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Biomedical subjects

M Broch

Publications and source records attributed to M Broch.

At least 19 recordsLinked to original sources
PubMed2006

IL-18: relationship with anthropometry, body composition parameters, leptin and arterial hypertension.

OBJECTIVE: Interleukin-18 (IL-18) is a potent pro-inflammatory cytokine with potential atherogenic properties whose role in human obesity has been recently suggested. The aim of our study was to analyze the physiologic distribution of IL-18 among sexes and all decades of the adult life in a healthy population randomly selected and to study its relationship with anthropometric, body composition measurements and leptin concentrations. We also studied the relationship of IL-18 with smoking and arterial hypertension, known risk factors implicated in atherogenesis. MATERIALS AND METHODS: One hundred and thirty four men and 127 healthy women were included in the study. Plasma concentrations of IL-18 and leptin were determined in all subjects. Body composition was evaluated by bioelectrical impedanciometry. RESULTS: IL-18 was distributed similarly in men and women and throughout decades. No significant differences were found in IL-18 between obese and normal-weight men and women according to their body mass index and body fat content. Higher IL-18 concentrations were found in subjects with arterial hypertension. In the bivariate correlation analysis only waist to hip ratio correlated weakly with IL-18 in the whole population (r=0.12, p=0.04). In the multiple regression analysis the relationship between IL-18 and waist to hip ratio lost significance after adjusting for age, sex and body mass index. However, IL-18 remained associated with arterial hypertension (adjusted r2=0.25, p=0.023). CONCLUSIONS: The lack of correlation between IL-18 with anthropometric, body composition variables and leptin in our healthy population argues against a role of this cytokine in obesity. Moreover, our findings suggest the implication of this interleukin in the atherogenic process induced by arterial hypertension.

Adolescent↗
PubMed2005

Diabetic neuropathy is associated with activation of the TNF-alpha system in subjects with type 1 diabetes mellitus.

OBJECTIVE: The development of diabetic neuropathy (DN) is predicted by cardiovascular risk factors associated with insulin resistance. As inflammation seems to be implicated in the pathogenesis of insulin resistance, we investigated whether subjects with type 1 diabetes mellitus (T1DM) and DN have an increase in plasma concentrations of inflammatory proteins involved in insulin resistance. DESIGN: Cross-sectional. Patients One hundred twenty subjects, all diagnosed with T1DM 14 years before. MEASUREMENTS: (1) Sex, age, body mass index, waist-to-hip ratio (WHR), blood pressure, smoking, alcohol intake, insulin dose, HbA1c and lipid profile; (2) DN (peripheral and cardiac autonomic), retinopathy and nephropathy; (3) plasma concentrations of soluble fractions of tumour necrosis factor alpha receptors 1 and 2 (sTNFR1 and sTNFR2), interleukin-6, high-sensitive C-reactive protein, adiponectin and leptin; and (4) insulin resistance (by way of a mathematical estimation of the glucose disposal rate - eGDR-). RESULTS: Thirty-six subjects had DN and 84 did not. Subjects with DN received higher insulin doses (57.6 +/- 16.7 vs. 49.2 +/- 15.0 IU/day; P = 0.008) and had higher WHR (0.85 +/- 0.07 vs. 0.81 +/- 0.10; P = 0.007) and HbA1c values (8.5 (7.6-9.6) vs. 7.7 (7.3-8.9)%; P = 0.049) than subjects without DN. They also had higher values of sTNFR1 (2.42 +/- 0.60 vs. 1.96 +/- 0.66 microg/l; P = 0.001) and sTNFR2 (4.73 +/- 1.33 vs. 4.14 +/- 1.09 microg/l; P = 0.015), and were more insulin resistant (eGDR values: 7.28 (5.83-8.03) vs. 8.30 (7.17-9.03) mg kg(-1) min(-1); P = 0.003). The relationship between DN and either sTNFR1 or sTNFR2 remained essentially unchanged after adjusting for several confounders, including glycaemic control, WHR, lipid profile, blood pressure and other microvascular complications (OR for sTNFR1: 2.592 (1.222-5.498), P = 0.013; OR for sTNFR2: 2.124 (1.258-3.587), P = 0.005). CONCLUSIONS: The activity of the TNF-alpha system is increased in subjects with type 1 diabetes mellitus and diabetic neuropathy, regardless of their glycaemic control and cardiovascular risk factors associated with insulin resistance. These results suggest that TNF-alpha may play a pathogenic role in the development of diabetic neuropathy.

