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| Brief Genetics Reports |
Type 1 diabetes is believed to be a Th1 lymphocyte-mediated disease, and both environmental and genetic factors play a role in its pathogenesis. It was recently found that that interleukin (IL)-18 is a pro-inflammatory cytokine in synergy with IL-12, promoting the development of Th1 lymphocyte response by induction of -interferon production. Higher levels of IL-18 were recently reported in the subclinical stage of type 1 diabetes. Studies recently described single-nucleotide polymorphisms of the promoter of IL-18 gene at posotion -137 and -607, suggested to cause differences in tanscription factor binding and impact on IL-18 gene activity. The genotype distribution differed significantly between patients with type 1 diabetes and control subjects. The difference reflected an increase in the GC genotypes and a decrease in GG genotypes at position -137 in the promoter of IL-18 gene. AA genotype at position -607 was found only in the control group. Studies also demonstrated that the contribution of -137GC genotypes to genetic susceptibility to type 1 diabetes differs depending on the combination of IL-18 promotor gene haplotypes. The study about IL-16 Promoter gave the first evidence of an association between type 1 daibetes and polymorphis in the promoter of IL-18 gene.
Recently it was reported Nicoletti et al. that interleukin (IL)-18 serum levels are increased in the subclinical stage of type 1 diabetes in first-degree relatives of type 1 diabetic patients. IL-18, which is predominantly secreted by activated monocytes/macrophages, is a pleiotropic cytokine involved in the regulation of innate and acquired immune response, playing a key role in autoimmune, inflammatory, and infectious diseases. IL-18 is a proinflammatory factor and, in synergy with IL-12, promotes development of Th1 lymphocyte response by induction of -interferon (IFN- ) production, modulates activity of NK cells, increases tumor necrosis factor- and IL-1 production by macrophages, up regulates the expression of adhesion molecules, and induces nitric oxide production in the area of chronic inflammation. Role of IL-18 in the animal model of autoimmune diabetes was first reported by Rothe and colleagues, who found that increased IL-18 mRNA production by macrophages followed by increased IFN- levels is associated with an active stage of autoimmune diabetes in NOD mice.
It was recently shown that in the course of insulitis, IL-18 is also produced by pancreatic B-cells, which induce the exacerbation of inflammation. It was found that systemic administration of exogenous IL-18 to NOD mice suppresses the development of diabetes, probably due to down regulation of the pro- inflammatory activities of the innate immune system. Type 1 diabetes in humans is believed to be a Th1 lymphocyte-mediated disease, and both environmental and genetic factors play a role in its pathogenesis. There have been no published studies that have estimated the role of IL-18 promoter polymorphisms in the predisposition to type 1 diabetes in humans. IL-18 gene locus on chromosome 11q22.2-q23.3 has not been mapped by whole-gene scan studies as a region conferring major susceptibility to type 1 diabetes.Studies were made to find its role as a candidate for type 1 susceptibility gene, since the genetic association between IL-18 and destructive insulitis has been suggested in the animal model of autoimmune diabetes. In the NOD mouse, which spontaneously develops autoimmune diabetes, IL-18 gene position is located within the Idd2 interval on mouse chromosone 9 and has been suggested as a candidate gene for the Idd2 susceptibility gene. Moreover, it was recently shown that IL-18 acts in synergy with IL-12 in enhancing IFN- mRNA transcription and also that IL12p40 gene locus is associated with type 1 diabetes (IDDM18). Results from the studies made suggest the first evidence for the association between type 1 diabetes and polymorphisms in the promoter of IL-18 gene. Giedriatis et al. speculated that there may be a possible link between G C polymorphism at position -137 of the promoter of IL-18 gene and the development of multiple sclerosis, but the higher frequency of allele C at position -137 observed in their study in subjects with sclerosis multiplex did not achieve statistical significance. However polymorphism at positions -137 and -607 in the promoter region of IL-18 gene appears to be functional, with increased transcriptional activity attributed to the variant alleles. Studies by Giedriatis et al, suggest that the increased of IL-18 in the preclinical stage of type 1 diabetes compared to the healthy control subjects found previously by Nicoletti et al are the result of a genetic predisposition for the upregulated expression of the promoter of IL-18 gene, resulting in Th1-directed immune response rather than only the secondary result of monocyte/macrophage activation during the autoimmunity.
Presence of the C allele at position -137 of the IL-18 promoter could have a role in the predisposition to type 1 diabetes. The studies study suggests that in the Polish population, subjects carrying AA genotype at position -607 of the promoter of IL-18 gene have a low risk of type 1 diabetes development.
| Brief Genetic Reports |
A polymorphism in the interleukin 12B gene was recently reported to be associated with type 1 diabetes in 422 Australian and British families. We analyzed the same polymorphism in 470 Italian type 1 diabetic patients and 544 matched control subjects were analyze and no evidence of association with the disease.
