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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2450.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Resequencing Genomic DNA of Patients With Severe Hypertriglyceridemia (MIM 144650)

Jian Wang; Henian Cao; Matthew R. Ban; Brooke A. Kennedy; Siqi Zhu; Sonia Anand; Salim Yusuf; Rebecca L. Pollex; Robert A. Hegele

From the Vascular Biology Research Group (J.W., H.C., M.R.B., B.A.K., S.Z., R.L.P., R.A.H.), Robarts Research Institute and Schulich School of Medicine and Dentistry, London, Ontario, Canada; and Population Health Research Institute (S.A., S.Y.), McMaster University, Hamilton Health Sciences, Hamilton, Ontario, Canada.

Correspondence to Dr Robert A. Hegele, MD, FRCPC, FACP, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 100 Perth Drive, Room 406, London, Ontario, Canada N6A 5K8. E-mail hegele{at}robarts.ca

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.

Severe hypertriglyceridemia has been presumed to have a genetic basis, but this has never been quantified. With resequencing, we now document a range of DNA variants in LPL, APOC2, and APOA5 genes which together were found in 41.8% of patients with severe HTG compared with 8.9% of control subjects (P<10^–13).

Key Words: complex trait • metabolism • atherosclerosis • pancreatitis • mutation

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