Accelerated Atherosclerosis in a Patient With Multifactorial Chylomicronemia Syndrome (MCS), Elevated Lp(a), APOE2/4 Genotype and Diabetes Mellitus.

Abstract

Background/Synopsis

Multifactorial chylomicronemia syndrome (MCS), also known as type V hyperlipoproteinemia, is a rare polygenic disorder characterized by severe hypertriglyceridemia. It is triggered by uncontrolled diabetes mellitus (DM), obesity, metabolic syndrome, and certain medications. It is not known whether hypertriglyceridemia associated with MCS accelerates atherosclerotic cardiovascular disease (ASCVD).

Objective/Purpose

To speculate the relationship between ASCVD in a patient with hypertriglyceridemia caused by MCS, uncontrolled DM, and polymorphic APOA5, APOE2/4, LMF1 and LP(a) intron mutations.

Methods

We present a 60-year-old male with PMH of severe hypertriglyceridemia (highest 6000mg/dL) with acute pancreatitis at age 40, CAD s/p CABG at age 50, PAD s/p bypass at age 57, HTN, mixed hyperlipidemia, uncontrolled DM, and family history of premature ASCVD. He was subsequently followed at the advanced lipid clinic where his medications included rosuvastatin, ezetimibe, evolocumab, fenofibrate, and icosapent ethyl. He underwent advanced genetic testing with GBinsight.

Results

GBinsight identified various polymorphic genes causing hypertriglyceridemia as follows:

APOA5 - c.*158C>T(rs2266788)

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  This variant is found in ∼10% of the global population and has been associated with hypertriglyceridemia by multiple genome-wide association studies.

APOA5 - c.457G>A(p.Val153Met)(rs3135507)

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  This variant is found in ∼5-10% of the global population and has been associated with modest hypertriglyceridemia and lower HDL-C in the UKBiobank cohort.

APOE2

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  This allele has been associated with a reduction of the major lipolytic enzyme, lipoprotein lipase (LPL) activity, causing modest hypertriglyceridemia.

LMF1 - p.Arg354Trp(rs143076454)

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  This variant is found in ∼2% of the global population, and has been associated with a reduction of LPL activity causing modest hypertriglyceridemia.

GBinsight identified various pathogenic genes causing elevated Lp(a) as follows:

LPA - Heterozygous for intron c.3947+467T>C(rs10455872)

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  This variant serves a genetic proxy for short isoforms and is strongly associated with increased Lp(a), total and LDL-cholesterol levels, and increased ASCVD risk.

APOE4

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  This allele is associated with increased Lp(a) levels.

Conclusions

We speculate that the combination of these polymorphisms works together to increase risk of severe hypertriglyceridemia, also known as MCS. Several smaller studies have suggested MCS is caused by either of the two major mechanisms: (1) some combination of minor genetic polymorphisms, or (2) presence of a single genetic mutation in one of the five genes regulating triglyceride metabolism including LPL, APOC2, APOA5, GPHIBP1, and LMF1.

We postulate acceleration of ASCVD in our patient with MCS was multifactorial, including deposition of atherogenic triglyceride rich lipoproteins within blood vessels, in addition to the independent risk factor of elevated Lp(a). Furthermore, he had poorly controlled DM and insulin resistance owing to the increased circulating triglycerides, which further increased endothelial lining damage and accelerated ASCVD.