Adult↗
PubMed2005

Tumour necrosis factor receptors (TNFRs) in Type 2 diabetes. Analysis of soluble plasma fractions and genetic variations of TNFR2 gene in a case-control study.

AIMS: We have studied the relationships between soluble fractions of tumour necrosis factor receptors (sTNFR1 and sTNFR2) in Type 2 diabetes (DM2) and its chronic microvascular complications. Likewise, we have analysed the genetic susceptibility of 196T > G exon6/CA-repeat intron 4 mutations in the TNFR2 gene in this population. METHODS: A case-control study was conducted to examine the role of sTNFRs in 345 DM2 patients and 173 healthy subjects. The mutations were studied in all healthy subjects and in a subset of 232 patients. RESULTS: sTNFRs levels were similar in healthy and DM2 patients. A positive correlation between age and both sTNFRs was observed in healthy subjects. In DM2 patients, sTNFR1 showed a positive correlation with age, systolic blood pressure and leptin levels (r = 0.53, P < 0.0001; r = 0.28, P = 0.005; r = 0.46, P < 0.0001, respectively) and sTNFR2 was positively correlated with age, triglycerides and leptin levels (r = 0.34, P < 0.0001; r = 0.21, P < 0.0001; r = 0.28, P = 0.002, respectively). Patients with micro- or macroalbuminuria showed higher plasma levels of sTNFR1 and sTNFR2 than normoalbuminuric patients, after adjusting for confounding variables (B = 0.85, P = 0.022, 95% CI: 0.12-1.58 for sTNFR1 and B = 1.50, P < 0.001, 95% CI: 0.67-2.33 for sTNFR2). In DM2 patients, TT-exon 6 homozygous showed lower levels of sTNFR1 [2,4 (1.1) vs. 3.4 (1.2) ng/ml], and the CA273-allele tracked with elevated plasma HDL-cholesterol [1.8 (0.7), 1.4 (0.3) and 1.3 (0.3) mm, for CA273/273, CA273/- and CA-/-, respectively]. No association was seen with other analysed variables. CONCLUSIONS: Our findings suggest that chronic TNF activation may have some pathogenic role in diabetic nephropathy in DM2 patients. Genetic variations in exon 6/intron 4 of the TNFR2 gene do not predispose to a major risk for DM2 or its microvascular complications.

Adult↗
PubMed2005

The tumour necrosis factor (TNF)-alpha system is activated in accordance with pulse pressure in normotensive subjects with type 1 diabetes mellitus.

OBJECTIVE: Pulse pressure (PP) and inflammation are important predictors of cardiovascular disease (CVD), even in the normotensive. The age-related increase in PP can be diagnosed up to 20 years earlier in subjects with type 1 diabetes mellitus (T1DM) than in the general population. Some evidence suggests that PP can stimulate inflammation. Our aim was to study the relationship between PP and plasma inflammatory proteins in normotensive subjects with T1DM. DESIGN: This was a cross-sectional study of a group of normotensive (<140/80 mmHg) subjects diagnosed with T1DM 14 years before. None of them had clinically proven CVD or inflammatory conditions or were on antiplatelet, antihypertensive, anti-inflammatory or lipid-lowering treatment. METHODS: The following information was recorded: sex, age, body-mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), PP, mean blood pressure (MBP), smoking, alcohol intake, insulin dose, lipid profile, HbA1c, microvascular complications, and plasma concentrations of soluble receptor types 1 and 2 of tumour necrosis factor (TNF)-alpha (sTNFR1 and sTNFR2, respectively), interleukin-6, C-reactive protein, adiponectin and leptin. RESULTS: A total of 112 subjects were evaluated (aged 27.4+/-6.6 years, 52.7% women, BMI: 20.4+/-2.7 kg/m2, WHR: 0.82+/-0.09, SBP: 112+/-12 mmHg, DBP: 68+/-9 mmHg, PP: 45+/-9 mmHg, MBP: 82+/-9 mmHg, HbA1c: 8.2% (7.3-9.0%), 41.1% microvascular complications). After adjusting for potential confounders, only inflammatory markers of the TNF-alpha system correlated significantly with PP (Pearson correlation coefficient between sTNFR1 and PP: r = 0.215, P = 0.030; and between PP and sTNFR2: r = 0.238, P = 0.020). CONCLUSION: In normotensive subjects with T1DM after 14 years of diagnosis, the activation of the TNF-alpha system is positively associated with PP levels. This finding might suggest a pathogenic role of the TNF-alpha system in the development of cardiovascular disease in T1DM.

