Rare LPL gene variants attenuate triglyceride reduction and HDL cholesterol increase in response to fenofibric acid therapy in individuals with mixed dyslipidemia.
OBJECTIVE
Individuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency ≤ 1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy.


METHODS
Four genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis.


RESULTS
Synonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P = 9 × 10(-4)) and TG percent change (P = 6.76 × 10(-4)) in those treated with FA only. Participants with these rare variants had a 2 mg/dL increase in HDL-C and 39 mg/dL decrease in TG as compared to 6.2 mg/dL increase in HDL-C and 100 mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3 mg/dL less reduction in APOB (P = 8.72 × 10(-4)) in those receiving FA and statin.


CONCLUSIONS
In individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA.
Feng
F
Gao
Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA.
Christie
C
Ballantyne
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA; Department of Animal and Avian Sciences, University of Maryland, College Park, MD, USA.
Li
L
Ma
Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA; Michael E. DeBakey Veterans Affairs Medical Center Health Services Research and Development Center for Innovations, Houston, TX, USA.
Salim S
SS
Virani
Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA. Electronic address: ak735@cornell.edu.
Alon
A
Keinan
Section of Cardiovascular Research, Baylor College of Medicine, Houston, TX, USA; Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, Houston, TX, USA; Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA. Electronic address: brautbar@bcm.edu.
Ariel
A
Brautbar
D053299:Apolipoprotein B-100 / Q000097:blood; D053305:Apolipoprotein C-III / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D011345:Fenofibrate / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008071:Lipoprotein Lipase / Q000235:genetics*; D008297:Male; D010597:Pharmacogenetics; D010641:Phenotype; D011446:Prospective Studies; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood*
C569471:APOB protein, human; D053299:Apolipoprotein B-100; D053305:Apolipoprotein C-III; D015415:Biomarkers; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase; D011345:Fenofibrate
Dyslipidemia; Fenofibric acid; High-density lipoprotein cholesterol; LPL gene variants