Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial versus non-familial hypertriglyceridemia

• Published in: Journal of clinical lipidology 2016
• Main Authors: De Castro-Orós, Isabel, Civeira, Fernando, Pueyo, María Jesús, Mateo-Gallego, Rocío, Bolado-Carrancio, Alfonso, Lamíquiz-Moneo, Itziar, Álvarez-Sala, Luis, Fabiani, Fernando, Cofán, Montserrat, Cenarro, Ana, Rodríguez-Rey, José Carlos, Ros, Emilio, Pocoví, Miguel
• Format: Article
• Language: English
• Subjects: Cardiovascular
• ISSN: 1933-2874
• DOI: 10.1016/j.jacl.2016.02.010

Abstract Background Most primary severe hypertriglyceridemias (HTGs) are diagnosed in adults, but their molecular foundations have not been completely elucidated. Objective 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. Methods 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. Results 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 while 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. Conclusions 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.