Adult↗
PubMed2003

Lower rate of tumor necrosis factor-alpha -863A allele and higher concentration of tumor necrosis factor-alpha receptor 2 in first-degree relatives of subjects with type 2 diabetes.

Allelic variants of the tumor necrosis factor-alpha (TNF-alpha) gene seem to contribute to insulin resistance increasing the transcription rate of TNF-alpha. The TNF-alpha -863A allele is associated with a lower expression of TNF-alpha gene and less secretion of the cytokine. To investigate whether an abnormal TNF-alpha system regulation may contribute to early impairment of insulin action in first-degree relatives of patients with type 2 diabetes mellitus (DM), we studied the TNF-alpha -863C/A polymorphism and the soluble fraction of TNF-alpha receptor-2 (sTNFR2) concentration in these subjects in comparison to a control group. A total of 52% of subjects in the relatives' group showed an abnormal oral glucose tolerance (either as impaired glucose tolerance [IGT] or diabetes) and had more features of the insulin resistance syndrome, despite showing similar body composition as controls. The plasma concentration of the sTNFR2 was higher and insulin sensitivity (%S) was lower in the relatives' group than in the controls. Likewise, the TNF-alpha -863A allele was more commonly detected in the control group (10 of 41) than in the relative's group (2 of 36, P =.029). In a multivariate linear regression analysis, neither TNF-alpha -863A allele nor sTNFR2 independently determined %S. Only body mass index (BMI) and the presence of a positive family history of DM were independent determinants of insulin resistance. In summary, our study showed a lower rate of TNF-alpha -863A allele and higher concentrations of sTNFR2 in first-degree relatives of DM subjects. These findings could be included among the genetic, metabolic, and clinical heterogeneity that characterizes the pathophysiology of DM. The presence of abnormalities in the TNF-alpha pathway could predispose to the development of DM in subjects at risk for the disease.

Adult↗
PubMed2003

Smoking, fat mass and activation of the tumor necrosis factor-alpha pathway.

OBJECTIVE: Obesity may be associated with increased markers of inflammation that could be triggered by metabolic, physical, infectious or environmental processes. As smoking significantly increases cytokine production, we aimed to study how smoking influences the relationship between fat mass and soluble tumor necrosis factor-alpha (TNF-alpha) receptors 1 and 2 (sTNFR1 and sTNFR2). DESIGN: Cross-sectional, clinical observational study. SUBJECTS: A total of 133 healthy men (age: 27-53 y, body mass index (BMI): 24-30.2 kg/m(2)), 80 of whom were never-smokers and 53 smokers, matched for age, BMI and waist-to-hip ratio. MEASUREMENTS: Circulating soluble fractions of the TNF-alpha receptors sTNFR1 and sTNFR2 were measured to study their relationship with fat mass (bioelectric impedance). RESULTS: Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass and insulin, smokers showed significantly increased circulating sTNFR2 levels (3.7+/-0.8 vs 3.4+/-0.7 ng/ml, P=0.03). The slopes of the relationships between sTNFR1 and fat mass, and between sTNFR2 and fat mass, were significantly steeper in smokers than in nonsmokers. In a stepwise multiple linear regression analysis, both fat mass (P<0.00001) and smoking (P=0.025) independently contributed to 13% of sTNFR1 variance and to 4% of sTNFR2 variance (P=0.03). CONCLUSION: Both fat mass and smoking are related to increased activity of the TNF-alpha axis.

Adipose Tissue↗
PubMed2002

Bone mineral mass is associated with interleukin 1 receptor autoantigen and TNF-alpha gene polymorphisms in post-menopausal Mediterranean women.

