Translational Research

2010-03-01

Genetic regulation of serum cytokines in systemic lupus erythematosus

Silvia N. Kariuki, Timothy B. Niewold — 2009-09-25

Genetic association studies in systemic lupus erythematosus (SLE) have been extremely successful in recent years, identifying several loci associated with disease susceptibility. Much work remains to integrate these loci into the functional pathogenic pathways that characterize the disease. Our working hypothesis is that many genetic variations linked to SLE and autoimmunity mediate the risk of disease by altering cytokine profiles or responses to cytokine signaling. Genetic polymorphisms that affect cytokine signaling could alter thresholds for immune responses, resulting in proinflammatory presentation of self-antigens and the subsequent misdirection of adaptive immunity against self, which is observed in autoimmune disease. SLE is clinically heterogeneous and genetically complex, and we expect that individual genes and cytokine patterns will be more or less important to different disease manifestations and subgroups of patients. Defining these genotype-cytokine-phenotype relationships will increase our understanding of both initial disease pathogenesis as well as subsequent response/nonresponse to various therapies. In this review, we summarize some recent work in the area of SLE cytokine genetics and describe the implications for SLE, autoimmunity, and immune system homeostasis, which are revealed by these investigations.

Albumin Benkovac (c.1175 A > G; p.Glu392Gly): a novel genetic variant of human serum albumin

2009-10-30

The gene of human serum albumin, the major blood protein, exhibits a significant degree of DNA polymorphism. Mutations in this gene may cause the presence of 2 circulating forms of the protein (bisalbuminemia or alloalbuminemia, MIM 103600) or a significant reduction of albumin in the blood (analbuminemia, MIM 103600, or congenital hypoalbuminemia). Bisalbuminemia is a rare inherited trait that usually is detected during screening of plasma proteins either in routine clinical electrophoresis or in systematic genetics surveys. In the average population, the occurrence of 2 albumin bands has a frequency of 0.0003–0.0010, and it is not clearly associated with disease. The only reported exceptions are the Arg218→His and Arg218→Pro mutations, which have been found to be responsible for the clinical condition of familial dysalbuminemic hyperthyroxinemia, and the Leu 66→Pro mutation, which is responsible for familial dysalbuminemic hypertriiodothyroninemia. In addition, a possible predictive link between bisalbuminemia and the predisposition to type II diabetes mellitus has been hypothesized recently. Alloalbumins are of interest because they are markers of migration and for population genetics, and because they can provide a model for the study of neutral molecular evolution. In the last 25 years, genetic variants of human serum albumin have been studied in several laboratories in order to define their molecular defects and correlate them to the functional properties and stability of the molecule. These studies have allowed the characterization by protein and/or DNA sequence analysis of 65 different genetic mutations and have provided unique insights into the ligand binding sites of the molecule.

Is there a role for tetrathiomolybdate in the treatment of primary biliary cirrhosis?

Marina G. Silveira, Keith D. Lindor — 2009-12-03

Article on page 123

Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial

2009-10-15

The results of a double-blind trial of tetrathiomolybdate therapy and standard of care, versus placebo and standard of care treatment, in primary biliary cirrhosis patients are presented. Baseline studies of liver function, various safety variables, ceruloplasmin, a liver biopsy for histologic analysis, and for various cytokine analyses were carried out. Patients were observed every 4 months for up to 2 years of treatment by a hepatologist for clinical evaluation and repeat of all the baseline studies except liver biopsy, which was repeated at 2 years. The primary end points were improvement in 2 liver function tests and in 1 inflammatory cytokine. Fifteen placebo patients were followed for an average of 13 months, and 13 tetrathiomolybdate patients were followed for an average of 14 months. The predefined primary end points for efficacy were met. Tetrathiomolybdate was well tolerated. Because tetrathiomolybdate has been shown in numerous animal studies to inhibit autoimmune and inflammatory processes, and because primary biliary cirrhosis is an autoimmune attack on bile ducts, these positive findings on efficacy of tetrathiomolybdate therapy in primary biliary cirrhosis fit with the animal studies and suggest the need for a longer clinical trial to examine transplant-free survival.

Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats

Hiroshi Kono, Hideki Fujii, Kenichi Ishii, Naohiro Hosomura, Masahito Ogiku — 2009-09-23

The effects of dietary medium-chain triglycerides (MCTs) on experimental colitis induced by 2,4,6-trinitrobenzene sulphonic acid (TNBS) were investigated in rats. Male Wistar rats were given an intracolonic injection of TNBS and were then fed liquid diets containing MCTs or corn oil (AIN93) as controls. Serum and tissue samples were collected 1 week after TNBS enema. The severity of colitis was evaluated pathologically, and tissue myeloperoxidase (MPO) activity was measured. Furthermore, messenger RNA (mRNA) and protein levels for inflammatory cytokines and a chemokine were assessed by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In another set of experiments, the protein expression of Toll-like receptor (TLR)-4 in the colon was measured 1 week after feeding of liquid diets. To investigate the effects of MCTs on macrophages, RAW246.7 macrophages were incubated with media containing albumin conjugated with MCT or linoleic acid, which is the major component of corn oil. Then, the production of tumor necrosis factor-α (TNF-α) was measured. Dietary MCTs blunted significantly the protein levels of TLR-4 in the colon. Furthermore, the expression of TLR-4 was significantly blunted in RAW264.7 cells incubated with MCTs compared with cells incubated with linoleic acid. Induction of interleukin 1β (IL-1β), TNF-α, and macrophage inflammatory protein-2 (MIP-2) in the colon was attenuated by dietary MCT. Furthermore, MPO activities in the colonic tissue were significantly blunted in animals fed the MCT diets compared with those fed the control diets. As a result, dietary MCTs improved chemically induced colitis significantly. MCTs most likely are useful for the therapy of inflammatory bowel disease as an anti-inflammatory immunomodulating nutrient.

Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients

Sabir Hussain, Muhammad Asghar, Qamar Javed — 2009-11-06

Resistin, a novel cytokine, is associated with an inflammatory process and is suggested to induce hypertrophy in rat cardiomyocytes. Resistin gene expression has not been investigated in patients with hypertrophic cardiomyopathy (HCM). This study investigates resistin levels in HCM patients and healthy controls and the molecular basis for the regulation of the resistin gene (RETN) in a Pakistani population. Patients with HCM (n = 105) and healthy individuals (n = 110) were enrolled in this investigation. Serum resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). RETN genotyping was performed by polymerase chain reaction (PCR) and DNA sequencing. Our data showed a statistically significant increase in resistin levels from HCM patients compared with healthy subjects (6.3 ± 2.7 ng/mL in patients vs 3.4 ± 2.1 ng/mL in controls, P < 0.0001). The RETN –420 C > G polymorphism was significantly high in patients with HCM compared with the control group (P < 0.001). There was a significant difference between the C and G alleles from HCM cases and controls (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 2.36–5.30, P < 0.0001). Logistic-regression analysis showed that the increased resistin levels, and the RETN–420 C > G polymorphism were significantly associated with HCM. Our data suggest that the elevated resistin levels and the RETN –420 C > G polymorphism may be associated with cardiac hypertrophy in the study population.

Novel technique for rapid detection of α-globin gene mutations and deletions

2009-11-11

Populations in Southeast Asia and South China have high frequencies of α-thalassemia caused by α-globin gene mutations and/or deletions. This study was designed to find an efficient and simple diagnostic test for the mutations and deletions. A duplex polymerase chain reaction (PCR)/denaturing high-pressure liquid chromatography (DHPLC) was used to detect the mutations and deletions. A blinded study of 110 samples, which included 92 α-thalassemia samples with various genotypes and 18 normal DNA samples, was carried out by the methods. The duplex PCR products of the sample with known Constand spring mutation (CS)/αα, Quonsze mutation (QS)/αα, and Weastmead mutation (WS)/αα DNA showed significantly different profiles, which suggests that DHPLC analysis at 63.8°C can detect potential mutations directly. The DHPLC at 50°C analysis can distinguish the --SEA and nondeletional alleles. The new assay is 100% concordant with the original genotype. In conclusion, the technique including the duplex PCR assay followed by DHPLC analysis can be used to diagnose α-thalassemia; this methodology is simple, rapid, accurate, semiautomatic, and high output, and thus, it is suitable for large-scale screening.

Information for Readers

2010-03-01

Masthead

2010-03-01

Editorial Advisory Board

2010-03-01

Author Guidelines

2010-03-01

Translational Research

Contents

Genetic regulation of serum cytokines in systemic lupus erythematosus

Albumin Benkovac (c.1175 A > G; p.Glu392Gly): a novel genetic variant of human serum albumin

Is there a role for tetrathiomolybdate in the treatment of primary biliary cirrhosis?

Treatment of primary biliary cirrhosis with tetrathiomolybdate: results of a double-blind trial

Dietary medium-chain triglycerides prevent chemically induced experimental colitis in rats

Resistin gene promoter region polymorphism and the risk of hypertrophic cardiomyopathy in patients

Novel technique for rapid detection of α-globin gene mutations and deletions

Information for Readers

Contents

Masthead

Editorial Advisory Board

Author Guidelines