A number sign (#) is used with this entry because susceptibility to hypertriglyceridemia has been associated with mutation in the apolipoprotein A5 gene (APOA5; 606368).Description
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.Clinical Features
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.
Austin et al. (2000) provided 20-year follow-up on 101 families with combined hyperlipidemia (see 144250) or hypertriglyceridemia, ascertained in 2 studies conducted in the early 1970s. Compared with spouse controls, 20-year mortality risk from cardiovascular disease (CVD) was significantly increased among sibs and offspring in familial combined hyperlipidemia (relative risk, 1.7) but not in hypertriglyceridemia families. However, baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in hypertriglyceridemia families (relative risk, 2.7), but not in combined hyperlipidemia families.Mapping
Duggirala et al. (2000) conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. They used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). After accounting for the effects of sex and sex-specific age terms, they found significant evidence for linkage (lod = 3.88) of ln TG levels to a genetic location between the markers GABRB3 (137192) located at 15q11.2 and D15S165 located at 15q12-q13.1. This putative locus explains 39.7 +/- 7% (p = 0.000012) of total phenotypic variation in ln TG levels. Some evidence for linkage to 2 different locations on chromosome 7 was found.Molecular Genetics
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.
The APOA5*2 haplotype includes the rare C allele of the SNP c.*158C-T (rs2266788; 606368.0004), located in the 3-prime untranslated region (UTR), in strong linkage disequilibrium with 3 other SNPs. Individuals with APOA5*2 display reduced APOA5 expression at the posttranscriptional level. Caussy et al. (2014) hypothesized that the hypertriglyceridemic effects of APOA5*2 could involve miRNA regulation in the APOA5 3-prime UTR. Bioinformatic studies identified the creation of a potential miRNA binding site for liver-expressed MIR485 (615385)-5p in the mutant APOA5 3-prime UTR with the c.*158C allele. In HEK293T cells cotransfected with an APOA5 3-prime UTR luciferase reporter vector and a MIR485-5p precursor, c.*158C allele expression was significantly decreased. Moreover, in Huh-7 cells endogenously expressing MIR485-5p, Caussy et al. (2014) observed that luciferase activity was significantly lower in the presence of the c.*158C allele than in the presence of the c.*158T allele, which was completely reversed by a MIR485-5p inhibitor. Caussy et al. (2014) suggested that the well-documented hypertriglyceridemic effect of APOA5*2 involves an APOA5 posttranscriptional downregulation mediated by MIR485-5p.
Do et al. (2015) found that a burden of rare alleles in APOA5 and LDLR contributes to risk for myocardial infarction, with APOA5 mutation carriers having higher plasma triglycerides and LDLR mutation carriers having higher plasma LDL cholesterol (see Other Associations).
In a study of a total of 555 individuals with hypertriglyceridemia, 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 hypertriglyceridemia. Resequencing of these genes revealed a significant burden of 154 rare missense or nonsense variants in 438 individuals with hypertriglyceridemia 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.
In a 5-generation family of European American descent previously ascertained as part of a cohort for a study of familial combined hyperlipidemia (Austin et al., 2000), Rosenthal et al. (2013) performed Bayesian Markov chain Monte Carlo joint oligogenic linkage and association analysis combined with whole-exome sequencing data and detected shared, highly conserved, private missense variants in both SLC25A40 (610821) on chromosome 7 and PLD2 (602384) on chromosome 17. Jointly, these variants explained 49% of the genetic variance in triglyceridemia; however, only the SLC25A40 variant was significantly associated with triglyceride levels (p = 0.0001). The c.374A-G transition in exon 7 of the SLC25A40 gene results in a highly disruptive tyr125-to-cys (Y125C) substitution at a highly conserved residue just outside the second helical transmembrane region of the inner mitochondrial membrane transport protein. Rosenthal et al. (2013) noted that it is possible that the Y125C variant is not pathogenic but is in linkage disequilibrium with a causal variant. Whole-genome testing using Exome Sequencing Project data confirmed the association between 5 rare missense variants in SLC25A40 and triglyceride levels.
Do et al. (2015) sequenced the protein-coding regions of 9,793 genomes from patients with myocardial infarction (MI) at an early age (50 years or younger in males and 60 years or younger in females) along with MI-free controls. They identified 2 genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exomewide significance: LDLR (606945) and APOA5 (606368). Carriers of rare nonsynonymous mutations in LDLR were at 4.2-fold increased risk for MI, while carriers of null alleles in LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbor a rare, damaging mutation in LDLR; this estimate is similar to one made by Goldstein et al. (1973) using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol greater than 190 mg/dl. Carriers of rare nonsynonymous mutations in APOA5 were at 2.2-fold increased risk for MI. When compared with noncarriers, LDLR mutation carriers had higher plasma LDL cholesterol (see 143890), whereas APOA5 mutation carriers had higher plasma triglycerides. Evidence has connected MI risk with coding-sequence mutations at 2 genes functionally related to APOA5, namely lipoprotein lipase (LPL; 609708) and apolipoprotein C-III (APOC3; 107720). Do et al. (2015) concluded that LDL cholesterol as well as disordered metabolism of triglyceride-rich lipoproteins contributes to myocardial infarction risk.
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.