Rare genetic variants with large effect on triglycerides in subjects with a clinical diagnosis of familial vs nonfamilial hypertriglyceridemia
| Autor: | Rocio Mateo-Gallego, Fernando Civeira, Alfonso Bolado-Carrancio, Emilio Ros, Itziar Lamiquiz-Moneo, José C. Rodríguez-Rey, Montserrat Cofán, Luis Álvarez-Sala, María Jesús Pueyo, Fernando Fabiani, Isabel De Castro-Orós, Miguel Pocovi, Ana Cenarro |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine Adolescent Endocrinology Diabetes and Metabolism 030204 cardiovascular system & hematology Biology medicine.disease_cause Hyperlipoproteinemia Type IV Young Adult 03 medical and health sciences Exon 0302 clinical medicine Internal Medicine medicine Humans Allele Gene Triglycerides Aged Genetics Mutation Lipoprotein lipase Nutrition and Dietetics Base Sequence Hypertriglyceridemia GPIHBP1 Genetic Variation Middle Aged medicine.disease Phenotype 030104 developmental biology Female Cardiology and Cardiovascular Medicine |
| Zdroj: | Journal of Clinical Lipidology. 10:790-797 |
| ISSN: | 1933-2874 |
| DOI: | 10.1016/j.jacl.2016.02.010 |
| Popis: | 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, 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. 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. |
| Databáze: | OpenAIRE |
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