Bone mass is known to be under genetic control. Interleukin-1 (IL-1), interleukin-6 (IL-6) and TNF-alpha are strong inductors of bone resorption. The estrogenic deficiency that occurs during menopause leads to an increase in the production of these cytokines. We analyzed the genetic susceptibility of several polymorphisms of the interleukin-1 receptor antagonist (IL-1ra), IL-6 and TNF-alpha genes in lumbar spine and hip bone mass in a sample of post-menopausal Caucasian Mediterranean women with osteoporosis. 104 post-menopausal osteoporotic women (58.6+/-4.8 yr) and 51 post-menopausal women without osteoporosis as the control group (57.2+/-4.5 yr) were studied. The osteoporotic group was in turn sub-classified into severe and non-severe osteoporosis. The variable number of tandem repeats IL1-ra, IL-6 SfaNI and TNF-alpha NcoI genetic polymorphisms were studied. Biochemical markers of bone turnover were measured in blood and urine. Women carrying the A2 allele (A2+) of the IL-1ra gene showed greater BMD in the lumbar spine (p=0.02) and hip (p=0.006), compared to those not carrying the allele (A2-). The IL-6 polymorphism studied in its 5' flanking region did not show any association with BMD values. The TNF-alpha gene G allele was associated with a greater bone mass in the non-severe osteoporotic subgroup, both in the lumbar spine (p=0.0007) and in the hip (p=0.02). Likewise, genotype combination A2+GG was associated to a greater hip BMD at the femoral neck and Ward triangle levels (p=0.02). We conclude that both IL-1ra and TNF-alpha can be candidate loci to be studied in the susceptibility to develop post-menopausal osteoporosis.

Alleles↗
PubMed2001

Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.

There is increasing evidence that systemic inflammation and insulin resistance constitute interrelated events that contribute to atherosclerosis. We studied the effect of the association between circulating interleukin 6 (IL-6) levels, one of the major mediators of inflammation, and C-reactive protein on insulin resistance and blood pressure in 228 healthy volunteers. The plasma IL-6 concentration was significantly and similarly associated with systolic (SBP) and diastolic (DBP) blood pressure, fasting insulin, and the fasting insulin resistance index (FIRI) in all subjects. When smokers were excluded from the analysis, plasma IL-6 levels correlated with percent fat mass (r = 0.19; P = 0.02), absolute fat mass (r = 0.17; P = 0.03), SBP, DBP, fasting insulin levels, and FIRI. The latter associations persisted after controlling for body mass index (r = 0.15 and r = 0.19; P = 0.02 and P: = 0.0004 for SBP and DBP, respectively; r = 0.24 and r = 0.19, P = 0.004 and P = 0.03, for fasting insulin and FIRI, respectively). Gender and smoking status significantly influenced the results. Although IL-6 levels were significantly associated with fasting insulin and FIRI in men, these significant correlations were not observed in women. Conversely, although IL-6 levels were significantly associated with SBP and DBP in women, these coefficients were not statistically significant in men. All of these associations were lost among smokers and remained significant in nonsmokers. As IL-6 is the major mediator of the acute phase response by hepatocytes and induces the synthesis of C-reactive protein (CRP), we also controlled for the latter. Serum CRP levels correlated significantly with IL-6 in all the subjects, but mainly in nonsmokers and men. Of note was that this significant relationship was lost among smokers. CRP was associated with fasting insulin (r = 0.28; P < 0.0001) and FIRI (r = 0.25; P < 0.0001), but not with SBP or DBP (P = NS), in all subjects. Unlike IL-6, the associations between CRP and these parameters were similar in men and women and in smokers and nonsmokers. For insulin and FIRI they were stronger in women and in nonsmokers. CPR significantly correlated with the WHR only in men (r = 0.22; P = 0.01). Using multiple linear regression in a stepwise manner to predict circulating IL-6 levels, smoking status (P = 0.0059) and FIRI (P = 0.03), but not fat mass or SBP, independently contributed to 11% of its variance in men. When CRP was introduced into the model, the latter (P < 0.0001) and smoking status (P = 0.02), but not FIRI, fat mass, or SBP, contributed to 33% of the variance in IL-6 levels. In women, only SBP (P = 0.04) contributed to 5% of its variance. When CRP was introduced into the model, again only SBP (P = 0.01) contributed to 10% of the variance in IL-6 levels. In 25 of these subjects, insulin sensitivity was determined using the frequently sampled iv glucose tolerance test with minimal model analysis, and circulating IL-6 levels were strongly associated with the insulin sensitivity index (r = -0.65; P < 0.0001). Again, this relationship was even stronger in men (r = -0.75; P < 0.001) and was not significant in women (r = -0.26; P = NS). In all of these subjects, only insulin sensitivity (P = 0.0037), not fat mass, contributed to 21% of the variance of IL-6 levels in a multiple linear regression analysis. In summary, circulating IL-6 levels, by inducing either hypertension in women or insulin resistance in men, constitute a significant proatherogenic cytokine. The mechanisms of these associations should be further investigated.

