Genetic variation in apolipoprotein A-V in hypertriglyceridemia.

PURPOSE OF REVIEW: While biallelic rare APOA5 pathogenic loss-of-function (LOF) variants cause familial chylomicronemia syndrome, heterozygosity for such variants is associated with highly variable triglyceride phenotypes ranging from normal to severe hypertriglyceridemia, often in the same individual at different time points. Here we provide an updated overview of rare APOA5 variants in hypertriglyceridemia. RECENT FINDINGS: Currently, most variants in APOA5 that are considered to be pathogenic according to guidelines of the American College of Medical Genetics and Genomics are those resulting in premature termination codons. There are minimal high quality functional data on the impact of most rare APOA5 missense variants; many are considered as variants of unknown or uncertain significance. Furthermore, particular common polymorphisms of APOA5 , such as p.Ser19Trp and p.Gly185Cys in Caucasian and Asian populations, respectively, are statistically overrepresented in hypertriglyceridemia cohorts and are sometimes misattributed as being causal for chylomicronemia, when they are merely risk alleles for hypertriglyceridemia. SUMMARY: Both biallelic and monoallelic LOF variants in APOA5 are associated with severe hypertriglyceridemia, although the biochemical phenotype in the monoallelic state is highly variable and is often exacerbated by secondary factors. Currently, with few exceptions, the principal definitive mechanism for APOA5 pathogenicity is through premature truncation. The pathogenic mechanisms of most missense variants in APOA5 remain unclear and require additional functional experiments or family studies.

Variability of longitudinal triglyceride phenotype in patients heterozygous for pathogenic APOA5 variants.

BACKGROUND: Biallelic pathogenic variants in APOA5 are an infrequent cause of familial chylomicronemia syndrome characterized by severe, refractory hypertriglyceridemia (HTG), and fasting plasma triglyceride (TG) >10 mmol/L (>875 mg/dL). The TG phenotype of heterozygous individuals with one copy of a pathogenic APOA5 variant is less familiar. We evaluated the longitudinal TG phenotype of individuals with a single pathogenic APOA5 variant allele. METHODS: Medically stable outpatients from Ontario, Canada were selected for study based on having: 1) a rare pathogenic APOA5 variant in a single allele; and 2) at least three serial fasting TG measurements obtained over >1.5 years of follow-up. RESULTS: Seven patients were followed for a mean of 5.3 ± 3.7 years. Fasting TG levels varied widely both within and between patients. Three patients displayed at least one normal TG measurement (<2.0 mmol/L or <175 mg/dL). All patients displayed mild-to-moderate HTG (2 to 9.9 mmol/L or 175 to 875 mg/dL) at multiple time points. Five patients displayed at least one severe HTG measurement. 10%, 54%, and 36% of all TG measurements were in normal, mild-to-moderate, and severe HTG ranges, respectively. CONCLUSIONS: Heterozygosity for pathogenic variants in APOA5 is associated with highly variable TG phenotypes both within and between patients. Heterozygosity confers susceptibility to elevated TG levels, with secondary factors likely modulating the phenotypic severity.

The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants.

BACKGROUND: Biallelic pathogenic variants in lipoprotein lipase (LPL) cause familial chylomicronemia syndrome with severe hypertriglyceridemia (HTG), defined as plasma triglycerides (TG) > 10 mmol/L (> 885 mg/dL). TG levels in individuals with one copy of a pathogenic LPL gene variant is less familiar; some assume that the phenotype is intermediate between homozygotes and controls. OBJECTIVE: We undertook an evaluation of the longitudinal TG phenotype of individuals heterozygous for pathogenic LPL variants. METHODS: Medically stable outpatients were evaluated based on having: (1) a single copy of a rare pathogenic LPL variant; and (2) serial fasting TG measurements obtained over > 1.5 years of follow-up. RESULTS: Fifteen patients with a single pathogenic LPL variant were followed for a mean of 10.3 years (range 1.5 to 30.3 years). TG levels varied widely both within and between patients. One patient had normal TG levels < 2.0 mmol/L (< 175 mg/dL) continuously, while four patients had at least one normal TG level. Most patients fluctuated between mild-to-moderate and severe HTG: five patients had only mild-to-moderate HTG, with TG levels ranging from 2.0 to 9.9 mmol/L (175 to 885 mg/dL), while 6 patients had at least one instance of severe HTG. Of the 203 total TG measurements from these patients, 14.8%, 67.0% and 18.2% were in the normal, mild-to-moderate and severe HTG ranges, respectively. CONCLUSION: The heterozygous LPL deficient phenotype is highly variable both within and between patients. Heterozygosity confers susceptibility to a wide range of TG phenotypes, with severity likely depending on secondary factors.

Preprint servers in lipidology: current status and future role.

PURPOSE OF REVIEW: Preprinting, or the sharing of non-peer reviewed, unpublished scholarly manuscripts, has exploded in all fields of science and medicine over the past 5 years. We searched the literature and evaluated the posting and uptake of preprint publications in the field of lipidology in bioRxiv and medRxiv servers. We also contacted the editorial offices of 20 journals that publish original research in lipidology to gauge their policies on preprints. RECENT FINDINGS: All 20 journals contacted indicated that they accepted preprints. As of 31 May 2021, 473 and 231 preprints in lipidology had been submitted to bioRxiv and medRxiv, respectively. About half of all lipidology preprints were related to cardiovascular, cardiometabolic, and/or metabolic diseases (CVMD) and their risk factors, but at least 12 other disease categories were also represented. 16.9% and 1.08% of medRxiv and bioRxiv preprints, respectively, were related to coronavirus disease 2019 (COVID-19). SUMMARY: All identified journals accept lipidology themed preprints for submission, removing any barriers authors may have had regarding preprinting. Based on growing experience with preprinting, this trend should encourage increased community feedback and facilitate higher quality lipidology research in the future.