Most individuals with familial hypertriglyceridemia have a hyperlipoproteinemia IV (144600) phenotype. Relatives of affected persons (ascertained in a study of survivors of coronary occlusion) were found to have normal cholesterol distribution and bimodal triglyceride distribution (Goldstein et al., ... Most individuals with familial hypertriglyceridemia have a hyperlipoproteinemia IV (144600) phenotype. Relatives of affected persons (ascertained in a study of survivors of coronary occlusion) were found to have normal cholesterol distribution and bimodal triglyceride distribution (Goldstein et al., 1973). Hypertriglyceridemia is not completely expressed in affected children. - Genetic Heterogeneity of Hypertriglyceridemia Hypertriglyceridemia has many causes but, whatever its cause, there is evidence for its role as a coronary heart disease risk factor. Hypertriglyceridemia is commonly found in individuals with type II diabetes mellitus (125853). Several genetic bases for hypertriglyceridemia have been identified. Familial combined hyperlipidemia (HYPLIP1; 602491) is due to variation in the USF1 gene (191523) on chromosome 1q21-q23. Some mutations in the ABCA1 gene (600046) caused Tangier disease (205400), whereas others caused a mild disorder called type II familial high density lipoprotein deficiency, or hypoalphalipoproteinemia (604091). Both disorders are associated with hypertriglyceridemia.
Namboodiri et al. (1977) studied a large kindred with a high frequency of cardiac illness and with hyperlipidemia. Triglycerides showed 75% of the 'variance accountable by genetic transmission' and cholesterol 52%. Whether the disorder in this kindred should ... Namboodiri et al. (1977) studied a large kindred with a high frequency of cardiac illness and with hyperlipidemia. Triglycerides showed 75% of the 'variance accountable by genetic transmission' and cholesterol 52%. Whether the disorder in this kindred should be called hypertriglyceridemia or combined hyperlipidemia (144250) is not clear. The authors chose to call it hypertriglyceridemia. Hypertriglyceridemia gave a good fit to autosomal dominant inheritance, the minimal probability of misclassification being 9.3%. Linkage analysis with 27 markers showed a positive score only with pepsinogen (169700): lod of 0.73 at recombination fraction of 0.1. In a 59-year-old man with severe hypertriglyceridemia, Breckenridge et al. (1978) found deficiency of apolipoprotein C-II (APOC2; 207750), which is an activator for lipoprotein lipase (LPL; 609708). After transfusion of 1 unit of plasma the patient's triglycerides fell, within 1 day, from 1000 to 250 mg per deciliter and remained below preinfusion concentration for 6 days.
In DNA studies that showed that the APOA1 gene (107680) and the APOC3 gene (107720) are in close physical linkage, Karathanasis et al. (1983) also showed that the 2 genes are 'convergently transcribed' and that the polymorphism reported ... In DNA studies that showed that the APOA1 gene (107680) and the APOC3 gene (107720) are in close physical linkage, Karathanasis et al. (1983) also showed that the 2 genes are 'convergently transcribed' and that the polymorphism reported by Rees et al. (1983) to be associated with hypertriglyceridemia may be due to a single basepair substitution in the 3-prime-noncoding region of apoC-III mRNA. The apolipoprotein A5 gene (APOA5; 606368) plays an important role in determining plasma triglyceride concentrations in humans. Kao et al. (2003) described a novel variant in APOA5, G553T (606368.0001), that is associated with hypertriglyceridemia. The variant results in substitution of cysteine for glycine-185. The minor allele frequencies were 0.042 and 0.27 (P less than 0.001) for Chinese control and hypertriglyceridemic patients, respectively. The serum triglyceride level was significantly different among the genotypic groups (G/G 92.5 +/- 37.8 mg/dl, G/T 106.6 +/- 34.8 mg/dl, T/T 183.0 mg/dl, P = 0.014) in control subjects. Multiple logistic regression revealed that individuals carrying the minor allele had age, gender, and BMI (body mass index)-adjusted odds ratio of 11.73 (95% confidence interval of 6.617-20.793; P less than 0.0001) for developing hypertriglyceridemia in comparison to individuals without that allele. Wen et al. (2003) identified 2 Caucasian hypertriglyceridemic individuals who were heterozygous for a G-to-A transition at nucleotide 164 of the LIPI gene, resulting in cys55-to-tyr (C55Y; 609252.0001) substitution. They identified 2 other coding SNPs that were associated with variation in plasma HDL cholesterol in independent normolipidemic populations. In a study of a total of 555 individuals with hypertriglyceridemia (HTG), diagnosed with Fredrickson hyperlipoproteinemia phenotypes 2B (144250), 3 (107741), 4 (144600), or 5 (144650), and 1,319 controls, Johansen et al. (2010) first performed a genomewide association study and identified common variants in the APOA5, GCKR (600842), LPL, and APOB (107730) genes that were associated with HTG. Resquencing 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% in affected individuals and 15.3% in controls (p = 2.6 x 10(-5)). Johansen et al. (2010) concluded that an accumulation of rare variants contributes to the heritability of complex traits among individuals at the extreme of a lipid phenotype.