THE GENETICS OF NONTRADITIONAL GLYCEMIC BIOMARKERS OF TYPE 2 DIABETES
Embargo until
2019-08-01
Date
2018-06-25
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Johns Hopkins University
Abstract
Type 2 diabetes is a major public health problem that affects over 10% of the US adult population. It is associated with substantially increased risks of mortality and serious clinical outcomes such as heart disease, stroke, kidney disease and retinopathy. Diabetes is defined by hyperglycemia, or elevated glucose concentrations in the blood, which are commonly measured by fasting glucose and hemoglobin A1c (HbA1c), but these have limitations. As a result, nontraditional glycemic biomarkers, fructosamine, glycated albumin and 1,5-anhydroglucitol (1,5-AG) are gaining interest. While it is established that genetics play a role in type 2 diabetes, fasting glucose, and HbA1c, the genetics of fructosamine, glycated albumin, and 1,5-AG have not been well explored. This dissertation sought to determine the amount of variation in each biomarker due to genetics through heritability estimation, and to determine the specific genetic variants associated with each biomarker though genome wide association study (GWAS) analysis, multivariate phenotype analysis, and exome sequencing analysis.
Heritability estimates showed a substantial portion of fructosamine, glycated albumin and 1,5-AG variation was due to genetics, which is likely comprised of both common and rare variants. GWAS identified common variants associated with fructosamine and glycated albumin including a known diabetes variant and a likely nonglycemic variant. Exome sequencing did not identify variants associated with fructosamine and glycated albumin, but multivariate phenotype analysis identified a potentially interesting region in a gene that alters bilirubin levels that may affect fructosamine in a nonglycemic manner. Exome sequencing identified rare, coding variants with large effect size in a glucose transporting gene associated with 1,5-AG which inform the biology and may impact the clinical interpretation of 1,5-AG. Analyzing the genetics of nontraditional glycemic biomarkers of type 2 diabetes has increased the understanding of these biomarkers, including their underlying biology, and may aid in decisions about their clinical implementation.
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Keywords
type 2 diabetes, biomarkers, fructosamine, glycated albumin, 1,5-AG, exome sequencing, heritability, GWAS