0009). CONCLUSIONS: No association between the CCR5 haplotype HHC and susceptibility to sarcoidosis was observed, indicating that this relevant gene only operates after disease induction. In summary, we report a strong association between CCR5 haplotype HHC and persistent lung involvement in sarcoidosis.     

Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis

Transforming growth factor-beta1 (TGF-beta1) is a cytokine that plays a key role in the development of idiopathic pulmonary fibrosis. There have been reports on the presence of two genetic polymorphisms in the DNA sequence encoding the leader sequence of the TGF-beta1 protein, located in codons 10 and 25. The objective of this study was to investigate the association between TGF-beta1 gene polymorphisms in codons 10 and 25 and the susceptibility to idiopathic pulmonary fibrosis and the progression of the disease. Compared with healthy control subjects (n = 140), patients with idiopathic pulmonary fibrosis (n = 128) showed no significant deviations in genotype or allele frequencies. One hundred and ten patients with idiopathic pulmonary fibrosis were followed up for 30.3 +/- 25 months. The presence of a proline allele at codon 10 was independently associated with a significant increase in alveolar arterial oxygen tension difference during follow-up, after controlling for the effect of treatment (coefficient = 0.59; 95% confidence intervals, 0.23 to 0.96; p = 0.002). These findings suggest that (1) TGF-beta1 gene polymorphisms in codons 10 and 25 do not predispose to the development of idiopathic pulmonary fibrosis; and (2) TGF-beta1 gene polymorphisms may affect disease progression in patients with idiopathic pulmonary fibrosis.     

Mast cells in bronchoalveolar lavage fluid of patients with interstitial lung diseases

Mast cells play an important role in tissue inflammation, fibrosis and remodelling. They are found in bronchoalveolar lavage fluid (BAL) of healthy persons only in small numbers. We investigated the number of mast cells in interstitial lung diseases and analysed our data for correlations with clinical parameters, cellular and non-cellular parameters of BAL. We found following counts of mast cells in % of total BAL cells: Sarcoidosis (n = 123); 0.22 +/- 0,04 %, idiopathic pulmonary fibrosis (IPF) (n = 35); 0.39 +/- 0.47 %, cryptogenic organising pneumonia (COP) (n = 27); 2.05 +/- 2.19 %, hypersensitivity pneumonitis (HP) (n = 24); 1.02 +/- 1.05 %, rheumatoid lung (n = 20); 0.21 +/- 0.21 %, respiratory bronchiolitis-associated interstitial lung disease (RBILD) (n = 11); 0.16 +/- 0.29 %) and control group (n = 16); 0.06 +/- 0.16 %. Compared to controls mast cells were increased in COP (p < 0.001) and HP (p < 0,01). Correlation analysis showed that an increased mast cell count correlated with: Higher age (sarcoidosis (p = 0.03); smaller vital capacity (sarcoidosis (p = 0.01)), smaller FEV 1 (sarcoidosis (p = 0.04), RBILD (p = 0.04)); higher alkaline phosphatase in BAL (sarcoidosis (p = 0.004), HP (p = 0.02), COP (p = 0.04); higher albumin level in BAL (sarcoidosis (p = 0.000), IPF (p = 0.003); higher cell counts in BAL (sarcoidosis (p = 0.013), COP (p = 0.04)); lower portion of macrophages in BAL cells (sarcoidosis (p = 0.001), HP (p = 0.02), COP (p = 0.02)); higher portion of lymphocytes in BAL cells (sarcoidosis (p = 0.03)); higher portion of neutrophils in BAL cells (sarcoidosis (p = 0.007)); higher portion of eosinophils in BAL cells (sarcoidosis (p = 0.001), HP (p = 0.006)). Correlations to smoking history in pack years and to lymphocyte surface markers CD3, CD4, CD8 were not found. In conclusion comparing different interstitial lung diseases we found significantly increased mast cell counts in COP and HP. Moreover there were correlations of increased mast cell counts with more intensive alveolitis and exudation.     

