Rare APOA5 promoter variants associated with paradoxical HDL cholesterol decrease in response to fenofibric acid therapy

Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins Individuals with mixed dyslipidemia, including high triglycerides (TGs) and low high density lipoprotein cholesterol (HDL-C), have increased risk for coronary events. We examined the effect of rare genetic variants in the APOA5 gene region on plasma HDL-C, apolipoprotein A-I (apoA-I), and TG response to fenofibric acid monotherapy and in combination with statins. The APOA5 gene region was sequenced in 1,612 individuals with mixed dyslipidemia in a randomized trial of fenofibric acid alone and in combination with statins. Student's t-test and rare variant burden tests were used to examine plasma HDL-C, apoA-I, and TG response. Rare APOA5 promoter region variants were associated with decreased HDL-C and apoA-I levels in response to fenofibric acid therapy; rare missense variants were associated with increased TG response to combination therapy. Further study is needed to examine the effect of these rare variants on coronary outcomes in this population in response to fenofibric acid monotherapy or combined with statins Mixed dyslipidemia, which occurs frequently in individuals with insulin resistance, such as those with metabolic syndrome, is characterized by elevated triglycerides (TGs) and decreased high density lipoprotein cholesterol (HDL-C). Genome-wide association studies have demonstrated associations between common genetic variants and interindividual differences in serum TGs and HDL-C (1Kathiresan S. Willer C.J. Peloso G.M. Demissie S. Musunuru K. Schadt E.E. Kaplan L. Bennett B. Li Y. Tanaka T. et al.Common variants at 30 loci contribute to polygenic dyslipidemia.Nat. Genet. 2009; 41: 56-65Crossref PubMed Scopus (1085) Google Scholar, 2Teslovich T.M. Musunuru K. Smith A.V. Edmondson A.C. Stylianou I.M. Koseki M. Pirruccello J.P. Ripatti S. Chasman D.I. Willer C.J. et al.Biological, clinical and population relevance of 95 loci for blood lipids.Nature. 2010; 466: 707-713Crossref PubMed Scopus (2781) Google Scholar). Rarer genetic variants, with frequency of less than 1%, discovered by DNA sequencing show a larger effect size on the respective quantitative traits (3Johansen C.T. Wang J. Lanktree M.B. Cao H. McIntyre A.D. Ban M.R. Martins R.A. Kennedy B.A. Hassell R.G. Visser M.E. et al.Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.Nat. Genet. 2010; 42: 684-687Crossref PubMed Scopus (373) Google Scholar, 4Vergeer M. Korporaal S.J. Franssen R. Meurs I. Out R. Hovingh G.K. Hoekstra M. Sierts J.A. Dallinga-Thie G.M. Motazacker M.M. et al.Genetic variant of the scavenger receptor BI in humans.N. Engl. J. Med. 2011; 364: 136-145Crossref PubMed Scopus (266) Google Scholar). An important potential application of common and rare variants is to improve prediction of individualized response to therapy and personalize therapy based on that information. Fibrates, including fenofibric acid, increase HDL-C and apolipoprotein A-I (apoA-I) and decrease TGs in individuals with mixed dyslipidemia who are at increased risk for coronary heart disease (5Birjmohun R.S. Hutten B.A. Kastelein J.J. Stroes E.S. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials.J. Am. Coll. Cardiol. 2005; 45: 185-197Crossref PubMed Scopus (372) Google Scholar, 6Farnier M. Freeman M.W. Macdonell G. Perevozskaya I. Davies M.J. Mitchel Y.B. Gumbiner B. Ezetimibe Study Group Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia.Eur. Heart J. 2005; 26: 897-905Crossref PubMed Scopus (171) Google Scholar, 7Farnier M. Roth E. Gil-Extremera B. Mendez G.F. Macdonell G. Hamlin C. Perevozskaya I. Davies M.J. Kush D. Mitchel Y.B. Ezetimibe/Simvastatin + Fenofibrate Study Group Efficacy and safety of the coadministration of ezetimibe/simvastatin with fenofibrate in patients with mixed hyperlipidemia.. 2007; 153: 335.e1-335.e8Google Scholar, 8Staels B. Dallongeville J. Auwerx J. Schoonjans K. Leitersdorf E. Fruchart J.C. Mechanism of action of fibrates on lipid and lipoprotein metabolism.Circulation. 1998; 98: 2088-2093Crossref PubMed Scopus (1409) Google Scholar). Fenofibric acid is a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, and as such, its effect can be influenced by common and rare variants in genes involved in the PPAR-α pathway. ApoA5 is an important component of TG lipolysis while inhibiting production of very low density lipoprotein (LDL). Individuals with mutations in the APOA5 gene were found to have high TG. Common single nucleotide polymorphisms (SNPs) in the APOA5 gene region were found to be associated with TG and HDL-C levels (9Garelnabi M. Lor K. Jin J. Chai F. Santanam N. The paradox of ApoA5 modulcation of triglycerides: evidence from clinical and basic research.Clin. Biochem. 