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Friday, February 6, 2009

John Todd, University of Cambridge - “The Identification of Susceptibly Genes in Common Diseases Using Ultra-Deep Sequencing”

Type 1 diabetes: a common multifactorial disease. One of many immune-mediated disease that in total affect ~5% of the population. Distinct epidemiological & clinical features. Genome wide association success... but.. What's next?

There is a pandemic increase in type 1 diabetes. Since 1950's, there's an abrupt 3% increase each year. Age at diagnosis has been decreasing. Now 10-15% are diagnosed under 5 years old.

There is a strong north-south and seasonality bias to it. Something about this disease tracks with seasons.. vitamin D? Viruses?

Pathology: massive infiltration of beta cell islets.

In 1986: 1000 genotypes. In 1996: multiplexing allowed 1,000,000 genotypes, now allows full genome association.

Crones and diabetes are “the big winners” from the welcome trust – most heritable and easily diagnosed of the seven diseases originally selected.

Why do people get type 1 diabetes. Large effect at the HLA classII = immune recognition of beta cells. 100's of other genes in common and rare alleles of SNPs and SV in immune homesostatsis.

Disease = a threshold os susceptibility alleles and a permissive environment.

What will the next 20 years look like: National registers of diseases. (linkage to records and samples where available.) Mobile phone text health, identificaion of causal genes and their patheways (mechanisms), natural history of disease susceptibility and newborn susceptibility by their TID gneetic profile. What dietary, infectious, gut flora-host interactions modify these and which can we affect?

Can we slow the disease spread down?

There are 42 chromosome regions in type 1 diabetes, with 96 genes. Which are causal? What are the pathways? What are the rare variants? Geneome-wide gene-isoform expression. Genotype to protein information.

Ultra-deep sequencing study: 480 patients and 480 controls, PCR of exons and did 454. 95% probability of allele at .3%.

Found one hit: IFIH1. Followed up in 8000+ patients – found this gene was not associated with disease, but with protection from disease! Knock it out, and you become susceptible!

It's possible that this is associated with protection of viral infections. The 1000 genome project may also help give us better information for this type of study.

The major prevention trial to prevent type 1 diabetes is ingestion of insulin to restore immune tolerance to insulin.

Do we know enough about type 1 diabetes?

Maybe one of the pathways in type1 diabetes is a defect in oral tolerance?

Type 1 diabetes co-segregates with stuff like ciliac disease (wheat tolerance.) One of the rare auto immune diseases for which we know the environmental factor (gluton). Failure of gut immune to be tolerant of glutin.

The majority of loci between type 1 diabetes and cilliac are similar. (sister diseases)

Compared genes in Type 1 and Type 2 diabetes – they are not overlapping. No molecular basis for the grouping of these two diseases.

Common genotypes are ok for predicting type 1. ROC curve presented. Can identify population that is likely to develop T1D, but.... how do you treat?

Going from genome to treatment is not obvious, tho.

Healthy volunteers – recallable by genotype, age, etc (Near Cambridge).

Most susceptibility variants affect gene regulation & splicing. Genome wide expression analysis of mRNA and isoforms in pure cell population. Need to get down to lower volume of input material and lower costs.

Using high throughput sequencing with allele-specific expression(ASE). Looking or eQTLs for disease and biomarkers. Doing work on other susceptibility genes. (Using volunteers recallable by genotype).

Looking for new recruits: Chair of biomedical stats, head of informatics, chair of genomics clinical....



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