8293 The Genetic Landscape of Severe Hypertriglyceridemia in a Multiracial Latino Population
Authors: Mendivil C O , Puerto-Baracaldo K , Amaya-Montoya M , Parra-Serrano G , Prada-Robles D C , Serrano-Gómez S , Giraldo L M Restrepo , Fragozo-Ramos M C , Tangarife V , Giraldo-González G , Builes-Barrera C A , Naranjo-Vanegas M S , Gómez-Aldana A , Llano J P , Gil-Ochoa N , Nieves-Barreto L D , Gaete P V , Pérez-Mayorga M 
Published: October 2024

Disclosure: C.O. Mendivil: None. K. Puerto-Baracaldo: None. M. Amaya-Montoya: None. G. Parra-Serrano: None. D.C. Prada-Robles: None. S. Serrano-Gómez: None. L.M. Restrepo Giraldo: None. M.C. Fragozo-Ramos: None. V. Tangarife: None. G. Giraldo-González: None. C.A. Builes-Barrera: None. M.S. Naranjo-Vanegas: None. A. Gómez-Aldana: None. J.P. Llano: None. N. Gil-Ochoa: None. L.D. Nieves-Barreto: None. P.V. Gaete: None. M. Pérez-Mayorga: None.

Background: Severe hypertriglyceridemia (sHTG) increases the risk of life-threatening acute pancreatitis and several other conditions. Primary sHTG is often due to mutations in LPL, the gene encoding lipoprotein lipase, but may also result from mutations in genes for the proteins involved in LPL folding (LMF-1), transport (GPIHBP-1), polymerization (ApoA-V) or activation (apoC-II). Rare biallelic pathogenic mutations in these genes result in Familial Chylomicronemia Syndrome (FCS), while heterozygous mutations manifest as Multifactorial Chylomicronemia Syndrome (MCS). Plasma TG in these two conditions overlap. The genetic makeup of Latin Americans is quite particular, with intermixing of genetic pools of European, Native American, and African origin. Despite this, data on the genetic basis of HTG in Latin American populations are extremely scarce. We aimed to identify the most frequent genetic variants in these “canonical” sHTG genes in patients with sHTG from Colombia, South America. Methods: We studied individuals who had plasma TG&gt;=880 mg/dL at least once in their lifetime. We extracted from them blood, plasma, and leukocyte DNA, and collected clinical information. We amplified by PCR all the exons and intron/exon boundaries of LPL, APOC2, APOA5, GPIHBP1 and LMF1, sequenced the amplicons using capillary (Sanger)-based methodology, and performed bioinformatic analyses of the sequences. For each identified variant we ascertained its location (intronic, exonic or splice site), zygosity, whether it had been described previously, described allelic frequency (when applicable), and pathogenicity classification according to American College of Medical Genetics (ACMG) criteria, which we verified manually. Results: The study included 166 participants (62% male, mean age 50, mean BMI 27.0 Kg/m2, 20.6% had diabetes), peak TG levels ranged between 900 and 11,000 mg/dL. We identified 91 individual variants in the 166 patients. Eighteen of these variants had never been reported before (three in LPL, one in APOC2, three in GPIHBP1, eight in LMF1 and three in APOA5), highlighting the importance of ethnic diversity in studies of genetic causes of human metabolic alterations. We detected a known probably pathogenic variant in LPL (c.953A&gt;G == p.Asn318Ser), a new pathogenic nonsense mutation in LMF1 (c.41C&gt;A p.Ser14*), a new probably pathogenic mutation in LMF1 (c.1527 C&gt;T == p.Pro509Pro), and a known pathogenic mutation in LMF1 (c.779G&gt;A == p.Trp260Ter). In addition, we found in this phenotypically enriched sample a large number (23) of variants of undetermined significance as of the date the study execution was finished. Conclusion: Our results reveal a wide repertoire of plausible genetic causes for sHTG in a Latin American population and unveil LMF1 as a potential major player in the etiology of sHTG in people of Latino ethnicity.

Presentation: 6/1/2024