Clinical presentation of chronic hepatitis C in patients with end-stage renal disease and on hemodialysis versus those with normal renal function

BACKGROUND: The natural history of chronic hepatitis C (CHC) remains to be defined in patients with end-stage renal disease (ESRD). AIMS: To determine the clinical presentation of CHC and the factors associated with stage III-IV fibrosis in patients with CHC and ESRD. METHODS: The study included patients with CHC and ESRD (n = 91) or normal renal function (NRF, n = 159). Both groups were matched for mean age, gender, history of alcohol use, and estimated duration of hepatitis C virus (HCV) infection. RESULTS: Presentation of CHC and ESRD was independently associated with non-Caucasian ethnicity (OR = 3.24, p= 0.0003), a history of diabetes mellitus (DM, OR = 7.911, p < 0.0001), and lower frequencies of being obese (OR = 0.457, p= 0.035), of having hepatic steatosis (OR = 0.372, p= 0.003), and stage III-IV fibrosis (OR = 0.403, p= 0.016). After adjusting for serum levels of alpha-fetoprotein (AFP) and HCV RNA, CHC, and ESRD were independently associated with lower frequencies of elevated alanine aminotransferase (ALT, OR = 0.175, p= 0.02) and aspartate aminotransferase (AST, OR = 0.169, p= 0.04), but higher frequencies of AST/ALT ratio >1 (OR = 7.173, p= 0.002) and hypoalbuminemia (OR = 9.567, p= 0.0007). Compared to patients with NRF and stage III-IV fibrosis, those with ESRD and stage III-IV fibrosis had a significantly higher frequency of a history of DM (OR = 8.014, p= 0.0031) and lower frequency of elevated AST (OR = 0.054, p= 0.004), which were independent of the frequencies of lower levels of ALT and albumin, and AST/ALT ratio >1. In patients with CHC and ESRD, the presence of stage III-IV fibrosis was significantly associated with hepatic steatosis (OR = 4.523, p= 0.012) and thrombocytopenia (OR = 4.884, p= 0.044), which were independent of the frequencies of a history of DM, splenomegaly, and a higher level of AST. CONCLUSIONS: CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.     

Increased intrahepatic and circulating levels of endoglin, a TGF-beta1 co-receptor, in patients with chronic hepatitis C virus infection: relationship to histological and serum markers of hepatic fibrosis

Endoglin, a transforming growth factor (TGF)-beta1 co-receptor, has been associated with renal and cutaneous fibrosis, as overexpression of this protein has been observed in biopsies from patients with glomerulosclerosis and scleroderma, respectively. Our aim was to evaluate whether endoglin may be associated with hepatic fibrosis featuring chronic hepatitis C virus (HCV) infection. Fifty-two anti-HCV+ patients, five anti-HCV- patients and 27 healthy subjects were studied. Western blot and immunohistochemistry were used to quantify the expression levels of endoglin and TGF-beta1 in liver biopsy samples, and serum concentrations of endoglin and hyaluronic acid were determined by enzyme-linked immunosorbent assays (ELISAs). In patients with advanced fibrosis, intrahepatic expression levels of endoglin and TGF-beta1 were significantly higher than those in patients with early fibrosis (mean: 3- and 5.8-fold, respectively) and normal liver (mean: 3.9- and 12-fold, respectively). Interestingly, activated hepatic stellate cells as well as portal and septal myofibroblasts expressed endoglin. Serum levels of endoglin were also significantly higher in patients with advanced fibrosis than in those with early fibrosis (55.5 +/- 1.6 vs 47.5 +/- 0.9 ng/mL, P < 0.001), showing a positive correlation with serum hyaluronic acid concentrations (r = 0.57, P = 0.01). In conclusion, increased intrahepatic endoglin and TGF-beta1 expression is significantly associated with progressive hepatic fibrosis in chronic HCV infection. Circulating endoglin levels are elevated in HCV patients showing a significant correlation with histological and serum markers of hepatic fibrosis. These data suggest an active role for endoglin in the fibrotic process featuring chronic HCV infection.     

