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      Genes Involved in Type 1 Diabetes: An Update

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          Abstract

          Type 1 Diabetes (T1D) is a chronic multifactorial disease with a strong genetic component, which, through interactions with specific environmental factors, triggers disease onset. T1D typically manifests in early to mid childhood through the autoimmune destruction of pancreatic β cells resulting in a lack of insulin production. Historically, prior to genome-wide association studies (GWAS), six loci in the genome were fully established to be associated with T1D. With the advent of high-throughput single nucleotide polymorphism (SNP) genotyping array technologies, enabling investigators to perform high-density GWAS, many additional T1D susceptibility genes have been discovered. Indeed, recent meta-analyses of multiple datasets from independent investigators have brought the tally of well-validated T1D disease genes to almost 60. In this mini-review, we address recent advances in the genetics of T1D and provide an update on the latest susceptibility loci added to the list of genes involved in the pathogenesis of T1D.

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          Most cited references97

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          Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.

          The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up)
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            Shared and distinct genetic variants in type 1 diabetes and celiac disease.

            Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects. Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease. A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases. 2008 Massachusetts Medical Society
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              Sequence and characterization of a coactivator for the steroid hormone receptor superfamily.

              A yeast two-hybrid system was used to identify a protein that interacts with and enhances the human progesterone receptor (hPR) transcriptional activity without altering the basal activity of the promoter. Because the protein stimulated transactivation of all the steroid receptors tested, it has been termed steroid receptor coactivator-1 (SRC-1). Coexpression of SRC-1 reversed the ability of the estrogen receptor to squelch activation by hPR. Also, the amino terminal truncated form of SRC-1 acted as a dominant-negative repressor. Together, these results indicate that SRC-1 encodes a coactivator that is required for full transcriptional activity of the steroid receptor superfamily.
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                Author and article information

                Journal
                Genes (Basel)
                Genes (Basel)
                genes
                Genes
                MDPI
                2073-4425
                16 September 2013
                September 2013
                : 4
                : 3
                : 499-521
                Affiliations
                [1 ]Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; E-Mails: bakay@ 123456email.chop.edu (M.B.); pandeyr@ 123456email.chop.edu (R.P.)
                [2 ]Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
                Author notes
                [†]

                Those authors contributed equally to this work.

                [* ] Author to whom correspondence should be addressed; E-Mail: hakonarson@ 123456email.chop.edu ; Tel.: +1-267-426-0088; Fax: +1-267-426-0363.
                Article
                genes-04-00499
                10.3390/genes4030499
                3924830
                24705215
                d1f5e5e9-a1b0-4035-ae3f-0d92bc848e29
                © 2013 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                : 31 July 2013
                : 26 August 2013
                : 05 September 2013
                Categories
                Review

                type 1 diabetes (t1d),genome-wide association studies (gwas),immune system,susceptibility loci,natural killer (nk) cells,pancreatic β-cells

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