Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH...
-
Upload
conrad-simmons -
Category
Documents
-
view
215 -
download
0
Transcript of Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH...
![Page 1: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/1.jpg)
Baseline genetics and fenofibrateresponse in the ACCORD clinical
trial
Daniel Rotroff PhD, MSPH
September 18, 2015
Postdoctoral Research Fellow, Bioinformatics Research Center, North Carolina State University
![Page 2: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/2.jpg)
2Background on Dyslipidemia
o ~31.7% of adults in the U.S. have high LDL, and less than ½ are receiving cholesterol treatment.
o Individuals with high cholesterol are at ~2x risk for heart disease.
o People with type 2 diabetes are 2-3x more likely to develop cardiovascular disease, placing individuals with high cholesterol and type 2 diabetes at especially high risk.
![Page 3: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/3.jpg)
3Rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Clinical Trial
o All individuals enrolled have type 2 diabetes.
o Conclusion was that these treatments do not reduce cardiovascular events over standard treatments--one trial arm actually increased mortality.
o However, variability in response was observed.
“The purpose of this study is to prevent major cardiovascular events (heart attack, stroke, or cardiovascular death) in adults with type 2 diabetes mellitus using intensive glycemic control, intensive blood pressure control, and multiple lipid management.”-https://clinicaltrials.gov/ct2/show/study/NCT00000620
![Page 4: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/4.jpg)
4Our goals with the ACCORD data
o Start with baseline genetic mapping of lipid phenotypes
o Characterize background etiology of dyslipidemia in individuals with type II diabetes
o Refine rare-variant methods
o Interrogate drug response associations for major trial drugso Fenofibrateo Rosiglitazoneo Metformino Sulfonylureao Statino Insulin
o Collaborators: Alessandro Doria’s group at Joslin Diabetes Center and Harvard Medical School are investigating genetic associations with adverse cardiovascular outcomes
![Page 5: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/5.jpg)
5Genotyping Array and Study Design
o Genotyped using the Affymetrix Axiom Biobank Genotyping Array-exome chip.
o This platform became available on November 1, 2012 and this project was one of the first to use the array.
o The array contains several marker sets:
o The GWA markers were selected to maximize genome-wide coverage of imputed variants in European, Asian, African and Latino populations
~250k genome-wide association (GWA) markers, ~250k exome markers focusing on rare variants, ~70k novel loss-of-function markers, ~20k eQTLs and ~2k pharmacogenomic markers.
![Page 6: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/6.jpg)
6Genotyping Array and Study Design
o New platform-significant efforts to create a sound QC pipeline
o Duplicate samples and HapMap samples were included on each plate
o Considerations were made for:o Hardy-Weinberg equilibriumo Genomic inflationo Sample/probe concordanceo Plate effectso Predicted vs Recorded Gender o Autosomal heterozygosityo Cryptic relatednesso Population stratificationo Others…
o 583,613 variants after QC (from 628,679 total). o 89,212 of these were monomorphic
o Imputed using 1000 genomes reference panelo 26,862,499 imputed variants after QC (71.7% of total imputed
variants)
![Page 7: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/7.jpg)
7Genotyping Array and Study Design
o Population stratification across the ACCORD Trial (n=7929)
![Page 8: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/8.jpg)
8Genetic Associations with Baseline Lipids
o Common Variant Analysis (MAF ≥ 3%) and n=7929
o 292,816 genotyped and 7,812,348 imputed variants had MAF ≥ 3%
o Phenotypes: HDL, LDL, Total Cholesterol, Triglycerides
o Study parameters and covariates were incorporated into the model via expert opinion and backwards selection
![Page 9: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/9.jpg)
9
Genetic Associations with Baseline Lipids
Total Cholesterol LDL
HDL Triglycerides
![Page 10: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/10.jpg)
10
Genetic Associations with Baseline Lipids Total Cholesterol
LDL
![Page 11: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/11.jpg)
11
Genetic Associations with Baseline Lipids
HDL
Triglycerides
![Page 12: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/12.jpg)
12
Common Genetic Associations with Baseline Lipids
![Page 13: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/13.jpg)
13
Genetic Associations with Baseline Lipids
o Rare Variant Analysis (MAF 3%) and n=7929
o We used a suite of 5 commonly used methods
o All methods rely on collapsing of SNPs into geneso 16,480 genes that contained >1 SNP with MAF < 3%o 146,689 genotyped and 73,295 imputed SNPs were included
(median 9 SNPs/gene)
o 5 tests were combined using a correlated Lancaster approach*
o Methods were then adjusted for multiple comparisons using an FDR approach
*Hongying Dai, J., and Yuehua Cui. "A modified generalized Fisher method for combining probabilities from dependent tests." Frontiers in genetics 5 (2014).