SLC11A1 gene polymorphisms in Korean patients with Behçet's disease

OBJECTIVE: To investigate the potential susceptibility to the solute carrier family 11 member 1 (SLC11A1) gene polymorphisms of Korean patients with Beh?et's disease (BD). METHODS: Ninety-nine patients with BD and 98 controls were recruited. Analyses of three polymorphisms of the SLC11A1 gene [the 5'-promoter (GT)n, D543N and A318V] were performed, either by denaturing high-performance liquid chromatography for D543N and A318V or by using automatic DNA sequencing for the (GT)n. The genotypes and alleles between patients with BD and the controls were compared using the chi2 test and Yate's correction test. RESULTS: No significant differences were found in the distribution of genotypes and alleles of the (GT)n polymorphism between BD patients and the controls. However, subjects with the allele 3 or the genotype allele 3/allele 3 of this polymorphism had a significantly lower risk of developing BD than those without this allele or genotype [allele: p = 0.029, pc = 0.039, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.37-0.95; genotype: p = 0.036, pc = 0.048, OR = 0.54, 95% CI 0.31-0.96]. In addition, the distributions of genotypes and alleles of D543N were similar between BD patients and controls (p>0.05). In the case of A318V, all of the BD patients and controls had a wild-type genotype. CONCLUSION: The allele 3 and the genotype allele 3/allele 3 of the 5'-promoter (GT)n in the SLC11A1 gene may have a protective effect for the development of BD in the Korean population. Further studies in other populations are required to confirm our results.     

Clinical relevance of the risk factors for coronary artery lesions in Kawasaki disease

We aimed to investigate which factors are associated with coronary artery lesions (CALs) during the acute and chronic stages in Taiwanese children with Kawasaki disease (KD). A total of 216 children with KD were enrolled. Clinical and laboratory data were obtained for each child within 7 days of illness. The patients were classified into KD children without acute CALs (n=135) and those with acute CALs (n=81) according to echocardiography data at Week 2 after treatment. Then, KD children with acute CALs were further divided into those without chronic CALs (n=55) and with chronic CALs (n=26) according to annual echocardiography data. During acute stage of KD, neutrophil count (<54%) [odds ratio (OR)=0.44, p=0.041]; second dose of intravenous immunoglobulin (IVIG) treatment (OR=5.01, p=0.009); and platelet count (≤400,000) (OR=0.42, p=0.006) were correlated with the risk of acute CALs. During chronic stage of KD, age (12-60 months) (OR=0.25, p=0.042); first dose of IVIG treatment (OR=0.12, p=0.005); and band count (≥3%) (OR=3.51, p=0.032) were correlated with the risk of chronic CALs. Our results suggest that the effects of neutrophil count, doses of IVIG treatment, and platelet count on CALs in acute KD are important. Age, doses of IVIG treatment, and band count are related to the persistence of CALs in chronic stage of KD.     

Cytokine gene polymorphisms in idiopathic pulmonary fibrosis

Pro- and anti-fibrotic cytokine gene polymorphisms may affect expression of idiopathic pulmonary fibrosis (IPF). The aims of the present case-control study were to examine polymorphisms in the IL-6, transforming growth factor (TGF)-beta 1, tumour necrosis factor (TNF)-alpha and interleukin-1 (IL-1)Ra genes in patients with IPF (n = 22) -compared to healthy controls (n = 140). Genotyping was performed on DNA extracted from peripheral blood lymphocytes, using polymerase chain reaction - restriction fragment length polymorphism with gene polymorphisms determined according to -published techniques. The following sites were examined: (i) IL-1Ra*1-5 (86 bp variable tandem repeat intron 2), (ii) IL-6 (-174G > C), (iii) TNF-alpha (-308G > A) and (iv) TGF-beta 1 (Arg25Pro). The TNF-alpha (-308 A) allele was over-represented in the IPF (p(corr) = 0.004) group compared to controls. Risk of IPF was significant for heterozygotes for: (i) the TNF-alpha (-308 A) allele (A/G) (odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.2; P = 0.02), (ii) homozygotes (A/A) (OR 13.9; 95%CI 1.2-160; P = 0.04) and (iii) carriage of the allele (A/A + A/G) (OR 4; 95%CI 1.6-10.2; P = 0.003). The distribution of alleles and genotypes for IL-6, TGF-beta 1 and IL-1Ra between the two groups was not significantly different. This is the third study to independently confirm that there is a significant association of the TNF-alpha (-308 A) allele with IPF. Further research is needed to assess the utility of cytokine gene polymorphisms as markers of disease -susceptibility.     