Type 1 diabetes is caused by the immune-mediated destruction of the insulin-secreting pancreatic �-cells, which is under polygenic control. Several putative diabetes loci have been sorted by whole genome-linkage analyses or by directly testing an a priori hypothesis on selected genes or genomic regions. Recently linkage with chromosome 5q33-34 was detected in 249 sib-pairs from 187 British and Australian multiplex families Two noncoding polymorphisms of the interleukin 12B (IL12B) gene, mapping in the linked region, were strongly associated (P = 10-5) with the disease in the subset of siblings sharing two 5q33 identical-by-descent alleles. The polymorphisms were an AT repeat in intron 4 and an A-C substitution in the 3' untranslated region (UTR). Preferential transmission of the A allele (allele 1 in the original study) of the 3' UTR variation was replicated in an independent sample of 235 Australian type 1 diabetic simplex families (P = 10-4). Differences in the IL12B mRNA levels were related to the 3' UTR genotype. Large case-control study was performed in the continental Italian population. The A-C 3' UTR variation was typed in 470 unrelated type 1 diabetic patients and 544 unrelated control subjects. Allele, phenotype, and genotype frequencies did not significantly differ between type 1 diabetic patients and control subjects A slight, not significant, increase of the C allele (+1.9%) was observed in patients compared with unaffected subjects. Result goes in the opposite direction of that reported by Morahan et al, who showed a preferential transmission to diabetic patients of the more frequent A allele. No difference was detected in the frequencies of the 3' UTR alleles when the patients were stratified for each of the HLA high-risk (DR3/DR4, DR4/DR4, DR3/DR3, and DR4/DRX) and low-risk (DR3/DRX and DRX/DRX) genotypes. Sex or age at onset (before or after 15 years) did not affect the IL12B frequencies.
Endeavor toward the discovery of the primary cause of Type I DM must be supported thouroughly. This studies will pave the way for disease prevention and for a cause-effective management. The contributions of molecular biology towards new discoveries and better understanding of diseases makes the health care system more effective. I firmly believe that for better disease prevention students and medical practitioners should be equipped with the knowledge of the language of biochemistry.
American Diabetes Association, ATTN Customer Service, 1701 North Beauregard Street, Alexandria, VA 22311 Call (800-DIABETES) or (800-232-3472) Or on the Internet (http://www.diabetes.org/ ) This is the primary source for information on diabetes.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH, Building 31, Room 9A04, 31 Center Drive, MSC 2560, Bethesda, MD 20892-2560. Call (301) 654-3327 Or on the Internet (http://www.niddk.nih.gov/) A source of information for research advances and clinical trials currently underway. For those who have relatives with diabetes and may be at risk and are interested in participating in a trial on prevention, call (800-Halt-DM-1).
Juvenile Diabetes Research Foundation, International, 120 Wall Street, 19th floor, New York, NY 10005-4001 Call (800) 533-CURE (2873), or (212) 785-9500 Or on the Internet (http://www.jdrf.org/ )
National Eye Health Education Program, National Eye Institute, 2020 Vision Place, Bethesda MD 20892-3655 Call (301-496-5248) or (800-869-2020) Or on the Internet (http://www.nei.nih.gov/ )
Medic Alert, 2323 Colorado Ave., Turlock, CA 95380 Call (888-633-4298) Or on the Internet (http://www.medicalert.org/ ) This organization provides bracelets or neck chain emblems with critical personal medical information.
American Dietetic Association, 216 West Jackson Boulevard, Suite 800, Chicago IL 60606-6995. Call (312/899-0040) Or on the Internet (http://www.eatright.org/ ) This organization provides names of local dietitians and programs through their Dietitian Referral Hotline: Call (800-366-1655) from 9AM to 4PM.
For customized answers to food and nutrition questions: Call (900-225-5267) Charge is $1.95 for the first minute and $.95 for each additional minute.
The Islet Foundation, 61 Dalewood Rd., Toronto, Ont. Canada M4P2N4 Call (416-486-8784) or on the Internet (http://www.islet.org/ )
Inhale Therapeutic Systems Call (800-438-1985) or (650-631-3100) for information on the adult trial of the Exubera insulin inhaler. Or on the Internet (http://www.inhale.com/ )
On the Internet:Find clinical trials for Edmonton protocol on islet transplantation. (http://www.insulinfree.org/articisl.htm )
Find clinical trials for Diabetes Prevention (http://www.niddk.nih.gov/patient/dpt_1/dpt_1.htm )
Informational site for professionals (http://www.diabetesincontrol.com/ )
Very good site for diabetes products (http://www.diabetesnet.com/ )
Compare Insulin Pumps (http://www.diabetesnet.com/insulin_pump_models.html )
Well-reviewed software for managing diet and glucose control (http://www.healthviewdiabetes.com/ )