Li Ka Shing Learning Center (LKSC)
|DATE:||November 8, 2017|
|TIME:||1:30 - 3:00 pm|
|TITLE:||Transcription signature of diabetes risk|
||C Garrison Fathman, Professor of Medicine (Immunology and Rheumatology), Emeritus|
Type 1 diabetes results from the chronic gradual destruction of insulin-secreting beta cells in the pancreas. It is the most common autoimmune disease in children. The pathogenesis of this disease is complex and involves both genetic and environmental factors. There are currently no validated biomarkers that can reliably predict which individuals are susceptible to developing T1D and which individuals will progress to hyperglycemia. Although the presence of serum auto-antibodies to various islet cell antigens (AAs) is currently used to identify at-risk patients, the vast majority (~85%) of single AA+ individuals do not progress to T1D within a 10-year period and there is currently no way to identify which AA+ individuals will progress to hyperglycemia. Certain AAs are only detected during specific stages of disease, and even with the presence of multiple AAs, the cumulative risk of developing T1D over the next 5 years is 50-60%. Thus, based solely on the presence of serum AAs, it is difficult to determine with certainty which individuals will develop hyperglycemia or when this will occur. Similarly, Genome-Wide Association Studies (GWAS) have shown that multiple genes can confer increased susceptibility to developing T1D, but the ability of these genes to predict progression to T1D is poor. The goal of our study is identify gene expression biomarkers in whole blood that are consistently expressed during the early stages of disease development when there is still abundant beta cell mass remaining, and when intervention therapy has the greatest chance of success.
The first aim of our study is to determine if there is a gene expression signature of risk in the whole blood of AA- first-degree relatives (FDRs) of T1D patients, who are at higher risk to develop T1D compared to healthy non-T1D related controls. This is important since 85% of new onset T1D patients have no family history of T1D. These individuals are not monitored for serum AAs, and thus are unaware of their increased risk for developing T1D. The second aim of our study is to determine if there are peripheral blood gene expression biomarkers that could distinguish AA+ (and possibly AA-) FDRs who will progress to hyperglycemia from those who will not, and if changes in the levels of these genes might correlate with the rate of disease progression. The rate of progression varies greatly among subjects and is affected by a number of factors (number of AAs in the serum, the age at which seroconversion occurs, and the human leukocyte antigen (HLA) genotype. For this aim, isoform-level RNA-seq analysis will be performed in longitudinal samples of AA+ individuals who have progressed to hyperglycemia and compared to similar samples of AA+ individuals who have not progressed to hyperglycemia (over the same observation period of at least 5 years). Topics for discussion include confounders, sample size, software packages, and validation of results.
Yulan Jin et al. Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Children Can Be Further Stratified Using Expression Patterns of Multiple Genes Implicated in Peripheral Blood Lymphocyte Activation and Function 2014; 63:2506-2515.