The genetics of type 1 diabetes
There’s this question I’ve been asked many times: “Type 1 diabetes? Is that genetic?”
I was asked it again a couple of weeks ago and it caught me off-guard so I don’t think I was being quite as precise as I’d have liked to be – by having now written this post, I hope that I’ll do better next time (oh yes, there’ll be a next time…). Before going any further I should probably note here that even though I don’t know much about genetics, I estimate that I do know (/significantly?) more than most people who would choose to ask such a question: Having been exposed to stuff like Khan Academy, Razib Khan’s blog, Wikipedia (way too much to link to here), Russell, Dawkins and Majerus for instance means that I know the difference between a recessive allele and a linkage disequilibrium. It also means that I’m very inclined to answer a question like that one by asking another question: “What do you mean by ‘is it genetic?'” Genetics is complex stuff and there are many kinds of genetic disorders. I’ve tended to assume that people who ask do so more because of the implied blame-angle inherent in the question (‘it’s not your own fault you’re sick, right?’) than because of their deep interest in the disease etiology of type 1 diabetes – but I shouldn’t let that affect the way I respond, given that a reasonably clear answer to the question (…I assume they think they are asking) exists today (wikipedia):
“Type 1 diabetes is partly inherited and then triggered by certain infections, with some evidence pointing at Coxsackie B4 virus. There is a genetic element in individual susceptibility to some of these triggers which has been traced to particular HLA genotypes (i.e., the genetic “self” identifiers relied upon by the immune system). However, even in those who have inherited the susceptibility, type 1 diabetes mellitus seems to require an environmental trigger.”
So the simple version is that ‘genetics’ increases disease susceptibility and an infection then triggers the disease process. Here’s the abstract of a new study, Genetics of Type 1 Diabetes, by Steck and Rewers, providing a little more detail:
“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.”
“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” – in plain English, this means that almost half of all type 1 diabetics who show disease development before the age of 5 have this specific high-risk genotype. Note also how complex this disease is in terms of the genetics – ‘more than 40 non-HLA susceptibility gene markers have been confirmed’. Maybe some of them are just flukes due to p-value hunting, but that’s a lot of genes impacting disease risk.
Steno has some stuff in Danish here if people are interested. According to their numbers, if the mother has type 1 diabetes there’s a 2% risk that her child will have the disease. If the father has the disease the risk is 5%. Lægehåndbogen states that for monozygotic twins, if one twin develops the disease the risk that the other twin will also get it is 50%.