2013; 46: 12-19Crossref PubMed Scopus (48) Google Scholar). In recent studies, SNPs in the APOA5 gene region were shown to be significantly associated with both HDL-C and TG response to fibrate monotherapy or in combination with statins (10Brautbar A. Covarrubias D. Belmont J. Lara-Garduno F. Virani S.S. Jones P.H. Leal S.M. Ballantyne C.M. Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.Atherosclerosis. 2011; 219: 737-742Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 11Lai C.Q. Arnett D.K. Corella D. Straka R.J. Tsai M.Y. Peacock J.M. Adiconis X. Parnell L.D. Hixson J.E. Province M.A. et al.Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1417-1425Crossref PubMed Scopus (108) Google Scholar, 12Brautbar A. Virani S.S. Belmont J. Nambi V. Jones P.H. Ballantyne C.M. LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.J. Lipid Res. 2012; 53: 556-560Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 13Ma L. Ballantyne C.M. Belmont J.W. Keinan A. Brautbar A. Interaction between SNPs in the RXRA and near ANGPTL3 gene region inhibit apolipoprotein B reduction following statin-fenofibric acid therapy in individuals with mixed dyslipidemia.J. Lipid Res. 2012; 53: 2425-2428Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). In this study, we examined the association between rare genetic variants in the APOA5 gene region and change in HDL-C, apoA-I, and TG levels in response to FA alone and in combination with statins. We have included the introns, 3′ untranslated region (UTR), and promoter region of APOA5 as possible regulatory regions that may affect response to PPAR-α agonists. We hypothesized that rare genetic variants affect the response of HDL-C, apoA-I, and TGs to therapy with fenofibric acid in individuals with mixed dyslipidemia. Our study population included European-American participants from three concurrent prospective randomized double-blind clinical trials that examined the efficacy of fenofibric acid. A detailed description of the study design has been published previously (14Jones P.H. Bays H.E. Davidson M.H. Kelly M.T. Buttler S.M. Setze C.M. Sleep D.J. Stolzenbach J.C. Evaluation of a new formulation of fenofibric acid, ABT-335, co-administered with statins: study design and rationale of a phase III clinical programme.Clin. Drug Investig. 2008; 28: 625-634Crossref PubMed Scopus (36) Google Scholar). Individuals with TGs ≥150 mg/dl, HDL-C <40 mg/dl in men or <50 mg/dl in women, and low density lipoprotein cholesterol (LDL-C) ≥130 mg/dl were eligible and were randomized into six groups for each trial: fenofibric acid monotherapy, lower-dose statin monotherapy, moderate-dose statin monotherapy, higher-dose statin monotherapy, FA + lower-dose statin, and Fenofibric acid + higher-dose statin. Fenofibric acid was given in a 135 mg dose in the fenofibric acid only and statin + fenofibric acid groups. Each study used a different statin: rosuvastatin, atorvastatin, or simvastatin. In all studies, participants had a 6 week washout period with no lipid-modifying therapy followed by a 12 week treatment period. Lipid measurements were obtained at the beginning and end of the treatment period. To enhance statistical power, treatment groups of the original studies were collapsed into three major therapy groups: fenofibric acid monotherapy (n = 284), statin monotherapy (n = 753), and fenofibric acid + statin combination therapy (n = 575). The distribution of statins in the fenofibric acid + statin and statin alone groups is detailed in supplementary Table I. The study was approved by the Institutional Review Board of Baylor College of Medicine, and informed consent was obtained by Abbott Laboratories. The Sanger method was used to sequence the APOA5 gene including exons, introns, and promoter regions. Bidirectional sequencing of the APOA5 gene was performed at the Human Genome Sequencing Center at Baylor College of Medicine using intron-based exon-specific primers. Polymerase chain reactions (PCRs) were performed in 8 μl containing 10 ng of genomic DNA, 0.4 μM oligonucleotide primers, and 0.7× Qiagen® PCR HotStar Taq Master Mix containing buffer and polymerase. Cycling parameters were 95° for 15 min, 95° for 45 s, 60° for 45 s, and 72° for 45 s for 40 cycles, followed by a final extension at 72° for 7 min. After thermocycling, 5 μl of a 1:15 dilution of Exo-SAP was added to each well, and reactions were incubated at 37°C for 15 min prior to inactivation at 80° for 15 min. Reactions were diluted by 0.6×, and 2 μl were combined with 5 μl of 1/64 Applied Biosystems® BigDye™ sequencing reaction and as for Reactions were with in and on Applied sequencing using the and SNPs were identified using J. I. S. R. R.A. a for and Biol. 2005; PubMed Scopus Google Scholar). mutations were by of the original DNA The APOA5 gene was by a of The is and the of the is at that and to is untranslated and be of as the end of the The 2 is at or on The is at The from the end of the to the is which was as the promoter for the of the were used for the a we rare variants as and promoter frequency was by the following of + 2 tests used in the included and B. Leal S.M. for associations with rare variants for common application to of sequence J. Genet. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, S.M. J. association tests for rare variants in J. Genet. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, A association for rare mutations using a Genet. 2009; PubMed Scopus Google Scholar). prediction of or was in those the variants be to participants were in a a rare was at of the variant in a gene or gene participants were in a including and were for both rare and groups and were by to therapy was as the between and levels = final HDL-C were for and lipid or lipoprotein We obtained from the of = + + + + HDL-C and using Student's t-test or burden tests were for the which included the and the and therapy = + plasma of HDL-C, apoA-I, and TGs were significantly different the fenofibric acid + statin, statin monotherapy, and fenofibric acid monotherapy treatment groups. were differences between and for and based on the <40 for HDL-C <50 for were or differences for and were in with men of and on the treatment was a frequency of in women, this was of the study between and acid + acid acid + acid acid + acid acid + acid acid + acid acid + acid of is detailed in between and in a new The of is detailed in levels of HDL-C and apoA-I increased and TGs decreased in response to therapy in all treatment groups. the in HDL-C and apoA-I were in the fenofibric acid + statin combination and with statin A was for the decrease in TGs following therapy apoA-I, and TG levels in response to and therapy acid + acid acid + acid acid + acid to therapy is by levels is for Student's t-test of no and therapy in a new to therapy is by levels is for Student's t-test of no response. had HDL-C response to therapy than men in the groups fenofibric acid, alone or in to in the statin alone treatment response for for apoA-I therapy response in the fenofibric acid only for the fenofibric acid + statin A possible of the differences in HDL-C response between men and be to the in HDL-C and in had and were than this may have for therapy with fenofibric acid, with or for therapy fenofibric acid as in the statin of response to therapy between men and is detailed in supplementary Table the of the APOA5 gene in the of the variants, was an change in the acid we the rare DNA variants into six APOA5 3′ APOA5 APOA5 APOA5 and APOA5 rare variants with a frequency of were included in the rare variants, genomic frequency in population study, frequency in a sequencing or and of individuals who each variant in study are detailed in supplementary Table A of rare variants were of which were previously in an frequency between and were participants who had rare variants, and participants who had three We used to potential rare variant associations each method may have on the genetic of the of rare genetic variants in the APOA5 promoter demonstrated associations with in HDL-C and apoA-I in response to FA in to the The change in HDL-C following fenofibric acid monotherapy for participants with rare variants was for participants rare variants, the change in HDL-C following fenofibric acid monotherapy was of these using Student's t-test or by the frequency method = all participants in the fenofibric acid monotherapy with rare variants in the APOA5 promoter region had a decrease or a very increase in HDL-C in response to therapy the statin monotherapy and combination therapy HDL-C in response to therapy were significantly different in participants with participants rare variants in the APOA5 promoter A was for plasma apoA-I response to therapy; the change in apoA-I in response to fenofibric acid monotherapy was mg/dl in participants with rare variants in the APOA5 promoter region mg/dl in participants rare variants in the APOA5 promoter the between these was by Student's t-test and the method = were no associations between of APOA5 rare variants and HDL-C response to fenofibric acid of rare variants with change in rare HDL-C from of APOA5 by in are of participants with rare of Rare Variants Rare Variants acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy for HDL-C, and TGs by treatment in are of participants with rare of rare in a new of rare variants with change in rare apoA-I from of APOA5 variant by treatment in are of participants with rare of Rare Variants Rare Variants acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy for HDL-C, and TGs by treatment in are of participants with rare of rare in a new for HDL-C, and TGs by treatment groups. for HDL-C, and TGs by treatment groups. We a effect of missense variants in APOA5 on TG response to therapy The change in TGs in response to fenofibric acid + statin therapy was mg/dl in participants with rare missense variants in the APOA5 with mg/dl in participants rare variants in the the was using both the Student's t-test = and method = In the fenofibric acid monotherapy treatment change in TGs was significantly different between participants with rare missense variants and those only participants had rare missense variants in that treatment In to the of HDL-C response to was no association between the change in TGs following fenofibric acid monotherapy and rare variants in the region of the APOA5 promoter A in change in TGs in response to fenofibric acid monotherapy was found in participants with rare variants in the APOA5 only individuals had rare variants in that treatment of rare variants with change in rare TG from of APOA5 by in are of participants with rare of Rare Variants Rare Variants acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy acid + statin monotherapy acid monotherapy for HDL-C, and TGs by treatment in are of participants with rare of rare in a new for HDL-C, and TGs by treatment groups. In this study, we identified a of rare APOA5 gene promoter variants that were associated with a HDL-C response to fenofibric acid therapy; participants with these variants had a decrease or no change in HDL-C in response to fenofibric acid A was for apoA-I response to fenofibric acid that these variants affect the cholesterol as as the apolipoprotein component of the The APOA5 promoter has previously been shown to have an important effect on gene and N. H. M. E. H. B. J. et a of plasma triglyceride is to peroxisome proliferator-activated receptor a Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). et N. H. M. E. H. B. J. et a of plasma triglyceride is to peroxisome proliferator-activated receptor a Biol. Full Text Full Text PDF PubMed Scopus Google identified a of regions in the APOA5 promoter that gene including a peroxisome studies have shown the of a common APOA5 promoter for APOA5 in J. L. of the of common APOA5 Biol. 2005; Full Text Full Text PDF PubMed Scopus Google association with HDL-C, coronary disease in and N. E. S.M. H. D. et and coronary of 2010; Full Text Full Text PDF PubMed Scopus Google Scholar, R. L. R. D. F. F. D. S. L. D. association of the gene variant and 2011; Full Text Full Text PDF PubMed Scopus Google and response to fibrate therapy F. M. M. J. The of the APOA5 gene response to fenofibrate treatment in patients with the metabolic a postprandial 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). the of the APOA5 gene promoter as a of APOA5 and is the variants identified in study were in the region of the APOA5 is possible that APOA5 promoter in response to fenofibric acid and may have an inhibiting effect on gene with fenofibric acid. The possible clinical of the rare promoter variants identified in this study to fenofibric acid therapy in a study individuals with mixed dyslipidemia, such as the participants in this study, are at high risk for coronary heart disease events. from a of clinical trials that in individuals with mixed dyslipidemia, fibrate therapy may improve coronary monotherapy with fibrate and PPAR-α agonist, coronary in the Heart Study in men with mg/dl at M.H. K. V. et Heart trial with in men with dyslipidemia. of in risk and of coronary heart Engl. J. Med. PubMed Scopus Google and in the in men with HDL-C mg/dl S.J. D. J.W. M.B. E. G. et for the of coronary heart disease in men with low levels of high-density lipoprotein Study Engl. J. Med. PubMed Scopus Google Scholar). The was with fenofibrate in the Fenofibrate and in study A. R.J. J. R. M.R. A. T. D. D. M. M. C. M. study of fenofibrate therapy on in with 2 randomized controlled 2005; Full Text Full Text PDF PubMed Scopus Google with mixed dyslipidemia ≥150 mg/dl and HDL-C <40 mg/dl in men and <50 mg/dl in who had a reduction in risk for A. R.J. J. R. M.R. A. T. D. D. M. M. C. M. study of fenofibrate therapy on in with 2 randomized controlled 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). is possible that the rare APOA5 promoter variants identified in this study, which were associated with or no change in HDL-C and apoA-I may the coronary heart disease reduction effect of fenofibric acid in the mixed dyslipidemia a PPAR-α agonist, fenofibric acid including lipoprotein apoA-I, and the by which PPAR-α increase lipoprotein and apoA-I levels is Li M. P.H. proliferator-activated receptor a with a Res. PubMed Scopus Google Scholar). A of studies have examined the effect of missense common SNPs on response to fenofibrate therapy. et C.Q. Arnett D.K. Corella D. Straka R.J. Tsai M.Y. Peacock J.M. Adiconis X. Parnell L.D. Hixson J.E. Province M.A. et al.Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1417-1425Crossref PubMed Scopus (108) Google an association of a single in APOA5 with HDL-C and TG response to fenofibric acid therapy. In study, a reduction in TGs was for participants who had rare missense variants with those who in the fenofibric acid + statin combination therapy and a a in the fenofibric acid monotherapy Our study has a of was a clinical trial that included only individuals with mixed dyslipidemia which are to be of the population D. E.E. of lipid in the the and 2012; Full Text Full Text PDF PubMed Scopus Google and this had a effect on the of the study had a single that was based on published studies common SNPs in the including SNPs in the promoter which were shown to effect fibrate therapy response in studies (10Brautbar A. Covarrubias D. Belmont J. Lara-Garduno F. Virani S.S. Jones P.H. Leal S.M. Ballantyne C.M. Variants in the APOA5 gene region and the response to combination therapy with statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.Atherosclerosis. 2011; 219: 737-742Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 11Lai C.Q. Arnett D.K. Corella D. Straka R.J. Tsai M.Y. Peacock J.M. Adiconis X. Parnell L.D. Hixson J.E. Province M.A. et al.Fenofibrate effect on triglyceride and postprandial response of apolipoprotein A5 variants: the GOLDN study.Arterioscler. Thromb. Vasc. Biol. 2007; 27: 1417-1425Crossref PubMed Scopus (108) Google Scholar, F. M. M. J. The of the APOA5 gene response to fenofibrate treatment in patients with the metabolic a postprandial 2009; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J.M. G. Province M. Straka R.J. Tsai M.Y. C.Q. K. I. Hixson J.E. et association of the gene and lipid to the of and 2009; PubMed Scopus Google Scholar). In an in published studies rare variants of quantitative traits was to examine the of the distribution which is to be for rare the the study was to examine only individuals with elevated TGs and low HDL-C, and elevated the mixed dyslipidemia individuals are to be for rare variants in genes lipid including the APOA5 gene a larger size have been for the in this study and population of mixed dyslipidemia that is a of the population for rare variants, the size and study design were to the of the APOA5 gene in fibrate therapy response by the of rare variants in the response to fenofibric acid therapy. the distribution of the statins in the statin alone and statin + fenofibric acid treatment groups which the of the of each statin and major was in the fenofibric acid alone which was with to its therapy. is important to that was a increase in response to therapy levels of HDL-C, and based on the of therapy combination fenofibric acid was a response to statins a response to fenofibric acid and for the statin + fenofibric acid combination with fenofibric acid is in with studies response to statin and fibrate that study the therapy response in clinical different statins were the effect was to studies statins and combination with In the study is the to show that rare variants in the APOA5 gene promoter region are associated with a decrease in plasma HDL-C and apoA-I in response to fenofibric acid rare missense variants in the APOA5 gene were associated with reduction in TGs in response to the combination of fenofibric acid and statin. may be for the interindividual differences in response to fibrate therapy and may be associated with the effect of fibrate monotherapy, or in combination with on coronary outcomes in individuals with mixed dyslipidemia. sequencing and in the clinical rare variants such as those identified in this study may to personalize fibrate therapy. The to the of the following individuals the Human Genome Sequencing Center at Baylor College of and The of the for in this with high density lipoprotein cholesterol low density lipoprotein cholesterol peroxisome proliferator-activated receptor-α peroxisome high density lipoprotein cholesterol single nucleotide triglyceride untranslated region

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