Four studies, connecting genetic discovery to patient care.
From recall-by-genotype designs to pharmacogenetic drug trials, each study asks a specific question about how a person’s genetics should shape their diabetes care.
Targeted Assessment of participants through Recall by Genotype for Evaluation and Translation
The overall goal of this research is to leverage genomic information to identify individuals with high genetic risk for type 2 diabetes, assess their disease progression, accumulation of co-morbidities, and healthcare utilization, and characterize their beta-cell function, insulin resistance, and pharmacogenetic responses to type 2 diabetes therapies.
Aims
- Characterize the physiologic responses in individuals with extreme genetic risk for type 2 diabetes through a recall-by-genotype study.
- Characterize the pharmacological responses in individuals with extreme genetic risk for type 2 diabetes.
Outcomes Measured
- Pancreatic beta-cell function and insulin resistance, measured with a mixed meal tolerance test.
- Glycemic response to sulfonylurea as a drug challenge.
CGM-A1c Genetics
GWAS have reported over 200 hemoglobin A1c (HbA1c)-associated genetic variants, the majority of which affect HbA1c levels independently of glucose. Individuals who carry these nonglycemic HbA1c variants may have undetected hyperglycemia if HbA1c is used to diagnose diabetes or estimate glycemic control.
Aims
- Estimate the effects of nonglycemic HbA1c variants on HbA1c-glucose discordance and glycated proteins, by assessing the difference between measured and predicted HbA1c using 10–14 days of continuous glucose monitoring, plus albumin and fructosamine measurements.
- Use recall-by-genotype for enriched recruitment of subjects with African or European ancestry.
Outcomes
- HbA1c correlated well with CGM glucose across genotype groups, but the relationship differed by G6PD genotype, polygenic score, and ancestry.
- HbA1c-glycemia discordance differed by polygenic score in European ancestry, and by G6PD carrier status in African ancestry.
- HbA1c and glycated albumin were higher in African ancestry vs. European ancestry despite similar CGM glucose — suggesting glycation propensity may differ by ancestry.
Diabetes Genetics & COVID-19 Severity
Clinical experience suggested that patients with preexisting diabetes and concomitant cardiometabolic comorbidities are more likely to have poor clinical outcomes from COVID-19. This research examined diabetes-related complications in acute COVID-19 illness, including new and persistent hyperglycemia, diabetic ketoacidosis, and severe insulin resistance.
Aims
- Evaluate causal associations of cardiometabolic diseases and traits with COVID-19 severity.
- Examine whether global genetic risk, variation in candidate cardiometabolic genes, and molecular targets of diabetes drugs are associated with diabetes-related complications in acute COVID-19 illness.
- Test for mediation and interaction with prior diabetes diagnosis, prior A1C, obesity, diabetes drug exposures, and circulating ACE2, among other cardiometabolic biomarkers.
Outcomes
- Results support the conclusion that higher BMI is a causal risk factor for both COVID-19 susceptibility and severity.
PhaRmacogenetics Of the Glycemic RESponse to SGLT2 Inhibitors
PROGRESS is studying dapagliflozin (Farxiga) to understand the role of a patient’s genetic makeup in choosing what diabetes drug to prescribe. It’s one of the first pharmacogenetic investigations of SGLT2 inhibitors involving the acute response.
Aims
- Use integrated multi-omic analyses — genetics, metabolomics, and proteomics — to predict the effects of SGLT2 inhibitors.
- Tailor type 2 diabetes treatment by considering a patient’s genetic profile in drug choices.
- Identify patients across the spectrum of type 2 diabetes genetic risk and carriers of variants within SLC5A2, the gene encoding the molecular target of SGLT2 inhibitors.
- Assess whether the change in blood sugar due to SGLT2 inhibitors differs by genetic risk or SLC5A2 variation.
What Study Visits Involve
- A brief screening visit and blood draw, if recent bloodwork isn’t on file.
- Two five-hour visits, a week apart.
- If you have diabetes, pausing your home diabetes medication for 5 days before the first five-hour visit.
- At each visit: height and weight, glucose checks, blood draws, and urine collections.
- Taking the study drug daily for 5 days at home, and once during the second visit.