![Page 14: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/14.jpg)
14
Rare Genetic Associations with Baseline Lipids Total Cholesterol LDL
HDL Triglycerides
![Page 15: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/15.jpg)
15
Rare Genetic Associations with Baseline Lipids
![Page 16: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/16.jpg)
16
Baseline Common and Rare Variant Conclusions
o Most statistically significant SNPs are in genes previously identified in large meta-analyses
o Indicates that the QC and analysis pipeline for this exome chip are working as expected
o Suggests that the underlying genetic factors contributing to dyslipidemia are similar in patients with type 2 diabetes
o Patients in ACCORD were prescribed many different diabetes, blood pressure, and cholesterol lowering drugs
o We can modify the analysis pipeline used for the baseline analysis to interrogate variants associated with drug response
o Fenofibrate was the first drug chosen due to the ACCORD lipid arm trial design
Next Steps
![Page 17: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/17.jpg)
17
Background on Fibrateso Used to treat high cholesterol (↑HDL, ↓LDL), usually in
combination with statins.
o Use of fibrates alone has been shown to reduce the number of non-fatal myocardial infarctions, but not all-cause mortality.
o Have also been shown to reduce insulin resistance for individuals with type 2 diabetes.
o Activates PPARα, which regulates lipid metabolism in the liver.
![Page 18: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/18.jpg)
18
Study Designo All individuals were on statin and started fibrate at the beginning of
the trial
o Must maintain fibrate compliance for 90 (+/- 10) consecutive days
o Phenotypes: HDL, LDL, Triglycerides, Cholesterol
o Concomitant medications were a major challenge, with over 71 different drugs accounted for in the trial (with a varying degree of detailed records)o Created the following scoring metric:Not on medication during the time-frame0
On medication prior to pre-treatment time point, dropped medication prior to post-treatment time point
1Started medication at or after pre-treatment time point, but dropped prior to post-treatment time point
2Started medication at or after pre-treatment time point and complied through post-treatment time point
3
On medication prior to pre-treatment time point and complied to post-treatment time point4
![Page 19: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/19.jpg)
19
Variation in Fibrate Response
![Page 20: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/20.jpg)
20
Fibrate Common Variant Analysis
FCRL5
PRRX1SYN2
PTPRDOSTF1,NMRK1
LHFP
FGF14LOC102724939
MRPL2
SLC25A10LDLR GMIP, ATP13A1,
SNF101,ZNF101
LDLAll Races Combined
(n=1261)
![Page 21: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/21.jpg)
21
Fibrate Common Variant Analysis
IGSF21 NRXN1
MYT1L
GPR75-ASB3, ERLEC1
FOXP1
ROBO1
NLGN1, PEX5L
SORCS2
IPO11, IPO11-LRRC70
GRIA1OFCC1
ARHGEF5
CLN8
FRMD3
BICC1, LOC102724768, FAM13C
TTC5
RIN3 SMAD3
LOC102724716, DLGAP1 NFIC
LDLOnly Black Subjects
(n=137)
![Page 22: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/22.jpg)
22
Fibrate Common Variant Analysis
MAU2, GATAD2A, PBX4, GMIP, ATP13A1
LDLOnly White Subjects
(n=779)
![Page 23: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/23.jpg)
23
Rare Variant Analysis
23
TMEM210
DUSP3DCUN1D4
RAB27B
EVA1C
HES2
LOC101927763
LOC101928772
IDE
NHLRC1
CREG2MICU1
CDH6
TriglyceridesAll Races Combined
(n=1261)
![Page 24: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/24.jpg)
24
Functional Validation
Tested for significant changes in gene expression in mice treated with fenofibrate for 14 days vs vehicle.
