Ancestry-specific profiles of genetic determinants of severe hypertriglyceridemia

Praneet K Gill; Jacqueline S Dron; Allison A Dilliott; Adam D McIntyre; Henian Cao; Jian Wang; Irina G Movsesyan; Mary J Malloy; Clive R Pullinger; John P Kane; Robert A Hegele

doi:10.1016/j.jacl.2020.11.007

Ancestry-specific profiles of genetic determinants of severe hypertriglyceridemia

J Clin Lipidol. 2021 Jan-Feb;15(1):88-96. doi: 10.1016/j.jacl.2020.11.007. Epub 2020 Nov 24.

Affiliations

¹ Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
² Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada.
³ Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
⁴ Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada; Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, Schulich School of Medicine & Dentistry, Western University, London, Ontario, Canada. Electronic address: hegele@robarts.ca.

PMID: 33303403
DOI: 10.1016/j.jacl.2020.11.007

Abstract

Background: Susceptibility to severe hypertriglyceridemia (HTG), defined as plasma triglyceride (TG) levels ≥10 mmol/L (880 mg/dL), is conferred by both heterozygous rare variants in five genes involved in TG metabolism and numerous common single-nucleotide polymorphisms (SNPs) associated with TG levels.

Objective: To date, these genetic susceptibility factors have been comprehensively assessed primarily in severe HTG patients of European ancestry. Here, we expand our analysis to HTG patients of East Asian and Hispanic ancestry.

Methods: The genomic DNA of 336, 63 and 199 severe HTG patients of European, East Asian and Hispanic ancestry, respectively, was evaluated using a targeted next-generation sequencing panel to screen for: 1) rare variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1; 2) common, small-to-moderate effect SNPs, quantified using a polygenic score; and 3) common, large-effect polymorphisms, APOA5 p.G185C and p.S19W.

Results: While the proportion of individuals with high polygenic scores was similar, frequency of rare variant carriers varied across ancestries. Compared with ancestry-matched controls, Hispanic patients were the most likely to have a rare variant (OR = 5.02; 95% CI 3.07-8.21; p < 0.001), while European patients were the least likely (OR = 2.56; 95% CI 1.58-4.13; p < 0.001). The APOA5 p.G185C polymorphism, exclusive to East Asians, was significantly enriched in patients compared with controls (OR = 10.1; 95% CI 5.6-18.3; p < 0.001), showing the highest enrichment among the measured genetic factors.

Conclusion: While TG-associated rare variants and common SNPs are both found in statistical excess in severe HTG patients of different ancestral backgrounds, the overall genetic profiles of each ancestry group were distinct.

Keywords: Copy-number variation (CNV); Dyslipidemia; Polygenic risk score; Severe hypertriglyceridemia (HTG); Single-nucleotide polymorphism (SNP); Single-nucleotide variation (SNV); Triglyceride (TG).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Apolipoprotein A-V / genetics
Humans
Hypertriglyceridemia*
Middle Aged

Substances

Apolipoprotein A-V

Grants and funding

CIHR/Canada