Genetics of type 1 diabetes
AK Steck, MJ Rewers - Clinical chemistry, 2011 - academic.oup.com
AK Steck, MJ Rewers
Clinical chemistry, 2011•academic.oup.comBACKGROUND Type 1 diabetes, a multifactorial disease with a strong genetic component,
is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus
maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene
markers have been confirmed. CONTENT Although HLA class II alleles account for up to
30%–50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk
with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other …
is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus
maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene
markers have been confirmed. CONTENT Although HLA class II alleles account for up to
30%–50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk
with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other …
BACKGROUND
Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.
CONTENT
Although HLA class II alleles account for up to 30%–50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide–polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed.
Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband.
SUMMARY
Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.
Oxford University Press