Tested overlapping common variants (p < 1x10-6) and rare variants (q< .05).
![Page 25: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/25.jpg)
25
Functional Validation
Analysis
Entrez IDGene
SymbolGeneName
log2(fold change)
P value Q value
Common Variant
17127 s24166 Smad3
SMAD family member 3 (Mothers against
decapentaplegic homolog 3)
-2.231320.00288
40.10383
Rare Variant
100737 s13991 Dcun1d4
DCN1, defective in cullin neddylation 1, domain
containing 4 (S. cerevisiae)
1.4682730.01335
20.19161
1
Common Variant
170759 s02971 Atp13a1 ATPase type 13A1 -1.57890.01596
80.19161
1Common Variant
76582 s20442 Ipo11 importin 11 -1.8763 0.022410.20169
3Rare
Variant80718 s01094 Rab27b
RAB27b, member RAS oncogene family
-1.364060.03306
60.23807
2
![Page 26: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/26.jpg)
26
SMAD3
o Smad3-KO mice had lower plasma free fatty acid and glycerol, reduced adiposity.
o Was shown to alter regulation PPARγ and PPARβ.
Receptor-regulated SMAD that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases. Binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. http://www.uniprot.org/uniprot/P84022
![Page 27: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/27.jpg)
27
SMAD3
o PPARα inhibits TGF-β
o TGF-β has been shown to regulate Smad 2, 3, and 4 transcription factors
o These pathways are clearly convoluted and have not yet been fully elucidated.
o There does appear to be the potential for an indirect interaction between fenofibrate and SMAD3.
o Downstream activity from PPARα may be altered due to rare variants in the SMAD3 gene, but much more work is needed to draw conclusions.
![Page 28: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/28.jpg)
28
Next Steps
o Additional validation in mice fed high-fat diets
o Collaborating with other lipid consortiums to investigate meta-analysis of RV
o Additional functional follow-up will probably be necessary (e.g. knockouts, forced expression)
o We are also exploring many other drugs related to diabetes and dyslipidemia.
![Page 29: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/29.jpg)
29
AcknowledgmentsNorth Carolina State UniversityAlison Motsinger-ReifSkylar MarvelChris SmithHillary Graham
UNC-Chapel HillMichael WagnerJohn BuseTammy HavenerSantica Marcovina
Moffitt Cancer CenterHoward McLeod
University of Kentucky-LexingtonGreg GrafSonja PijutXiaoxi LiuJingjing LiuShuang Liang
The ACCORD/ACCORDION Investigators
Joslin Diabetes Center and Harvard Medical SchoolAlessandro DoriaHetal ShahHe GaoJan SkupienMario-Luca MorieriChristine Mendonca
University of VirginiaJosyf Mychaleckyi
Harvard School of Public HealthPeter Kraft
Funding: This research was supported by an NHLBI grant to the University of North Carolina at Chapel Hill (5R01HL110380-04).
Bellvitge Biomedical Research Institute, Barcelona, SpainAgatha SchlüterStephane FourcadeAurora Pujol
University of Alabama-BirminghamStella Aslibekyan
![Page 31: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/31.jpg)
31
![Page 32: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/32.jpg)
32
Genetic Associations with Baseline Lipids
o The following covariates were forced into the linear model:o Trial armo Ageo Biguanideo Cardiovascular diseaseo Fibrate useo Gendero Insulino PC-1-3o Statino Years diabeteso Others…
o The following covariates were selected into the linear model:o Systolic blood pressureo HbA1co GFRo Smokingo Others…
![Page 33: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/33.jpg)
33
Genetic Associations with Baseline Lipids
o Covariate correlation matrix. Screat, dbp and waist_cm were removed from the lists of covariates due to correlations with gfr, sbp and bmi, respectively.
