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Plasma lipid levels are a complex trait with a genetic and an environmental component. There are two models for the genetic basis of complex traits: the common-disease common-variant hypothesis, in which susceptibility is due to variants occurring at relatively high frequency but low effect size; and the common-disease rare-variant hypothesis, where disease is due to multiple rare variants each occurring at low frequency but with high effect size. Genome-wide association studies have identified a number of common variants associated with plasma lipid levels. However, they account for only a proportion of the genetic variance. Resequencing studies are revealing the importance of rare variants in accounting for the missing variance. Next-generation sequencing will allow the relative importance of the two hypotheses to be assessed.

Background: APOE (apolipoprotein E gene) 2/2 genotype and an apolipoprotein B/total cholesterol (ApoB/TC) ratio <0.15 are diagnostic for type III hyperlipidemia. We hypothesized that patients with APOE genotype 2/3 or 2/4 and an ApoB/TC ratio <0.15 may have a mutation in their epsilon 3 or 4 allele, resulting in a type III hyperlipidemia phenotype. Objective: We tested this hypothesis. Methods: The DNA sequence of all 4 exons and exon/intron boundaries of the APOE (plus 600 bp upstream of exon 1) of 47 patients with APOE 2/3 and 18 patients with APOE 2/4 genotype and an ApoB/TC ratio <0.15 was determined. As controls the APOE sequence of 53 APOE genotype 2/3 and 20 APOE genotype 2/4 probands with ApoB/TC ratio >0.15 was determined. The sequence analysis was extended to include 47 patients with APOE genotype 3/3, 14 with APOE genotype 3/4, and 3 with APOE genotype 4/4 and an ApoB/TC ratio <0.15. Finally, we determined the sequence of the APOE gene in 145 patients with an ApoB/TC ratio >0.15 and who had triglycerides above the 90th percentile for age and sex. Results: No deleterious variants in the APOE gene were observed in patients with APOE genotype other than 2/2 and an ApoB/TC ratio <0.15. Only a single probably deleterious variant, K72E, was observed in patients with triglycerides above the 90th percentile. Conclusions: Patients with an ApoB/TC ratio <0.15 do not have an increased likelihood of mutation in the APOE gene, and rare variants in the APOE gene are not important in the development of hypertriglyceridemia. [Copyright &y& Elsevier]

Background: Rare variants in the protein coding regions of the lipoprotein lipase (LPL) gene have been shown to be important in the development of hypertriglyceridemia. Objectives: The aim of this study was to determine whether rare variants in the 3′ and 5′ untranslated regions (UTRs) of the LPL gene are also associated with severe hypertriglyceridemia. Methods: The DNA sequences of the 3′ and 5′ UTRs of the LPL gene of 63 patients with triglycerides > 875 mg/dL (10 mmol) and 69 probands with triglycerides below the 25th percentile for age and sex were determined. The sequence at the 5′ end was extended to include 2 further elements (−702 to −666 and −468 to −430) shown to be associated with the control of LPL expression. Results: No statistically significant difference was found in the occurrence of rare mutations in either the 3′ or the 5′ UTRs between the 2 groups. Sequence analysis allowed the genotyping of 47 single nucleotide polymorphisms (SNPs) in the 3′ UTR and 11 in the 5′ UTR. Two groups of SNPs in the 3′ UTR, based on allelic association, were statistically significantly associated with plasma triglycerides. Each of these groups contained SNPs in the target sequences for microRNAs. These findings were replicated in independently formed groups. Conclusion: We provide genetic evidence that microRNAs may play a role in the expression of LPL and thus plasma triglyceride levels. [Copyright &y& Elsevier]