RESUMO
OBJECTIVE: Combined hyperlipidemia is a common disorder, characterized by a highly atherogenic lipoprotein profile and a substantially increased risk of coronary heart disease. The purpose of this study was to establish whether variations of apolipoprotein A5 (APOA5), a newly discovered gene of lipid metabolism located 30 kbp downstream of the APOA1/C3/A4 gene cluster, contributes to the transmission of familial combined hyperlipidemia (FCHL). METHODS AND RESULTS: We performed linkage and association tests on 128 families. Two independent alleles, APOA5c.56G and APOC3c.386G, of the APOA1/C3/A4/A5 gene cluster were overtransmitted in FCHL (P=0.004 and 0.007, respectively). This was paired with reduced transmission of the common APOA1/C3/A4/A5 haplotype (frequency 0.4461) to affected subjects (P=0.012). The APOA5c.56G genotype accounted for 7.3% to 13.8% of the variance in plasma triglyceride levels in probands (P<0.004). The APOC3c.386G genotypes accounted for 4.4% to 5.1% of the variance in triglyceride levels in FCHL spouses (P<0.007), suggesting that this allele marks a FCHL quantitative trait as well as representing a susceptibility locus for the condition. CONCLUSIONS: A combined linkage and association analysis establishes that variation at the APOA1/C3/A4/A5 gene cluster contributes to FCHL transmission in a substantial proportion of northern European families.
Assuntos
Apolipoproteína A-I/genética , Apolipoproteínas A/genética , Apolipoproteínas C/genética , Apolipoproteínas/genética , Hiperlipidemia Familiar Combinada/genética , Alelos , Apolipoproteína A-V , Apolipoproteína C-III , Europa (Continente)/epidemiologia , Feminino , Ligação Genética , Predisposição Genética para Doença , Variação Genética , Haplótipos/genética , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/epidemiologia , Masculino , Família MultigênicaRESUMO
UNLABELLED: Background- Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown. METHODS AND RESULTS: We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P=0.005) and cholesterol (LOD, 2.2; P=0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P=0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P=0.0002). CONCLUSIONS: Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.
Assuntos
Colesterol/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Cromossomos Humanos Par 8 , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemia Familiar Combinada/metabolismo , Triglicerídeos/genética , Adulto , Idoso , Colesterol/metabolismo , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Triglicerídeos/metabolismoRESUMO
Dietary fat is an important source of nutrition. Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption. The Sar1 family of proteins initiates the intracellular transport of proteins in COPII (coat protein)-coated vesicles. Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell.
