95 research outputs found
Insulin dependent diabetes mellitus (IDDM): 12th International Histocompatibility Workshop study
No full textCTLA-4 as a genetic determinant in autoimmune Addison's disease
No full textIn common with several other autoimmune diseases, autoimmune Addison’s disease (AAD) is thought to be caused by a combination of deleterious susceptibility polymorphisms in several genes, together with undefined environmental factors and stochastic events. To date, the strongest genomic association with AAD has been with alleles at the HLA locus, DR3–DQ2 and DR4. The contribution of other genetic variants has been inconsistent. We have studied the association of 16 single-nucleotide polymorphisms (SNPs) within the CD28–CTLA-4–ICOS genomic locus, in a cohort comprising 691 AAD patients of Norwegian and UK origin with matched controls. We have also performed a meta-analysis including 1002 patients from European countries. The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10–1.66), P=0.004), but not in UK patients. The same allele is associated with AAD in the total European population (OR=1.37 (CI 1.13–1.66), P=0.002). A three-marker haplotype, comprising PROMOTER_1661, rs231726 and rs1896286 was found to be associated with AAD in the Norwegian cohort only (OR 2.43 (CI 1.68–3.51), P=0.00013). This study points to the CTLA-4 gene as a susceptibility locus for the development of AAD, and refines its mapping within the wider genomic locus
Common variants in the regulatory region of the insulin gene are associated with fasting plasma insulin levels in juvenile obesity
No full textHuman chromosome 18q12-q21 and distal rodent chromosome 18 are associated with multiple autoimmune phenotypes.
No full textCost-effectiveness of Implementing the Interventions for Diabetes Prevention and Control in the Community and Military Settings
No full textDiabetes is an increasingly prevalent and costly cause of morbidity and mortality, representing not only a major clinical care concern but an immense public health challenge. In 2010, diabetes affected 25.8 million Americans – 8.3% of the US population and 26.9% of those aged 65 years or older. People with diabetes are disproportionately affected by eye and renal disease, non-traumatic amputations, and cardiovascular disease, which result in significant health-care costs of 42,179-42,051-17,186 and 7,777-18,263-$29,331 per QALY gained. Generally, these results were robust in sensitivity analyses. This dissertation provided supporting evidence that compared with usual care or PROV, the CCM for secondary and tertiary diabetes prevention in the community and military settings as well as the ODPP for primary diabetes prevention in the primary care setting appear to be economically reasonable interventions for diabetes management. These findings are of public health significance as the economic evaluation conducted in this dissertation is an important component of evidence-based clinical and public health practices, which is a decision making aid to help assess the relative value of alternative interventions that can enhance clinical care and public health
Vitamin D status and pathway genes in five European autoimmune Addison\u27s disease cohorts
No full textObjective: While vitamin D regulates immune cells, little is known about it in autoimmune Addison\u27s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. Design: Cross-sectional study. Methods: A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). Results: Vitamin D deficiency (25(OH)D3 10-20 ng/mL) was highly prevalent in AAD patients (34-57%), 5-22% were severely deficient (<10 ng/mL), 28-38% insufficient (20-30 ng/mL) and only 7-14% sufficient (>30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1
7 10-5/< 1
7 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. Conclusion: Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year
Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11
No full textA region of linkage to type 1 diabetes has been defined on human chromosome 10p11-q11 (IDDM10; P = 0.0007) using 236 UK and 76 US affected sibpairs and al cM resolution microsatellite marker map, Analysis by the transmission disequilibrium test (TDT) in 1159 families with at least one diabetic child, from the UK, the US, Norway, Sardinia and Italy provided additional support for linkage at D10S193 (P = 0.006, P-c = 0.17), Notably, 5.1 cM distal to D10S193, marker D10S588 also provided positive TDT results (P = 0.009, P-c = 0.25) but the allele under analysis was also preferentially transmitted to nonaffected siblings (P = 0.0008, P-c = 0.02), This allele was positively associated in an independent UK case control study and, importantly, was neutrally transmitted in control CEPH families, These results suggest a type 1 diabetes susceptibility locus on chromosome 10p11-q11 (provisionally designated IDDM10) and demonstrate the necessity of analysis of non affected siblings in disease families, as well as analysis of control families
Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type I diabetes.
No full textBACKGROUND: One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18).
RESULTS: Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls.
CONCLUSION: None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied
Vitamin D status and pathway genes in five European autoimmune Addison's disease cohorts
No full textObjective: While vitamin D regulates immune cells, little is known about i t in autoimmune Addison's disease (AAD). We investigated the vitamin D status in AAD patients from five Euro pean populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism an d pathway genes. Design: Cross-sectional study. Methods: A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). Results: Vitamin D deficiency (25(OH)D3 10-20 ng/mL) was highly prevalent in AAD patients (34-57%), 5- 22% were severely deficient (30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD ( P = 0.03/0.003 and P = 1 × 10- 5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/ mL) and synthesize less 1,25(OH)2D3. Conclusion: Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vit amin D requirements throughout the year
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