Adult↗
PubMed2000

Genetic polymorphism of alcohol dehydrogenase in europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1.

Polymorphism at the ADH2 and ADH3 loci of alcohol dehydrogenase (ADH) has been shown to have an effect on the predisposition to alcoholism in Asian individuals. However, the results are not conclusive for white individuals. We have analyzed the ADH genotype of 876 white individuals from Spain (n = 251), France (n = 160), Germany (n = 184), Sweden (n = 88), and Poland (n = 193). Peripheral blood samples from healthy controls and groups of patients with viral cirrhosis and alcohol-induced cirrhosis, as well as alcoholics with no liver disease, were collected on filter paper. Genotyping of the ADH2 and ADH3 loci was performed using polymerase chain reaction-restriction fragment length polymorphism methods on white cell DNA. In healthy controls, ADH2*2 frequencies ranged from 0% (France) to 5.4% (Spain), whereas ADH3*1 frequencies ranged from 47. 6% (Germany) to 62.5% (Sweden). Statistically significant differences were not found, however, between controls from different countries, nor between patients with alcoholism and/or liver disease. When all individuals were grouped in nonalcoholics (n = 451) and alcoholics (n = 425), ADH2*2 frequency was higher in nonalcoholics (3.8%) than in alcoholics (1.3%) (P =.0016), whereas the ADH3 alleles did not show differences. Linkage disequilibrium was found between ADH2 and ADH3, resulting in an association of the alleles ADH2*2 and ADH3*1, both coding for the most active enzymatic forms. In conclusion, the ADH2*2 allele decreases the risk for alcoholism, whereas the ADH2*2 and ADH3*1 alleles are found to be associated in the European population.

Adult↗
PubMed2000

Interleukin-6 gene polymorphism and lipid abnormalities in healthy subjects.

Several lines of evidence indicate that interleukin-6 (IL-6) is involved not only in the hepatic acute phase response but also in adipose tissue metabolism, lipoprotein lipase activity, and hepatic triglyceride secretion. A polymorphism in the IL-6 gene, associated with differences in IL-6 transcription rate, has been recently described. We aimed to study whether this IL-6 gene polymorphism leads to differences in fasting and postglucose load plasma lipids in healthy subjects. Subjects with G at position -174 of the IL-6 gene were similar in age, sex, body mass index, and waist to hip ratio in comparison with carriers of the C allele. However, G carriers showed almost twice plasma triglycerides (1.5 +/- 0.9 vs. 0.90 +/- 0.37 mmol/L; P = 0.01), very low-density lipoprotein (VLDL)-triglycerides (0.97 +/- 0.69 vs. 0.42 +/- 0.2 mmol/L; P = 0.002), higher fasting (881 vs. 458 micromol/L; P = 0.01), and postglucose load free fatty acids (299 vs. 90.5 micromol/L; P = 0.03), slightly lower high-density lipoprotein-2 cholesterol (0.25 +/- 0.14 vs. 0.39 +/- 0.26 mmol/L; P = 0.058), and similar cholesterol and LDL-cholesterol levels than carriers of the C allele. Serum IL-6 levels correlated positively with fasting triglycerides, VLDL-triglycerides, and postload free fatty acids (r = 0.61, 0.65 and 0.60, respectively; P < 0.001) and negatively with high-density lipoprotein-cholesterol (r = -0.42, P < 0.05). A tendency toward higher serum IL-6 levels was observed among G carriers (9.9 +/- 6.9 vs. 6.85 +/- 1.7 pg/mL; P = 0.09). The -174G construct was recently reported to show higher expression of IL-6 in He La cells and was associated with higher plasma IL-6 levels than the -174C allele. Thus, the results of the present study suggest that subjects with the G allele, associated to higher IL-6 secretion, are prone to lipid abnormalities. Whether this polymorphism contributes to lipid alterations associated with other metabolic disorders awaits additional studies.