Expression of Ki-67, transforming growth factor beta1, and B-cell lymphoma-leukemia-2 in liver tissue of patients with chronic liver diseases

BACKGROUND: The purpose of the present paper was to assess expression of proliferation, fibrosis and apoptosis markers in different phases of chronic liver diseases. METHODS: Sixty-six adults with chronic liver diseases (chronic hepatitis C, n = 48; chronic hepatitis B, n = 10; alcohol chronic liver disease, n = 8) treated at the Department of Infectious Diseases and Hepatology from 1999 to 2001, composed the study group. Liver biopsy specimens were used for immunohistochemical assessment of expression of Ki-67, transforming growth factor beta1 (TGF-beta1) and B-cell lymphoma-leukemia-2 (Bcl-2). Grade of liver inflammation and stage of fibrosis were evaluated according to the Scheuer scale. RESULTS: Expression of Ki-67 in hepatocytes was most intensive in patients with grade 2 and 3 inflammation. The expression in patients with grade 4 inflammation was low. The expression of Ki-67 in lymphocytes was most intensive in patients with grade 2 inflammation. Expression of TGF-beta1 in hepatocytes reached a maximum in patients with grade 2 or 3 inflammation and dropped in patients with grade 4 inflammation. There was a statistically significant correlation between stage of fibrosis and expression of TGF-beta1 in liver stromal cells. A very strong correlation was found between the expression of Bcl-2 in bile ductules epithelium and the grade of inflammation (P = 0.006). The expression of Bcl-2 in hepatocytes was observed only in patients with very intense liver inflammation (grade 3) and in patients with stage 3 or 4 fibrosis. CONCLUSION: Processes of proliferation, fibrosis and apoptosis are not directly correlated to progression of liver disease. Expression of studied markers can be used for analysis of dynamics of these processes.     

Anemia in rheumatoid arthritis: association with polymorphism in the tumor necrosis factor receptor I and II genes

OBJECTIVE: To investigate whether polymorphisms in the tumor necrosis factor receptor I (TNFRSF1A) and receptor II (TNFRSF1B) genes are associated with the anemia observed in rheumatoid arthritis (RA). METHODS: We studied a group of Caucasian patients (n = 160) with established RA on whom longitudinal data of hemoglobin (Hb) levels over 5 years were recorded. A second group of patients (n = 102) with early RA was used for a confirmation study. Polymerase chain reaction restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNFRSF1A gene, and the T676G polymorphism in TNFRSF1B. Serum levels of ferritin were determined by ELISA and used to differentiate between iron deficiency anemia (IDA) and anemia of chronic disease (ACD). Data were analyzed by Kruskal-Wallis analysis of variance and logistic regression analysis. RESULTS: The TNFRSF1A GG genotype was associated with lower 5-year mean area under the curve Hb levels compared with other genotypes (p = 0.01). Analysis of anemic status showed an increased frequency of anemia in patients carrying a G allele, with the highest frequency in GG homozygotes. The TNFRSF1A GG genotype was significantly associated with IDA in established RA (OR 4.3, p = 0.01), and this was confirmed in a group of patients with early RA (OR 4.8, p = 0.04). Analysis of the combined groups also showed a weak association of the G allele with ACD (OR 2.2, p = 0.04). No association was found between TNFRSF1B variants and anemia when the cohorts were analyzed separately, but an association between carriage of the T allele and ACD was found when the 2 groups were combined (OR 11.5, p = 0.01). CONCLUSION: Our data suggest that polymorphisms within the TNFRSF1A and TNFRSF1B genes are associated with IDA and/or ACD in patients with RA.     

