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Title: Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study

Author
item WOJCZYNSKI, MARY - University Of Alabama
item GAO, GUIMIN - University Of Alabama
item BORECKI, INGRID - Washington University School Of Medicine
item HOPKINS, PAUL - University Of Utah
item Parnell, Laurence
item Lai, Chao Qiang
item ORDOVAS, JOSE - Tufts University
item ARNETT, DONNA - University Of Alabama

Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/19/2010
Publication Date: 11/1/2010
Citation: Wojczynski, M.K., Gao, G., Borecki, I., Hopkins, P.N., Parnell, L.D., Lai, C., Ordovas, J.M., Arnett, D.K. 2010. Apolipoprotein B genetic variants modify the response to fenofibrate: a GOLDN study. Journal of Lipid Research. 51(11):3316-3323.

Interpretive Summary: Hypertriglyceridemia is defined as elevated blood levels of triglyceride (TG), above 150 mg/dl. This condition is found in about 34% of adult Americans. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. Furthermore, fibrates can activate a set of genes that serve to regulate key aspects of fat metabolism. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential participant in triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in TG response to fenofibrate treatment. 958 participants of the of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate. Associations of four APOB gene variants (rs934197, rs693, rs676210, and rs1042031) were tested for the TG response to fenofibrate in specific statistical models. One of these genetic variants, rs676210, showed a relationship with the TG response to fenofibrate such that persons carrying two copies of the rare variant (T) showed a greater lowering of TG than those persons carrying two copies of the common variant (C). This finding reached statistical significance. We conclude that the APOB rs676210 variant may identify individuals who respond better to fenofibrate for the treatment of hypertriglyceridemia.

Technical Abstract: Hypertriglyceridemia, defined as a triglyceride measurement > 150 mg/dl, occurs in up to 34% of adults. Fenofibrate is a commonly used drug to treat hypertriglyceridemia, but response to fenofibrate varies considerably among individuals. We sought to determine if genetic variation in apolipoprotein B (APOB), an essential core of triglyceride-rich lipoprotein formation, may account for some of the inter-individual differences observed in triglyceride (TG) response to fenofibrate treatment. Participants (N=958) from the Genetics of Lipid Lowering Drugs and Diet Network study completed a three-week intervention with fenofibrate 160 mg/day. Associations of four APOB gene single nucleotide polymorphisms (SNPs) (rs934197, rs693, rs676210, and rs1042031) were tested for the TG response to fenofibrate using a mixed growth curve model where the familial structure was modeled as a random effect and cardiovascular risk factors were included as covariates. Three of these four SNPs change the amino acid sequence of APOB and the fourth is in the promoter region. TG response to fenofibrate treatment was associated with one APOB SNP, rs676210, such that participants with the TT genotype of rs676210 had greater TG lowering than those with the CC genotype (additive model, p=0.0017). We conclude the rs676210 variant may identify individuals who respond best to fenofibrate for TG reduction.