title: Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia.
abstract: Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated.
  
  
  
  We aimed to identify rare dysfunctional mutations in genes encoding regulators of lipoprotein lipase (LPL) function in patients with familial and non-familial primary HTG.
  
  
  
  We sequenced promoters, exons, and exon-intron boundaries of LPL, APOA5, LMF1, and GPIHBP1 in 118 patients with severe primary HTG (triglycerides >500 mg/dL) and 53 normolipidemic controls. Variant functionality was analyzed using predictive software and functional assays for mutations in regulatory regions.
  
  
  
  We identified 29 rare variants, 10 of which had not been previously described: c.(-16A>G), c.(1018+2G>A), and p.(His80Arg) in LPL; p.(Arg143Alafs*57) in APOA5; p.(Val140Ile), p.(Leu235Ile), p.(Lys520*), and p.(Leu552Arg) in LMF1; and c.(-83G>A) and c.(-192A>G) in GPIHBP1. The c.(1018+2G>A) variant led to deletion of exon 6 in LPL cDNA, whereas the c.(-16A>G) analysis showed differences in the affinity for nuclear proteins. Overall, 20 (17.0%) of the patients carried at least one allele with a rare pathogenic variant in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant was not associated with lipid values, family history of HTG, clinical diagnosis, or previous pancreatitis.
  
  
  
  Less than one in five subjects with triglycerides >500 mg/dL and no major secondary cause for HTG may carry a rare pathogenic mutation in LPL, APOA5, LMF1, or GPIHBP1. The presence of a rare pathogenic variant is not associated with a differential phenotype.
authors: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain; Dpto. Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain. Electronic address: isadco@gmail.com.
authors: Isabel
authors: I
authors: De Castro-Orós
authors: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
authors: Fernando
authors: F
authors: Civeira
authors: Dpto. Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors: María Jesús
authors: MJ
authors: Pueyo
authors: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
authors: Rocío
authors: R
authors: Mateo-Gallego
authors: Dpto. Biología Molecular. Facultad de Medicina, Universidad de Cantabria and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Cantabria, Spain.
authors: Alfonso
authors: A
authors: Bolado-Carrancio
authors: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
authors: Itziar
authors: I
authors: Lamíquiz-Moneo
authors: Lipid Unit, Medicina Interna, Hospital Universitario Gregorio Marañón, RIC, Instituto de Salud Carlos III (ISCIII), Instituto de Investigación Sanitaria Gregorio Marañón and Dpto. Medicina, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
authors: Luis
authors: L
authors: Álvarez-Sala
authors: Departamento de Bioquímica Clínica, Hospital Universitario Virgen Macarena, Universidad de Sevilla, Sevilla, Spain.
authors: Fernando
authors: F
authors: Fabiani
authors: Servei d'Endocrinologia i Nutrició, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, Barcelona and Ciber Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
authors: Montserrat
authors: M
authors: Cofán
authors: Unidad Clínica y de Investigación en Lípidos y Arteriosclerosis, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain.
authors: Ana
authors: A
authors: Cenarro
authors: Dpto. Biología Molecular. Facultad de Medicina, Universidad de Cantabria and Instituto de Formación e Investigación Marqués de Valdecilla (IFIMAV), Santander, Cantabria, Spain.
authors: José Carlos
authors: JC
authors: Rodríguez-Rey
authors: Servei d'Endocrinologia i Nutrició, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), Hospital Clínic, Barcelona and Ciber Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), Barcelona, Spain.
authors: Emilio
authors: E
authors: Ros
authors: Dpto. Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors: Miguel
authors: M
authors: Pocoví
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D005260:Female; D014644:Genetic Variation; D006801:Humans; D006953:Hyperlipoproteinemia Type IV / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D014280:Triglycerides / Q000097:blood*; D055815:Young Adult
chemical_list: D014280:Triglycerides
keywords: APOA5; GPIHBP1; Hypertriglyceridemia; LMF1; LPL; Mutation