August 24, 2007Open Access
View Full PaperResequencing Genomic DNA of Patients With Severe Hypertriglyceridemia (MIM 144650)
Key Result
Rare mutations in LPL, APOC2, or APOA5, or the APOA5 p.S19W variant, were present in 41.8% of patients with severe hypertriglyceridemia versus 8.9% of controls (OR 7.4; 95% CI 4.5-12.0).
Study Design
Type
Case-Control (n=582)
Structured PICO
Do coding sequence variants in LPL, APOC2, and APOA5 genes associate with severe hypertriglyceridemia in nondiabetic adults?
P
Population
582 adults, comprising 110 nondiabetic patients with severe hypertriglyceridemia and 472 age- and sex-matched normolipidemic controls.
E
Exposure
Resequencing of candidate genes LPL, APOC2, and APOA5
C
Comparator
Normolipidemic controls
O
Outcome
Prevalence of coding sequence variants (missense mutations) in candidate genessurrogate
Rare and common DNA variants in LPL, APOC2, and APOA5 genes are present in a substantial proportion of patients with severe hypertriglyceridemia, highlighting the genetic basis of the disorder.
Main Result
Odds Ratio: 7.4 (95% CI 4.5–12)
Absolute Event Rate: 41.8% vs 8.9%
Abstract
OBJECTIVE: The genetic determinants of severe hypertriglyceridemia (HTG; MIM 144650) in adults are poorly defined. We therefore resequenced 3 candidate genes, namely LPL, APOC2, and APOA5, to search for accumulation of missense mutations in patients with severe HTG compared with normolipidemic subjects. METHODS AND RESULTS: We resequenced >2 million base pairs of genomic DNA from 110 nondiabetic patients with severe HTG and determined the prevalence of coding sequence variants compared with 472 age- and sex-matched normolipidemic controls. We found: (1) heterozygous mutations (LPL p.Q-12E >11X, p.D25H, p.W86R, p.G188E, p.I194T and p.P207L; APOC2 p.K19T and IVS2-30G>A) in 10.0% of severe HTG patients compared with 0.2% of controls (carrier odds ratio OR 52, 95% confidence interval CI 8.6 to 319); and (2) an association of the APOA5 p.S19W missense variant with severe HTG (carrier OR 5.5 95% CI 3.3 to 9.1). Furthermore, either rare mutations or the APOA5 p.S19W variant were found in 41.8% of HTG subjects compared with 8.9% of controls (carrier OR 7.4, 95% CI 4.5 to 12.0). Also, heterozygotes for rare mutations had a significantly reduced plasma triglyceride response to fibrate monotherapy. CONCLUSIONS: Both common and rare DNA variants in candidate genes were found in a substantial proportion of severe HTG patients. The findings underscore the value of candidate gene resequencing to understand the genetic contribution in complex lipoprotein and metabolic disorders.