Collagen synthesis by normal and fibrotic human lung fibroblasts and the effect of transforming growth factor-beta

Collagen accumulation is a major feature of pulmonary fibrosis and other fibrotic lesions. We have studied the synthesis of collagens in fibroblasts cultured from normal and fibrotic human lung specimens and evaluated how it is affected by transforming growth factor-beta (TGF-beta). Fibroblasts were obtained from normal and fibrotic adult human lungs (n = 11; normal = 6, idiopathic pulmonary fibrosis = 5). They were exposed to TGF-beta and pulse-labeled with [3H]proline and [3H]glycine. Collagen production was measured as bacterial collagenase-susceptible radioactivity, and collagen mRNA levels were determined by a solution hybridization assay using labeled procollagen alpha 1[I] cDNA clone HF677 as probe. Synthesis of collagen types I, III, and V were assessed after separating them by DEAE-cellulose chromatography and SDS-polyacrylamide gel electrophoresis. The results showed that both normal and fibrotic lung fibroblasts synthesized similar amounts of collagen. Type I was the major collagen species synthesized by both normal and fibrotic cell types, and the relative proportion of type I, III, and V collagens was similar in both cell types. TGF-beta caused a two to fourfold increase in stimulation of collagen production and collagen mRNA levels, and no differences were detected in the response of normal and fibrotic lung fibroblasts. All collagen types were stimulated by the TGF-beta. TGF-beta did not increase fibroblast proliferation and the majority of normal and fibrotic lung cells exposed to TGF-beta remained in G1 phase of the cell cycle. We conclude that fibroblasts of normal and fibrotic human synthesize similar amounts of collagens.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transforming growth factor beta-1 signalling in canine hepatic diseases: new models for human fibrotic liver pathologies.

BACKGROUND/AIMS: The purpose of this study was to validate spontaneous chronic hepatitis and cirrhosis in dogs as a potential large animal model for fibrotic liver disease in humans by evaluating their molecular pathophysiology. METHODS: Transforming growth factor-beta1 (TGF-beta1) signalling was analysed in liver samples of dogs with acute hepatitis (AH), chronic hepatitis (CH), cirrhosis (CIRR), and a specific form of cirrhosis, lobular dissecting hepatitis (LDH), in comparison with human cirrhotic samples from alcohol abuse (ALC) and hepatitis C (HC). RESULTS: Canine samples were investigated with quantitative real-time PCR (Q-PCR) and Western blotting on TGF-beta1 signalling including Smad2/3 phosphorylation. Immunohistochemistry on collagens I and III was performed. Q-PCR showed an increase in TGF-beta1 levels and downstream effector gene products in CH, LDH, and CIRR. The same fibrotic diseases also showed an increase in phosphorylated Smad2/3 and a higher deposition of collagens I and III. In contrast, in AH neither active TGF-beta1 signalling nor collagen deposition was observed. Western blot analysis on human ALC and HC indicated a high similarity with canine samples in TGF-beta1 expression and Smad2/3 phosphorylation. CONCLUSIONS: Our results demonstrate that fibrosis in spontaneous dog liver diseases is highly comparable to their human counterparts and might serve as models for anti-fibrotic strategies.     

Chymase gene (CMA1) polymorphisms in Dutch and Japanese sarcoidosis patients

BACKGROUND: Chymase is released from mast cells following activation. Evidence suggests that chymase plays an important role in tissue injury and remodeling of the lungs, heart and skin. OBJECTIVE: We postulated that chymase gene (CMA1) polymorphisms are associated with pulmonary fibrosis in Dutch and with cardiac and skin involvement in Japanese sarcoidosis patients. PATIENTS AND METHODS: Dutch (n = 153) and Japanese (n = 122) sarcoidosis patients with controls (Dutch, n = 309; Japanese, n = 111) were studied. Pulmonary involvement in Dutch patients as well as clinical manifestations in Japanese patients was evaluated for association with five CMA1 polymorphisms. RESULTS: The CMA1 polymorphisms were not associated with disease susceptibility in either population, or with radiographic evolution in the Dutch or with cardiac or skin involvement in the Japanese patients. The -526 T allele was associated with a lower iVC in Dutch patients. CONCLUSIONS: The CMA1 polymorphisms studied do not contribute to disease susceptibility in Japanese or Dutch sarcoidosis patients. CMA1 polymorphisms do not influence radiographic evolution in Dutch sarcoidosis patients, nor do they predispose to cardiac or skin involvement in Japanese patients. However, the association between CMA1 -526 C/T and iVC in the Dutch patients suggests that chymase may modify the functional outcome of pulmonary sarcoidosis.     

