학술논문
Polygenic risk for triglyceride levels in the presence of a high impact rare variant
Document Type
Academic Journal
Author
Source
BMC Medical Genomics. November 8, 2023, Vol. 16 Issue 1
Subject
Language
English
ISSN
1755-8794
Abstract
Author(s): Shengjie Ying[sup.1,2,3], Tracy Heung[sup.3,4], Bhooma Thiruvahindrapuram[sup.5], Worrawat Engchuan[sup.5], Yue Yin[sup.5], Christina Blagojevic[sup.3], Zhaolei Zhang[sup.6,7,8], Robert A. Hegele[sup.2], Ryan K. C. Yuen[sup.5,6] and Anne S. Bassett[sup.1,3,4,9,10] Background Elevated circulating triglyceride [...]
Background Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia. Methods We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status. Results The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (p.sub.model = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI [greater than or equal to] 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively. Conclusions These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels. Keywords: Triglyceride, Lipid, Polygenic risk score, 22q11.2 microdeletion, Genome sequencing
Background Elevated triglyceride (TG) levels are a heritable and modifiable risk factor for cardiovascular disease and have well-established associations with common genetic variation captured in a polygenic risk score (PRS). In young adulthood, the 22q11.2 microdeletion conveys a 2-fold increased risk for mild-moderate hypertriglyceridemia. This study aimed to assess the role of the TG-PRS in individuals with this elevated baseline risk for mild-moderate hypertriglyceridemia. Methods We studied a deeply phenotyped cohort of adults (n = 157, median age 34 years) with a 22q11.2 microdeletion and available genome sequencing, lipid level, and other clinical data. The association between a previously developed TG-PRS and TG levels was assessed using a multivariable regression model adjusting for effects of sex, BMI, and other covariates. We also constructed receiver operating characteristic (ROC) curves using logistic regression models to assess the ability of TG-PRS and significant clinical variables to predict mild-moderate hypertriglyceridemia status. Results The TG-PRS was a significant predictor of TG-levels (p = 1.52E-04), along with male sex and BMI, in a multivariable model (p.sub.model = 7.26E-05). The effect of TG-PRS appeared to be slightly stronger in individuals with obesity (BMI [greater than or equal to] 30) (beta = 0.4617) than without (beta = 0.1778), in a model unadjusted for other covariates (p-interaction = 0.045). Among ROC curves constructed, the inclusion of TG-PRS, sex, and BMI as predictor variables produced the greatest area under the curve (0.749) for classifying those with mild-moderate hypertriglyceridemia, achieving an optimal sensitivity and specificity of 0.746 and 0.707, respectively. Conclusions These results demonstrate that in addition to significant effects of sex and BMI, genome-wide common variation captured in a PRS also contributes to the variable expression of the 22q11.2 microdeletion with respect to elevated TG levels. Keywords: Triglyceride, Lipid, Polygenic risk score, 22q11.2 microdeletion, Genome sequencing