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Extreme genetic risk for type 1A diabetes in the post-genome era

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Abstract

A series of genes and loci influencing the genetic risk of type 1A (immune-mediated) diabetes are now well characterized. These include genes of the major histocompatibility complex (MHC), polymorphisms 5′ of the insulin gene, and PTPN22, as well as more recently defined loci from genome-wide association studies. By far the major determinants of risk for type 1A diabetes are genes within or linked to the MHC and in particular alleles of class II genes (HLA-DR, DQ, and DP). There is evidence that MHC class I alleles contribute and there are additional MHC-linked influences such that for a major subset of relatives of patients there is a risk as high as 80% for siblings, and for the general population a risk as high as 20% can be defined at birth just by analyzing the MHC. We believe the search for additional MHC loci will require analysis of the remarkable long-range identity (up to 9 million base pairs) of extended MHC haplotypes. Current prediction algorithms will likely be greatly improved for the general population when the additional contributing loci of the MHC are defined.

Introduction

Multiple genetic syndromes are associated with the development of immune mediated diabetes of man. In particular, there are two rare “monogenic disorders” that provide important insight into pathways leading to autoimmune destruction of islet beta cells: IPEX (Immune dysfunction, Polyendocrinopathy, Enteropathy, X-linked) and APS-I (Autoimmune Polyendocrine Syndrome Type 1) syndromes. IPEX syndrome results from mutations of the FOXP3 gene leading to a lack of a major population of regulatory T lymphocytes with resulting overwhelming autoimmunity and development of diabetes in approximately 80% of the children with this disorder. Diabetes can occur as early as two days of age. For the APS-I syndrome, and the related mouse model with mutations of the AIRE (Autoimmune Regulator) gene, it is hypothesized that abnormalities in expression of peripheral antigens within the thymus and/or abnormalities of negative selection result in widespread autoimmunity. Approximately 18% of children with this syndrome develop type 1A diabetes.

The more common type 1A diabetes is a “polygenic” disorder primarily determined by genes within or linked to the major histocompatibility complex (MHC).

Section snippets

Multiple genes determining susceptibility

Type 1A diabetes has a strong genetic component. First degree relatives have a higher risk for type 1A diabetes than the general population, and siblings have a higher risk than offspring. The sibling relative risk for type 1A diabetes is 15 (λS, a measure of familial clustering) [1].

Monozygotic twins of patients with type 1A diabetes

In a study of 44 monozygotic and 183 dizygotic twin pairs from the Finnish Twin Cohort the 10-year progression rate to diabetes for monozygotic (MZ) twin-mates was 33%, whereas dizygotic (DZ) twin-mates only had a risk of 3% [53]. The study reported probandwise concordance rates of 42.9% for MZ twins and 7.4% for DZ twins [53]. In addition, they reported that an additive model was the best fit for type 1A diabetes risk, suggesting that 88% of phenotypic variance in type 1A diabetes is due to

Environmental factors affecting type 1A diabetes susceptibility

There is compelling evidence that the incidence of type 1A diabetes is doubling approximately every 20 years in developed countries [58], [59], and thus environmental factors are of importance. Environmental determinants of type 1A diabetes are likely to be common, given the ability to define high genetic risk (perhaps similar to celiac disease with almost universal exposure to a dietary inciting factor, gliadin) [60]. A recent report implicates decreased omega-3 polyunsaturated fatty acid

Conclusion

With the advent of whole-genome SNP genotyping studies in the past several years, many additional non-MHC loci have been identified that contribute to type 1A diabetes risk. In addition, non-DR/DQ loci within the MHC have been identified that contribute to prediction of type 1A diabetes in the general population (i.e. HLA-DP). These will allow for the potential to identify individuals at extreme risk for type 1A diabetes at birth, and currently clinical trials are forming to prevent disease

Acknowledgements

This work is supported by grants from the National Institutes of Health (DK32083, DK55969, DK62718, AI50864, DK32493, DK064605), the Diabetes Endocrine Research Center grant from the National Institute of Diabetes and Digestive and Kidney Diseases (P30 DK57516), the American Diabetes Association, the Juvenile Diabetes Foundation (JDRF1-2006-16), and the Children's Diabetes Foundation.

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