Linkage and Association With Type 1 Diabetes on Chromosome 1q42

Ewens, Kathryn G.; Johnson, Lindsey N.; Wapelhorst, Beth; O’Brien, Kristin M.; Gutin, Sarah A.; Morrison, V. Anne; Street, Craig; Gregory, Simon G.; Spielman, Richard S.; Concannon, Patrick

doi:10.2337/diabetes.51.11.3318

Cited by 15 publications

(8 citation statements)

References 23 publications

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“…In a combined analysis of animal model and human linkage data from a number of autoimmune diseases, chromosome 18q12-q21 demonstrated evidence of linkage, which has now been supported by the analysis of congenic strains in NOD mice (48). There was no support for loci on chromosome 18 at P Ͻ 0.05 in the current study.…”

Section: ϫ5contrasting

confidence: 53%

Type 1 Diabetes

Concannon¹,

Erlich²,

Julier³

et al. 2005

Diabetes

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218

176

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Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [ S ] ϳ 15).Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific S ϳ 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] ϳ 1.9), CTLA4 (chromosome 2q33, allelic OR ϳ 1.2), and PTPN22 (chromosome 1p13, allelic OR ϳ 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P ‫؍‬ 2.0 ؋ 10 ؊52 ), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10 ؊4 ). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect ( S > 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations. Diabetes 54:2995-3001, 2005

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Section: ϫ5contrasting

confidence: 53%

Type 1 Diabetes

Concannon¹,

Erlich²,

Julier³

et al. 2005

Diabetes

Self Cite

218

176

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“…This region has also been mapped to susceptibility to collagen-induced arthritis (42) and it was linked to murine cerebral malaria (43). Finally, the human equivalent synteny, which lies on distal chromosome 1q, was linked to type 1 diabetes susceptibility (44,45). This region, therefore, seems to be an important one to investigate the genetic basis of autoimmune disorders, notably including type 1 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Functional Analysis of theNkt1Locus Using Congenic NOD Mice

et al. 2006

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Defective invariant natural killer T-cells (iNKT cells) havebeen implicated in the etiology of type 1 diabetes in nonobese diabetic (NOD) mice. In a genome scan of a cross between NOD and C57BL/6 mice, the most significant locus controlling the number of iNKT cells, referred to as Nkt1, was recently mapped to distal chromosome 1. Here, using congenic mice for this chromosomal segment, we definitively demonstrate the existence of Nkt1 and show that introgression of the C57BL/6 allele onto the NOD background improves both the number of iNKT cells and their rapid production of cytokines elicited by ␣-galactosylceramide treatment, explaining at least half of the difference between the NOD and C57BL/6 strains. Using new subcongenic lines, we circumscribed the Nkt1 locus to a 8.7-cM segment, between the NR1i3 and D1Mit458 markers, that notably includes the SLAM (signaling lymphocytic activation molecule) gene cluster, recently involved in murine lupus susceptibility. However, despite a significant correction of the iNKT cell defect, the Nkt1 locus did not alter the course of spontaneous diabetes in congenic mice. Our findings indicate a complex relationship between iNKT cells and autoimmune susceptibility. Congenic lines nonetheless provide powerful models to dissect the biology of iNKT cells.

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“…Previous genetic studies have shown that defective plasmalogen synthesis associates with impaired membrane trafficking [28] although the implications for type 1 diabetes remain to be established [29]. Plasmalogen synthesis-related genes such as DHAPAT clearly need to be evaluated as potential type 1 diabetes susceptibility genes.…”

Section: Resultsmentioning

confidence: 99%

Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse

et al. 2009

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Recent clinical evidence suggests important role of lipid and amino acid metabolism in early pre-autoimmune stages of type 1 diabetes pathogenesis. We study the molecular paths associated with the incidence of insulitis and type 1 diabetes in the Non-Obese Diabetic (NOD) mouse model using available gene expression data from the pancreatic tissue from young pre-diabetic mice. We apply a graph-theoretic approach by using a modified color coding algorithm to detect optimal molecular paths associated with specific phenotypes in an integrated biological network encompassing heterogeneous interaction data types. In agreement with our recent clinical findings, we identified a path downregulated in early insulitis involving dihydroxyacetone phosphate acyltransferase (DHAPAT), a key regulator of ether phospholipid synthesis. The pathway involving serine/threonine-protein phosphatase (PP2A), an upstream regulator of lipid metabolism and insulin secretion, was found upregulated in early insulitis. Our findings provide further evidence for an important role of lipid metabolism in early stages of type 1 diabetes pathogenesis, as well as suggest that such dysregulation of lipids and related increased oxidative stress can be tracked to beta cells.

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Linkage and Association With Type 1 Diabetes on Chromosome 1q42

Cited by 15 publications

References 23 publications

Type 1 Diabetes

Type 1 Diabetes

Genetic and Functional Analysis of theNkt1Locus Using Congenic NOD Mice

Detection of Molecular Paths Associated with Insulitis and Type 1 Diabetes in Non-Obese Diabetic Mouse

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