Adult↗
PubMed2000

Interleukin-6 gene polymorphism and insulin sensitivity.

Type 2 diabetes and the insulin resistance syndrome have been hypothesized to constitute manifestations of an ongoing acute-phase response. We aimed to study an interleukin-6 (IL-6) gene polymorphism in relation to insulin sensitivity (IL-6 is the main cytokine involved in an acute-phase response). Subjects homozygous for the C allele at position -174 of the IL-6 gene (SfaNI genotype), associated to lower plasma IL-6 levels, showed significantly lower integrated area under the curve of serum glucose concentrations (AUCglucose) after an oral glucose tolerance test, lower blood glycosylated hemoglobin, lower fasting insulin levels, lower total and differential white blood cell count (a putative marker of peripheral IL-6 action), and an increased insulin sensitivity index than carriers of the G allele, despite similar age and body composition. A gene dosage effect was especially remarkable for AUCglucose (6.4 vs. 9.3 vs. 9.7 mmol/l in C/C, C/G, and G/G individuals, respectively). The serum concentration of fully glycosylated cortisol binding globulin (another marker of IL-6 action), suggested by concanavalin A adsorption, was lower in C/C subjects than in G/G individuals (32.6+/-2.9 vs. 37.6+/-4.6 mg/l, P = 0.03). In summary, a polymorphism of the IL-6 gene influences the relationship among insulin sensitivity, postload glucose levels, and peripheral white blood cell count.

Adult↗
PubMed2000

Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients.

OBJECTIVE: Mice lacking the tumor necrosis factor-alpha receptor 2 (TNFR2) gene fed a high-fat diet gain less weight and display reduced leptin and insulin levels. In humans, plasma levels of the soluble fraction of TNFR2 (sTNFR2) circulate in proportion to the degree of insulin resistance. The purpose of this study was to evaluate a polymorphism in the 3' untranslated region of the TNFR2 gene on chromosome 1 in relation to BMI, leptin levels, and insulin resistance. RESEARCH DESIGN AND METHODS: Using single-strand conformation polymorphism, the polymorphism was analyzed in 107 nondiabetic subjects (60 women, 47 men) and in 110 consecutive patients with type 2 diabetes (79 women, 31 men). In a subset of 33 healthy subjects, insulin sensitivity (minimal model analysis) was also evaluated. RESULTS: Four alleles of the TNFR2 gene were identified (A1, A2, A3, and A4). BMI and serum leptin levels were significantly increased in young carriers of the A2 allele. Plasma sTNFR2 levels were similar among the different TNFR2 gene variants. However, in subjects who did not carry the A2 allele, in young subjects, and in women, plasma sTNFR2 levels were proportional to BMI and leptin levels. In the study sample, carriers of the A2 allele (n = 18) showed significantly increased BMI, fat mass, waist-to-hip ratio, serum total and VLDL triglyceride levels, and leptin levels and had a lower insulin sensitivity index than noncarriers of the A2 variant (n = 15). The frequency of the different alleles among diabetic subjects was similar to that in the control population. However, diet-treated diabetic subjects (n = 49) who were carriers of the A2 allele exhibited significantly higher BMI and leptin levels than diet-treated noncarriers of the A2 allele. CONCLUSIONS: The presence of the A2 allele in the TNFR2 gene may predispose subjects to obesity and higher leptin levels, which may in turn predispose them to insulin resistance or vice versa. The TNFR2 gene may be involved in weight-control mechanisms.

3' Untranslated Regions↗
PubMed1999

Genetic heterogeneity within ulcerative colitis determined by an interleukin-1 receptor antagonist gene polymorphism and antineutrophil cytoplasmic antibodies.