Association between the HLA-DRB1 gene and clinical features of systemic sclerosis in Korea

OBJECTIVE: To determine whether HLA-DR alleles are associated with the development and clinical features of systemic sclerosis (SSc) in Koreans. METHODS: Seventy-nine patients (74 women and five men; 45 diffuse types and 34 limited types; mean age at diagnosis 43.9 years) fulfilling the American College of Rheumatology (ACR) classification criteria for SSc were enrolled. The controls were 144 healthy, disease-free Koreans. HLA-DRB1 genotypes were assessed by the polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. RESULTS: The HLA-DRB1*15 allele was increased in anti-topoisomerase I autoantibody (anti-topo I)-positive SSc patients [p = 0.003, p corrected (p(corr)) = 0.039, odds ratio (OR) = 3.43, 95% confidence interval (CI) 1.45-8.13] compared with controls. The DRB1*11 allele was also observed more frequently in anti-topo I-positive SSc than in controls (13.3% vs. 4.2%) but not statistically significant (p = 0.053, p(corr) = 0.689). In patients with SSc, the DRB1*04 allele was associated with subcutaneous calcinosis (p = 0.048, OR = 4.56, 95% CI 1.07-19.37). Patients with overlap syndrome showed a negative association with the DRB1*04 allele (p = 0.036, OR = 0.26, 95% CI 0.08-0.91). CONCLUSION: The HLA-DRB1*15 allele was associated with the development of anti-topo I-positive SSc in Koreans. In addition, the DRB1*04 allele was associated with certain clinical features in SSc patients.     

Crackles in interstitial lung disease. Comparison of sarcoidosis and fibrosing alveolitis

STUDY OBJECTIVE: Determine why crackles on chest auscultation are characteristic of most interstitial lung diseases, but may not be heard in sarcoidosis. DESIGN: All patients with sarcoidosis or cryptogenic fibrosing alveolitis seen during a four-week period were studied. In a second study to relate ausculatory findings to anatomy, patients with fibrotic changes on their chest roentgenogram were studied. SETTING: Patients were recruited from outpatient clinics. PATIENTS: In the first part, all patients seen over the course of one month were studied. In the second study, patients with pulmonary fibrosis seen on chest roentgenograms were studied. INTERVENTIONS: For the first study, two independent observers performed auscultation on five sites for crackles and reviewed four roentgenogram quadrants for changes. For the second study, patients underwent VC measurements, auscultation, and high resolution computer tomography scans. MEASUREMENTS AND RESULTS: For the first study, crackles were noted at greater than 2 sites in all 11 CFA patients, but only one of 17 SARC patients (p less than 0.001). Roentgenogram changes were seen in greater than 2 quadrants in nine of 11 CFA patients and eight of 17 SARC patients (p = ns). In the second study, the VC was similar in the two groups: SARC: 1.96 +/- .90 L (means +/- SD), 58 +/- 20.4 percent predicted; CFA: 1.81 +/- .33 L, 59 +/- 9.2 percent predicted). Only two of 14 SARC patients had crackles in greater than 1 area, while all 14 CFA patients had crackles at greater than 2 sites. The HRCT studies were read by a radiologist unaware of the diagnosis. The presence and degree (0 to 3 scale) of subpleural and peribronchial fibrosis were scored. Twelve SARC patients had peribronchial changes (mean score 1.9 +/- 1.08), while only eight had subpleural fibrosis (mean score .6 +/- .52). There was a significantly different pattern in the CFA patients, where eight had peribronchial fibrosis (mean score = .9 +/- .78, p less than 0.05) and all 14 had subpleural fibrosis (mean score = 1.6 +/- .73, p less than 0.01). CONCLUSIONS: We conclude that crackles are more frequent in fibrosing alveolitis than in sarcoidosis; this difference may be due to the distribution of parenchymal fibrosis.