Genetic Testing for Hypertriglyceridemia in Academic Lipid Clinics - Implications for Precision Medicine

Abstract

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> GN HealthWatch. <h3>Background/Synopsis</h3> Most cases of severe hypertriglyceridemia (HTG) are polygenic disorders caused by the presence of rare heterozygous pathogenic variants (PV) and/or the accumulation of multiple common single-nucleotide polymorphisms (SNPs) as quantified by polygenic risk scores (PRSs). A high PRS (<b>≥</b>90th percentile in the general population) and the presence of PV have been shown to predict risk severe HTG. However, no data are available on the potential effects of PV and PRSs with respect to the risk for acute pancreatitis. We examined the association of PVs and PRSs on severity of HTG and risk for acute pancreatitis. <h3>Objective/Purpose</h3> Determine if genetic testing for hypertriglyceridemia provide additional clinical information beyond measurement of triglycerides regarding the risk for pancreatitis. <h3>Methods</h3> We conducted a multicenter retrospective cohort study through 3 academic lipid clinics in patients with hypertriglyceridemia who underwent genetic testing. The presence of HTG pathogenic variants (PVs) and polygenic risk scores (PRSs) were assessed by GBinsight Comprehensive Dyslipidemia Panel. Patients' highest recorded fasting TG level was included for analysis. HTG was categorized as moderate (200-499 mg/dL), severe (500-999 mg/dL), and very severe (<b>≥</b>1000 mg/dL). Multivariable logistic regression analysis was used to calculate odds ratio (OR) for acute pancreatitis in patients with PV, high PRS, or both. <h3>Results</h3> The risk for very severe HTG was increased in the presence of either PV or high PRS alone; however, this risk was attenuated when controlling for demographic factors (age, sex, BMI, and diabetes mellitus). In contrast, patients with both genetic risk factors (PV and high PRS) had significantly higher risk compared with those with neither genetic risk factor after adjustment for demographics (OR 58.72; 95% CI 8.29 - 415.57, p<0.001). Similarly, the risk for acute pancreatitis in those with PV or high PRS alone was attenuated after controlling for demographic factors and TG levels, whereas the increased risk for acute pancreatitis in patients with both PV and high PRS remained statistically significant (OR 4.28 (95% CI 1.01 - 18.14, p=0.048). <h3>Conclusions</h3> Patients with both a PV and a high PRS related to HTG have significantly higher risk for pancreatitis compared to those without a PV and a low PRS. However, the presence of a PV or high PRS alone did not result in a significant increase in risk. Genetic testing for patients with HTG has the potential to identify individuals at higher risk for pancreatitis and who are likely to benefit from novel therapies.