BACKGROUND: Although there is strong evidence implicating genetic predisposition in the pathogenesis of the chronic inflammatory bowel diseases, the number and identity of susceptibility genes remain uncertain. Cytokine genes are tentative candidate loci, but data regarding association studies in different populations are conflicting. AIMS: To determine potential associations of interleukin-1 receptor antagonist (IL-1ra), tumour necrosis factor alpha (TNF alpha), and tumour necrosis factor beta (TNF beta) gene polymorphisms with ulcerative colitis or subsets of ulcerative colitis in a Spanish population. METHODS: Genotyping for IL-1ra, TNF alpha and TNF beta gene polymorphisms was performed by the polymerase chain reaction in 95 patients with ulcerative colitis and 74 healthy controls. A variable number of tandem repeats (VNTR) in the IL-1ra gene, and a single base pair polymorphism in the TNF alpha gene promoter region (-308) and in the first intron of the TNF beta gene were analysed. Anti-neutrophil cytoplasmic antibodies (ANCA) were detected using an indirect immunofluorescence assay. RESULTS: There were no significant differences between ulcerative colitis patients and controls in either polymorphism analysed, nor between ulcerative colitis subgroups as a function of the clinical disease pattern. However, when stratified by their ANCA status, perinuclear ANCA (p-ANCA) ulcerative colitis showed an increased frequency of the genotype 1,2 of the IL-1ra gene compared with ANCA-negative ulcerative colitis (52% versus 28%; P = 0.02, Pcorr = 0.1). Furthermore, p-ANCA ulcerative colitis had a statistically significant increase of this genotype compared with cytoplasmic ANCA (c-ANCA)/ANCA-negative ulcerative colitis (52% versus 26.5%; P = 0.01, Pcorr = 0.05). CONCLUSIONS: In the Spanish population studied, the polymorphisms analysed in the IL-1ra, TNF alpha and TNF beta genes are unlikely to be important in the overall susceptibility to ulcerative colitis. However, the combination of a subclinical (p-ANCA) and a genetic (IL-1ra gene) marker identified a distinct ulcerative colitis subgroup (p-ANCA; IL-1ra genotype 1,2). These findings provide further evidence of genetic heterogeneity within ulcerative colitis, and support the concept that ANCA may represent a subclinical marker of genetic heterogeneity.

Adolescent↗
PubMed1999

Tumor necrosis factor system activity is associated with insulin resistance and dyslipidemia in myotonic dystrophy.

Myotonic dystrophy (MyD) is a multisystem autosomal dominant disorder associated with progressive muscle wasting and weakness. The striking metabolic abnormality in MyD is insulin resistance. The mechanism by which target tissues are insensitive to insulin action remains uncertain. In a recent study, plasma soluble tumor necrosis factor receptor (sTNFR)2 levels were found to be associated with muscle tissue mass and insulin resistance. Given these associations, we speculated that disorders of the muscle cell membrane could lead simultaneously to insulin insensitivity and sTNFR2 leakage in MyD. To test this hypothesis, we measured the levels of circulating sTNFR1 and sTNFR2 and insulin resistance in MyD patients. We studied 22 MyD patients and 24 age-, BMI-, and fat mass-matched control subjects. Both MyD men and women showed higher plasma insulin levels in the presence of comparable glucose concentrations than did control subjects. sTNFR2, but not sTNFR1, levels were approximately 1.5-fold higher in MyD patients. In parallel with these findings, the fasting insulin resistance index (FIRI) was also higher in MyD patients. In fact, in the whole population, fasting insulin and FIRI strongly correlated with sTNFR2 in both men (r = 0.77 and r = 0.81, P<0.0001, respectively) and women (r = 0.67 and r = 0.64, P = 0.001, respectively). sTNFR2 levels were also associated with the insulin sensitivity index (S(I)), calculated from an oral glucose tolerance test (OGTT) according to the method by Cederholm and Wibell (r = -0.43, P = 0.006). We constructed a multiple linear regression to predict FIRI, with BMI, waist-to-hip ratio, and sTNFR2 as independent variables. In this model, both BMI (P = 0.0014) and sTNFR2 (P = 0.0048) levels contributed independently to 46% of the variance of FIRI. In another model, in which FIRI was substituted for S(I) from the OGTT, both BMI (P = 0.0001) and sTNFR2 (P = 0.04) levels contributed independently to 48% of the variance of S(I) from the OGTT. Plasma cholesterol and triglyceride concentrations were significantly increased in MyD patients. sTNFR1 and sTNFR2 levels were found to be strongly associated with plasma cholesterol, LDL cholesterol, and triglycerides. sTNFR1 and sTNFR2 also correlated with serum creatine kinase activity in MyD patients (r = 0.57, P = 0.006; r = 0.75, P<0.0001, respectively). In conclusion, here we describe, for the first time to our knowledge, a relationship between insulin action and plasma sTNFR2 concentration in MyD patients. We have also found increased concentrations of plasma triglycerides and cholesterol levels in parallel with sTNFR1 and sTNFR2 concentrations in MyD patients. We speculate that the latter associations are dependent on, and secondary to, increased tumor necrosis factor (TNF)-alpha action. Whether TNF action is implicated in the pathogenesis of MyD or is a simple marker of disease activity awaits further studies.

