EGAGenomicsProbands; Mendelian; FamilydbGaPEGA study phs000511.v1.p1http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000511.v1.p1dbGaPEGArestrictedhttps://ega-archive.org/studies/phs000511.v1.p1<h4>Objective</h4>Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.<h4>Methods and results</h4>First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.<h4>Conclusions</h4>HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.<h4>Objectives</h4>The severe forms of hypertriglyceridaemia (HTG) are caused by mutations in genes that lead to the loss of function of lipoprotein lipase (LPL). In most patients with severe HTG (TG > 10 mmol L(-1) ), it is a challenge to define the underlying cause. We investigated the molecular basis of severe HTG in patients referred to the Lipid Clinic at the Academic Medical Center Amsterdam.<h4>Methods</h4>The coding regions of LPL, APOC2, APOA5 and two novel genes, lipase maturation factor 1 (LMF1) and GPI-anchored high-density lipoprotein (HDL)-binding protein 1 (GPIHBP1), were sequenced in 86 patients with type 1 and type 5 HTG and 327 controls.<h4>Results</h4>In 46 patients (54%), rare DNA sequence variants were identified, comprising variants in LPL (n = 19), APOC2 (n = 1), APOA5 (n = 2), GPIHBP1 (n = 3) and LMF1 (n = 8). In 22 patients (26%), only common variants in LPL (p.Asp36Asn, p.Asn318Ser and p.Ser474Ter) and APOA5 (p.Ser19Trp) could be identified, whereas no mutations were found in 18 patients (21%). In vitro validation revealed that the mutations in LMF1 were not associated with compromised LPL function. Consistent with this, five of the eight LMF1 variants were also found in controls and therefore cannot account for the observed phenotype.<h4>Conclusions</h4>The prevalence of mutations in LPL was 34% and mostly restricted to patients with type 1 HTG. Mutations in GPIHBP1 (n = 3), APOC2 (n = 1) and APOA5 (n = 2) were rare but the associated clinical phenotype was severe. Routine sequencing of candidate genes in severe HTG has improved our understanding of the molecular basis of this phenotype associated with acute pancreatitis and may help to guide future individualized therapeutic strategies.Genome-wide association studies (GWAS) have identified multiple loci associated with plasma lipid concentrations. Common variants at these loci together explain <10% of variation in each lipid trait. Rare variants with large individual effects may also contribute to the heritability of lipid traits; however, the extent to which rare variants affect lipid phenotypes remains to be determined. Here we show an accumulation of rare variants, or a mutation skew, in GWAS-identified genes in individuals with hypertriglyceridemia (HTG). Through GWAS, we identified common variants in APOA5, GCKR, LPL and APOB associated with HTG. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with HTG, compared to 53 variants in 327 controls (P = 6.2 x 10(-8)), corresponding to a carrier frequency of 28.1% of affected individuals and 15.3% of controls (P = 2.6 x 10(-5)). Considering rare variants in these genes incrementally increased the proportion of genetic variation contributing to HTG.Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia.An increased burden of common and rare lipid-associated risk alleles contributes to the phenotypic spectrum of hypertriglyceridemia.Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.Johansen Christopher T CT, Wang Jian J, Lanktree Matthew B MB, McIntyre Adam D AD, Ban Matthew R MR, Martins Rebecca A RA, Kennedy Brooke A BA, Hassell Reina G RG, Visser Maartje E ME, Schwartz Stephen M SM, Voight Benjamin F BF, Elosua Roberto R, Salomaa Veikko V, O'Donnell Christopher J CJ, Dallinga-Thie Geesje M GM, Anand Sonia S SS, Yusuf Salim S, Huff Murray W MW, Kathiresan Sekar S, Cao Henian H, Hegele Robert A RAJohansen Christopher T CT, Wang Jian J, Lanktree Matthew B MB, Cao Henian H, McIntyre Adam D AD, Ban Matthew R MR, Martins Rebecca A RA, Kennedy Brooke A BA, Hassell Reina G RG, Visser Maartje E ME, Schwartz Stephen M SM, Voight Benjamin F BF, Elosua Roberto R, Salomaa Veikko V, O'Donnell Christopher J CJ, Dallinga-Thie Geesje M GM, Anand Sonia S SS, Yusuf Salim S, Huff Murray W MW, Kathiresan Sekar S, Hegele Robert A RASurendran R P RP, Visser M E ME, Heemelaar S S, Wang J J, Peter J J, Defesche J C JC, Kuivenhoven J A JA, Hosseini M M, Péterfy M M, Kastelein J J P JJ, Johansen C T CT, Hegele R A RA, Stroes E S G ES, Dallinga-Thie G M GMtreatment, Therapy, MGC130048, gamma sarcoglycan, SGCG_HUMAN, DMDA1, 35 kDa dystrophin-associated glycoprotein, familial, SG-gamma, A4, Hypertriglyceridemias, gamma (35kDa dystrophin-associated glycoprotein), Treatments, TYPE, SGCG, genetic, hypertriglyceridemia (disease), DAGA4, DMDA, hypertriglyceridemia, Therapeutic, 35kD dystrophin-associated glycoprotein, SCARMD2, disease management, 35DAG, Therapies, gamma-sarcoglycan, Treatment, sarcoglycan, inherited genetic, LGMD2C., MAM, gamma-SG, constitutitional genetic, hereditary, SCG33.1.1.34, RGD1564237, lc64p, ApoC2, JFP11, Tmem112., APOAV, HEL-S-37, Apo C II, LIPD, UNQ411/PRO773, Hypertriglyceridemias, function, 2400010G15Rik, cld, GPI-HBP1, APOC-II, Client, PLS2, Mutations, HYPL1D, 1110002J19Rik, pls2, Apolipoprotein C 2, APO-CII, Apoprotein C-II, LC64P, Apolipoprotein C II, Apo C-II, HMFN1876, cp64, HDLCQ11, C16orf26, LPL, L-PLASTIN, Apoprotein C II, l-plastin, AW822050, Apolipoprotein CII, 1300007O05Rik, Apolipoprotein C-2, hypertriglyceridemia (disease), loss of, TMEM112A, hypertriglyceridemia, Patient, lpl, Clients, TMEM112, CP64, RAP3, Apoav3.1.1.34, RGD1564237, lc64p, cp64, HDLCQ11, ApoC2, JFP11, C16orf26, LPL, L-PLASTIN, APOAV, Apoprotein C II, l-plastin, HEL-S-37, Apo C II, LIPD, UNQ411/PRO773, 2400010G15Rik, AW822050, Apolipoprotein CII, 1300007O05Rik, cld, APOC-II, GPI-HBP1, Apolipoprotein C-2, Client, PLS2, Mutations, TMEM112A, HYPL1D, lpl, Patient, 1110002J19Rik, Clients, pls2, Apolipoprotein C 2, APO-CII, TMEM112, Apoprotein C-II, CP64, RAP3, LC64P, Apolipoprotein C II, Severe., Apo C-II, HMFN1876, Tmem112, Apoavdyslipidemia type 3, APO-E, Apo E Isoproteins, dysbetalipoproteinemia, CYPIIIA3, CYPIIIA4, Materials, degree (angle), Blood, Cathepsin G-like 1, NF-25, Circulating, cholesterol, composed of, lipoproteins, Relative, DDX13, Techniques, a triacylglycerol, Method, low density lipoprotein cholesterol level quantitative trait locus 5, Triglyceride, apolipoprotein E, Fragmentin-2, hyperkeratosis lenticularis perstans of Flegel, CSP-B, Fresh Frozen Plasmas, Fresh Frozen, increased, CCPI, Human lymphocyte protein, Circulating Lipoproteins, Isoproteins, apo-E, AW743261, composition, "hyperlipoproteinemia NOS" EXACT [MTHICD9_2006:272.4], Granzyme-2, procedures, ApoE, APOE, Triacylglycerols, genetic, HSD11, SECT, hyperlipidemia type 3, Methodological Studies, CORTRD2, AD2, Apo-E, s, Apolipoprotein E Isoproteins, associated, triacylglycerols, SDR26C1, plasma, CSPB, "hyperlipoproteinemia" EXACT [CSP2005:1749-0698], carbohydrate induced hyperlipemia, accumulated, familial hypercholesterolemia with hyperlipemia, Frozen Plasma, HIP5, Flegel's disease, P450PCN1, CRP4, CRP2, HDL-C, familial, THES2, Triacylglycerol, Procedure, Plasmas, CTLA1, results, AI255918, 170A, LDLCQ5, familial hypercholesterolaemia with hyperlipaemia, 3.6.4.-, Lipid, Relative Risks, Genetic Materials, HAP2, familial hyperlipoproteinemia type 3, Genetic Material, Risk, content, Heterogeneity, HDL, common, CGL1, Methodological, Remnant hyperlipidemia, Methodological Study, type III, familial dysbetalipoproteinemia, CTLA-1, Phenotypes, Triglycerid, Patient, Material, beta-lipoproteins, hyperlipoproteinemia type 3, Lipoproteins, floating-betalipoproteinemia, Cistron, inherited genetic, accessory, coronary artery disease, Fresh, lipids, Procedures, Fresh Frozen Plasma, Broad-betalipoproteinemia, hyperlipoproteinemia type III, Gene, supernumerary, associated., 11-beta-HSD1, APOEA, deficiency or defect of, High-density lipoprotein cholesterol, heredity, Genetic heterogeneity, Hyperlipoproteinemia Type III, familial type 3 hyperlipoproteinemia, ESP1, Studies, low-density lipoproteins, Triglyzerid, High-density lipoproteins, LDL lipoproteins, Technique, LPG, Blood Plasma, Ski2, SKI2, Genetic, familial Hyperbeta- and Prebetalipoproteinemia, Hyperlipoproteinemia, HLP type 3, CYP3A, Cytotoxic T-lymphocyte proteinase 2, hyperlipemia with Familial Hypercholesterolemic xanthomatosis, Familial dysbetalipoproteinemia, Genotypes, hypertriglyceridemia (disease), remnant hyperlipidemia, Study, HSD11B, hypertriglyceridemia, Remnant disease, triglycerides, Clients, Dyslipidemia type 3, 0610010I23Rik, Blood Plasmas, heterogeneity, HDL cholesterol, P450C3, Familial hyperlipoproteinemia type 3, constitutitional genetic, Lymphocyte protease, HSD11L, Apoproteins E, "hyperlipoproteinemia (disorder)" EXACT [SNOMEDCT_2005_07_31:3744001], high-density lipoprotein, Lipoprotein, Helicase-like protein, CP34, CP33, hHLP1, Hypertriglyceridemias, Broad beta disease, 11-DH, compositionality, Cistrons, Client, SKI2W, C11, Frozen Plasmas, remnant removal disease, Hyperlipidemia type 3, Genogroup, CTSGL1, Susceptibility to, rare (European definition), techniques, familial type 3 hyperlipoproteinemia (disorder), hyperlipoproteinemia, Relative Risk, Crp, Plasma, dysbetalipoproteinemia due to defect in apolipoprotein E-D, susceptibility, CYP3A3, HLP, Hlp, increased number, 3.4.21.79, alpha-lipoprotein cholesterol, Apoprotein (E), Risks, portion of plasma, LDL, Apolipoprotein E, arc degree, CGL-1, present in greater numbers in organism, Genogroups, Apo E, structure, low-density lipoprotein, SKIV2, hereditary, T-cell serine protease 1-3E, Severe, remnant disease, C77570, methodologyfalseTreatment of genetic screening of hypertriglyceridemia type I, III, and V - HTG Amsterdam<p>This is a cohort of patients with extreme hypertriglyceridemia. Patients have been screened for loss of function mutations in LPL, GPIHBP1, APOC2, APOA5 and LMF1.</p>
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