Genetics
eMERGE Network study fails to replicate the CETP-triglyceride association found in prior smaller studies (BMC Med Genomics 2021)
Original title: Association between triglycerides, known risk SNVs and conserved rare variation in SLC25A40 in a multi-ancestry cohort
This study analyzed a longitudinal, mixed-ancestry cohort of 8966 people from the Electronic Medical Record and Genomics (eMERGE) Network to test associations between median triglyceride levels and genes previously linked to hypertriglyceridemia, including a rare SLC25A40 variant the authors had previously identified in a family study, alongside known risk single-nucleotide variants in APOE, the APOA1/C3/A4/A5 gene cluster, INSR, CETP (rs7205804), and GCKR. Using linear regression adjusted for sex, median age, median BMI, and ancestry principal components, the study replicated known associations between triglycerides and APOC3, APOA5, APOE, the APOA1/C3/A4/A5 cluster, and GCKR. However, it failed to replicate the previously reported rare SLC25A40 variant association, as well as the risk variation at INSR and at CETP, which the authors attribute to limited sample size and missing drug information.
Original abstract
Background: Elevated triglycerides (TG) are associated with, and may be causal for, cardiovascular disease (CVD), and co-morbidities such as type II diabetes and metabolic syndrome. Pathogenic variants in APOA5 and APOC3 as well as risk SNVs in other genes [APOE (rs429358, rs7412), APOA1/C3/A4/A5 gene cluster (rs964184), INSR (rs7248104), CETP (rs7205804), GCKR (rs1260326)] have been shown to affect TG levels. Knowledge of genetic causes for elevated TG may lead to early intervention and targeted treatment for CVD. We previously identified linkage and association of a rare, highly conserved missense variant in SLC25A40, rs762174003, with hypertriglyceridemia (HTG) in a single large family, and replicated this association with rare, highly conserved missense variants in a European American and African American sample.
Methods: Here, we analyzed a longitudinal mixed-ancestry cohort (European, African and Asian ancestry, N = 8966) from the Electronic Medical Record and Genomics (eMERGE) Network. We tested associations between median TG and the genes of interest, using linear regression, adjusting for sex, median age, median BMI, and the first two principal components of ancestry.
Results: We replicated the association between TG and APOC3, APOA5, and risk variation at APOE, APOA1/C3/A4/A5 gene cluster, and GCKR. We failed to replicate the association between rare, highly conserved variation at SLC25A40 and TG, as well as for risk variation at INSR and CETP.
Conclusions: Analysis using data from electronic health records presents challenges that need to be overcome. Although large amounts of genotype data is becoming increasingly accessible, usable phenotype data can be challenging to obtain. We were able to replicate known, strong associations, but were unable to replicate moderate associations due to the limited sample size and missing drug information.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.