Turk Kardiyol Dern Ars. 2023; 51(1): 10-21 | DOI: 10.5543/tkda.2022.98544

Genetic Variants Associated with Severe Hypertriglyceridemia: LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE

Amir Hossein Abedi¹, Ilgın Yıldırım Şimşir², Fahri Bayram³, Huseyin Onay⁴, Su Özgür⁵, Adam Mcintyre⁶, Peter Toth⁷, Robert Hegele^6
1Erciyes University Faculty of Medicine, Department of Internal Medicine, Kayseri, Türkiye
²Ege University Faculty of Medicine, Division of Endocrinology and Metabolism Disorders, Izmir, Türkiye
³Erciyes University Faculty of Medicine, Division of Endocrinology and Metabolism Disorders, Kayseri, Türkiye
⁴Ege University Faculty of Medicine, Department of Medical Genetics, Izmir, Türkiye
⁵Ege University Faculty of Medicine, Department of Biostatistics and Medical Informatics, Izmir, Türkiye
⁶Robarts Research Institute, Schulich School of Medicine, Western University, London ON, Canada
⁷Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA

OBJECTIVE
High triglyceride (TG) levels are associated with an increased risk for atherosclerotic cardiovascular disease (ASCVD) and pancreatitis. The objectives for this study were to evaluate for the coexistence of severe HTG and pancreatitis in two different geographic regions of Turkey and to identify rare variants that cause monogenic HTG in our country.


METHODS
In our study from 2014 to 2019, patients with severe HTG who presented to the endocrinology outpatient clinics with TG levels >500 mg/dL (5.7 mmol/L) were evaluated. The LPL, APOC2, APOA5, GPIHBP1, LMF1, and APOE genes were sequenced using next generation sequencing to screen for potentially pathogenic variants.


RESULTS
Potentially pathogenic variants were identified in 64 (47.1%) of 136 patients. Variants in LPL were seen in 42 (30.9%) cases, APOA5 variants in 10 (7.4%) cases, APOC2 variants in 5 (3.7%) cases, LMF1 variants in 5 (3.7%) cases, and APOE mutations in 2 (1.5%) cases. In the subgroup that experienced pancreatitis (n = 76, 56.3%), LPL variants were seen at higher frequency (P <0.001) than in the subgroup with no history of pancreatitis (n = 60, 43.7%). Patients who developed pancreatitis (56.3%) demonstrated a median TG of 2083 mg/dL (23.5 mmol/L), and patients without pancreatitis (43.7%) demonstrated a median TG of 1244.5 mg/dL (14.1 mmol/L) (P <0.001).


CONCLUSION
Accurate approach to HTG diagnosis is important for the prevention of pancreatitis and ASCVD. Evaluation of variants in primary HTG after excluding secondary causes may help provide a patient-centric precision treatment plan.

Keywords: Apolipoprotein A5, apolipoprotein C2, apolipoprotein E, hypertriglyceridemia, lipoprotein lipase, lipase maturation factor 1, pancreatitis

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