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Clinical Gems

Our clinical gems come from the top selling medical books, and text books because knowledge is everything when it comes to diabetes.

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #168: Molecular Genetics of Type 1 Diabetes Part 5

Linkage studies identify regions of the genome that are shared more frequently than would be expected by chance by relatives affected by a particular disease. Most studies analyze affected sibling pairs and utilize genetic markers that are scattered throughout the genome at moderate density, typically microsatellites. A significant excess of allele sharing identical by-descent (IBD) in affected sibpairs suggests that the region containing the marker locus also contains a disease susceptibility locus. The first linkage scan for T1DM identified 20 chromosomal regions with suggestive evidence of linkage to disease, including the HLA and INS gene regions.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #167: Molecular Genetics of Type 1 Diabetes Part 4

The CTLA4 gene on chromosome 2q33.2 encodes a transmembrane co-receptor expressed on the surface of T cells. This functions as a negative regulator of T-cell activation via interaction with the B7 molecule on antigen-presenting cells (Figure 30.3). The G allele of the +49A/G SNP in exon 1 of CTLA4 has been implicated as a susceptibility marker for T1DM, but was rejected as a causal SNP by a fine-mapping study, which showed that its effect could be explained by more strongly associated variants in a 6.1 kb noncoding region, 3′ of the gene.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #166: Molecular Genetics of Type 1 Diabetes Part 3

Other HLA-encoded susceptibility determinants: The DR and DQ genes cannot completely explain the association between T1DM and the HLA gene region. Teasing out the contribution of other HLA loci, however, is complicated by the high level of linkage disequilibrium within the region, combined with the strong effects of DR and DQ. A number of different approaches have been employed to address this issue, including the analysis of case/control data matched for specific DR-DQ combinations, investigation of the transmission to affected and unaffected offspring of heterozygous markers from parents homozygous for DR-DQ alleles, conditional logistic regression and conditional haplotype analysis.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #165: Molecular Genetics of Type 1 Diabetes Part 2

HLA-DR and -DQ: The highest risk of T1DM is conferred by heterozygosity for the DRB1*0301-DQA1*0501-DQB1*0201 and DRB1*04-DQA1* 0301-DQB1*0302 haplotypes, referred to as the DR3.DQ2/DR4.DQ8 genotype. This allelic combination is carried by 30–40% of individuals with T1DM, but only around 2.5% of the general population [3]. A recent meta-analysis of multiple ethnic groups suggested that this translates into an OR value greater than 16, an unusually large odds ratio for a complex disease [14]. This is consistent with an earlier study which estimated that the risk of developing T1DM was between 1 in 15 and 1 in 25 among those with the DR3.DQ2/DR4.DQ8 genotype, compared with 1 in 300 in the general population [15]. High risk is also conferred by the DR3.DQ2/DR3.DQ2 and DR4.DQ8/DR4.DQ8 homozygous genotypes (OR = 6.32 and OR = 5.68, respectively, from meta-analysis).

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #164: Molecular Genetics of Type 1 Diabetes Part 1

Type 1 diabetes (T1DM) is a chronic autoimmune disease in which the beta cells of the islets of Langerhans are selectively destroyed, resulting in insulin deficiency and hyperglycemia. The disease develops in genetically susceptible individuals, most likely as a result of an environmental trigger. T1DM has an uneven geographical distribution; disease prevalence is highest in populations of white European origin and lowest in those of East Asian descent. A marked gradient in disease risk also exists in Europe, with higher prevalence of T1DM in northern countries, particularly Finland, compared with areas around the Mediterranean. This pattern could be attributed to genetic differences between the populations or to the presence/absence of environmental triggers.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #163: Immunopathogenesis of Type 1 Diabetes in Western Society Part 6

The relationship between pathogenic factors and beta-cell destruction remains poorly understood. Longitudinal studies of newborns and children at genetic risk and follow-up of at-risk first-degree relatives in natural history studies link the triggering of autoimmunity with the appearance of autoantibodies to one or more islet autoantigens; individuals with multiple autoantibodies have higher risk of diabetes progression.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #161: Immunopathogenesis of Type 1 Diabetes in Western Society Part 4

Genes and environment: a moving target? Studies from multiple populations have shown shifts of the typical HLA class II gene associations during the last few decades. Indeed, fewer patients carry the high risk heterozygous HLA-DR/DQ genotype, except among younger children [59–63], in whom the disease is becoming more common [4]. In contrast, more patients now carry moderate risk HLA types and genotypes. Such shifts in HLA associations may be explained by stronger environmental pressures that enhance HLA-mediated genetic predisposition and/or broaden the spectrum of diabetogenic gene–environment interactions. Viruses, and especially enteroviruses, rank at the top of the list of environmental factors that have been linked to T1DM.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #160: Immunopathogenesis of Type 1 Diabetes in Western Society Part 3

Insulin itself is a prototypical TRA, its synthesis being virtually restricted to pancreatic beta cells. Thymic insulin production is critical for establishing self-tolerance to beta cells; simply abolishing insulin expression in the thymus leads to the rapid onset of autoimmune diabetes even in mice lacking a diabetogenic genetic background [26]. In humans, thymic insulin expression is modulated by allelic variation and epigenetic effects at the insulin gene locus; this effect is largely mediated by a polymorphic variable nucleotide tandem repeat (VNTR) sequence.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #159: Immunopathogenesis of Type 1 Diabetes in Western Society Part 2

Genetic predisposition is an important component of the multifactorial pathogenesis of T1DM. Although often diagnosed in individuals with no known family history of T1DM, the disease is about 15 times more common in siblings of a patient than in the general population. Siblings have an average risk of 6%, although individual risk varies significantly in relation to the extent of sharing predisposing genes with the proband, which allele variants are shared, and other factors. The risk to the offspring of affected mothers and fathers is about 2–3% and 6–7%, respectively. Among twins, the observed disease concordance rates are approximately 8–10% in dizygotic twins and, with extended follow-up, more than 60% in monozygotic twins.

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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #158: Immunopathogenesis of Type 1 Diabetes in Western Society Part 1

Introduction: Type 1 diabetes (T1DM), formerly referred to as insulin dependent diabetes mellitus (IDDM) and juvenile diabetes, is considered a chronic autoimmune disease. Over time, the disease process results in the virtually complete elimination of pancreatic beta cells and lifelong insulin deficiency. In turn, patients become dependent on daily insulin injections to maintain an acceptable level of metabolic control. It is widely accepted that T1DM is a complex, multifactorial disease in which genetic predisposition and environmental exposures promote the triggering of multiple autoimmune responses against beta cells.

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