Assocation Between Variation in the Actin-Binding Gene Caldesmon and Diabetic Nephropathy in Type 1 Diabetes

Dysfunction of the actin cytoskeleton is a key event in the pathogenesis of diabetic nephropathy. We previously reported that certain cytoskeletal genes are upregulated in mesangial cells exposed to a high extracellular glucose concentration. One such gene, caldesmon, lies on chromosome 7q35, a region linked to nephropathy in family studies, making it a candidate susceptibility gene for diabetic nephropathy. We screened all exons, untranslated regions, and a 5-kb region upstream of the gene for variation using denaturing high-performance liquid chromatography technology. An A>G single nucleotide polymorphism (SNP) at position -579 in the promoter region was associated with nephropathy in a case-control study using 393 type 1 diabetic patients from Northern Ireland (odds ratio [OR] 1.38, 95% CI 1.02–1.86, P = 0.03). A similar trend was found in an independent sample from a second center. When the sample groups were combined (n = 606), the association between the -579G allele and nephropathy remained significant (OR 1.35, 1.07–1.70, P = 0.01). The haplotype structure in the surrounding 7-kb region was determined. No single haplotype was more strongly associated with nephropathy than the -579A>G SNP. These results suggest a role for the caldesmon gene in susceptibility to diabetic nephropathy in type 1 diabetes.

Interleukin 18 promoter polymorphisms are not strongly associated with type 1 diabetes in a UK population

Interleukin 18 (IL18) is a proinflammatory cytokine whose levels are increased in the subclinical stage of insulin-dependent (type I) diabetes mellitus. Previous case-control studies have reported associations between IL18 -607C>A and -137G>C promoter polymorphisms and type I diabetes. We performed case-control and family-based association studies employing Pyrosequencing to assess if these IL18 polymorphisms are also associated with the development of type I diabetes in the Northern Ireland population. The chi2 analysis of genotype and allele frequencies for the IL18 polymorphisms in cases (n=433) vs controls (n=426) revealed no significant differences (P>0.05). Assessment of allele transmission distortion from informative parents to affected offspring also failed to confirm previously reported associations. Stratification of these analyses for age-at-onset and HLA-DR type did not reveal any significance associations. In conclusion, our data do not support the strong positive associations of IL18 promoter polymorphisms with type I diabetes reported in previous smaller studies.

Is childhood type 1 diabetes a wealth-related disease? An ecological analysis of European incidence rates

Aims/Hypothesis: To describe the epidemiology of childhood-onset Type 1 (insulin-dependent) diabetes in Europe, the EURODIAB collaborative group has established prospective, geographically-defined registers of children diagnosed under 15 years. A total of 16,362 cases were registered by 44 centres during the period 1989-1994. The registers cover a population of approximately 28 million children with most European countries represented. Methods In most centres a primary and a secondary source of ascertainment were used so that the completeness of registration could be assessed by the capture-recapture method. Ecological correlation and regression analyses were used to study the relationship between incidence and various environmental, health and economic indicators. Findings: The standardised average annual incidence rate during the period 1989-94 ranged from 3.2 cases per 100,000 per annum in the Former Yugoslavian Republic of Macedonia to 40.2 cases per 100,000 per annum in Finland. Indicators of national prosperity such as infant mortality (r= -0.64) and gross domestic product (r= 0.58) were most strongly and significantly correlated with incidence rate, and previously-reported associations with coffee consumption (r= 0.51), milk consumption (r= 0.58) and latitude (r= 0.40) were also observed. Conclusion/Interpretation: The wide variation in childhood type 1 diabetes incidence rates within Europe could be partially explained by indicators of national prosperity. These indicators could reflect differences in environmental risk factors such as nutrition or lifestyle that are important in determining a country's incidence rate.

Co-inheritance of two rare genodermatoses (Papillon Lefevre syndrome and Oculocutaneous Albinism Type 1) in two families

The co-occurrence of two rare recessive genetic conditions in apparently unrelated individuals or families is extremely rare. Two geographically distant and apparently unrelated families were identified in which individuals were simultaneously affected by two rare recessive mendelian syndromes, Papillon-Lefevre syndrome and type 1 oculocutaneous albinism. The families were tested for mutations in the causative genes, cathepsin C (CTSC) and tyrosinase (TYR), respectively, by direct sequencing. To assess the relationship of the two families, both families were tested for polymorphisms at eight microsatellite markers spanning both CTSC and TYR loci. Independent mutations (c.318-1G-->A and c.817G-->C/p.W272C) were identified in CTSC and TYR, respectively, that were shared by the affected individuals in both families. The two affected genes lie close together on chromosome bands 11q14.2-14.3, and studies with linked genetic markers suggested that the families shared a small chromosomal segment carrying both mutations that had been transmitted intact from a remote common ancestor. The co-occurrence of the two rare diseases in multiple families depends on their shared chromosomal location, but not on any shared pathogenic mechanism.