Adult↗
PubMed1998

GLUT1 gene polymorphism in non-insulin-dependent diabetes mellitus: genetic susceptibility relationship with cardiovascular risk factors and microangiopathic complications in a Mediterranean population.

OBJECTIVE: It has been suggested that the polymorphic variation of GLUT1 glucose transporter may contribute to genetic susceptibility to type 2 diabetes in some populations. We have evaluated the GLUT1-XbaI polymorphism in an association study of a Caucasian Mediterranean population and its role in the susceptibility to displaying either microangiopathic complications or any of the risk factors associated with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 193 type 2 diabetic patients (104 women and 89 men, 31-82 years of age, diabetes duration 13.2 +/- 6.2 years) and 90 healthy subjects (48 women and 42 men, 20-72 years of age) were recruited for the association study. For the evaluation of nephropathy and retinopathy, type 2 diabetic patients were matched with those not having microangiopathic complications. RESULTS: Genotypic or allelic frequencies did not differ significantly between controls and type 2 diabetic patients. Regarding the distribution of clinical or metabolic parameters according to GLUT1 genotype, patients with X1X1 genotype tended to have higher diastolic blood pressure levels compared with the remaining genotypes (P = 0.008). There were no differences in genotypic or allelic distribution among patients for either the presence or absence of retinopathy or nephropathy. CONCLUSIONS: We conclude that GLUT1 loci did not contribute significantly to type 2 diabetes in this cohort and is not a determinant for cardiovascular risk factors or chronic microangiopathic complications associated with type 2 diabetes. The weak association with diastolic hypertension must be confirmed in other populations.

Adult↗
PubMed1998

Influence of chronic alcohol abuse and liver disease on hepatic aldehyde dehydrogenase activity.

Alcohol metabolism results in the production of acetaldehyde, a compound that is much more toxic than ethanol itself. Hepatic aldehyde dehydrogenase (ALDH) is the main enzymatic system responsible for acetaldehyde clearance from the hepatocyte. The objective of this study was to determine the modifications in ALDH activity due to chronic alcohol abuse and liver disease. ALDH activity was determined in samples of liver tissue from 69 alcoholic and 82 nonalcoholic subjects, with and without liver disease. According to the results of liver pathology examination, alcoholic patients were classified into the following groups: controls, with no liver disease (group 1), noncirrhotic liver disease patients (group 2), and cirrhotics (group 3). Nonalcoholic subjects were categorized, using the same criteria, into groups 4, 5, and 6, respectively. ALDH activity was determined spectrophotometrically at two substrate concentrations: 18 mM for total activity and 180 microM for low Km activity. High Km activity was calculated by subtracting the low Km activity value from that of total ALDH activity. Results obtained in each group were expressed as the mean +/- SD of mU of g of wet weight. There were no significant differences when the total ALDH activity from the alcoholic and the nonalcoholic patients with a similar degree of liver pathology were compared: group 1, 1257 +/- 587 vs. group 4, 1328.1 +/- 546.2 (p: NS); group 2, 919.1 +/- 452.4 vs. group 5, 753.5 +/- 412 (p: NS); and group 3, 430.2 +/- 162.4 vs. group 6, 473.2 +/- 225.3 (p: NS). On the other hand, total ALDH activity was significantly lower in cirrhotics than in controls, both among alcoholics (p < 0.01) and among nondrinkers (p < 0.05). The low Km activity was severely reduced in cirrhotics, both alcoholics and nonalcoholics (p < 0.01). High Km activities in cirrhotic patients were low, compared to controls, both in alcoholics and nonalcoholics, although the difference was nonsignificant. The results of the present study suggests that chronic alcohol abuse does not depress ALDH activity. A reduction in the ALDH activity detected in patients with severe liver disease (cirrhotics) was clearly a consequence of liver damage. This reduction was due mainly to a decrease of the low Km ALDH activity, but a trend to a decrease in the high Km ALDH activity was also detected.

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