![Page 34: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/34.jpg)
34
Genetic Associations with Baseline Lipids
o Residuals from linear regressions of the phenotypes against the pruned covariates.
![Page 35: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/35.jpg)
35
Fibrate-HDLFibrate
Placebo
N=1261
N=1183
![Page 36: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/36.jpg)
36
Fibrate-HDLFibrate Placebo
N=1261 N=1183
![Page 37: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/37.jpg)
37
Fibrate-HDL N=1261
LOC101928059, DENND4B
CAMTA1 ARPC2, LOC101928487
CSN1S2AP
AFAP1ZDHHC14
DPP6LOH12CR1, LOH12CR2
LINC00457
NBEA CYP4F22
CYP4F12
![Page 38: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/38.jpg)
38
Placebo-HDL N=1183
RPS6KA2
STK33 AQRSV2B
ACACA
LOC284294
![Page 39: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/39.jpg)
Fibrate-all races
Placebo-all races
Rare Variant Analysis-HDLRHOQ
LRRC20
IMPACT
SMAD6
PTGER4
DMRT1
SYMPK
LURAP1
MRPL18
MTHFD2
CHRNE
TMEM9B
NUF2
ITIH1
MB21D2
NUDT8
![Page 40: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/40.jpg)
40
Fibrate-LDL Fibrate
Placebo
N=1261
N=1183
![Page 41: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/41.jpg)
41
Fibrate-LDLFibrate Placebo
N=1261 N=1183
![Page 42: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/42.jpg)
42
Placebo-LDL N=1183
TOMM40
![Page 43: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/43.jpg)
43
Fibrate-all races
Placebo-all races
Rare Variant Analysis-LDL
ASIC5
E2F6POM121LS
OR5P2HSPB8
HMX1
MUC3A
![Page 44: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/44.jpg)
44
Fibrate-Triglycerides
Fibrate
Placebo
N=1261
N=1183
![Page 45: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/45.jpg)
45
Fibrate-Triglycerides
Fibrate Placebo
N=1261 N=1183
![Page 46: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/46.jpg)
46
Fibrate-Triglycerides
N=1261
XPR1
ATAD2BTOX CEP55,
FFAR4 BEST3 PGAM1P5ITGBL1
GALNT16RPGRIP1L, FTO
![Page 47: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/47.jpg)
47
Placebo-Triglycerides N=1183
HCN2TTC28
![Page 48: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/48.jpg)
48
Fibrate-all races
Placebo-all races
Rare Variant Analysis-Triglycerides
TMEM210
SNRNP40
ATG16L1
ZBTB5
THG1L
HHIPL1
ANKRD1
DHH
LOC101928218SMIM13
DUSP3DCUN1D4
RAB27B
EVA1C
HES2
LOC101927763
LOC101928772
IDE
NHLRC1
CREG2MICU1
CDH6
C8orf82
MND1
CX3CL1
SPAG9
HHIPL1C16ORF70
RNF111
CAMK2D
![Page 49: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/49.jpg)
49
Fibrate-Cholesterol Fibrate
Placebo
N=1261
N=1183
![Page 50: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/50.jpg)
50
Fibrate-Cholesterol
Fibrate Placebo
N=1261 N=1183
![Page 51: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/51.jpg)
51
Fibrate-Cholesterol
N=1261
PRRX1
IL12RB2
FBXL7OFCC1 ZNF775
OSTF1, NMRK1
LINC00539,MIPEPP3
FGF14
SERPINA13P
MIR3185, HOXB13, PRAC2
MRPL12SLC25A10
GMIP, ATP13A1
ZNF101
![Page 52: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/52.jpg)
52
Placebo-CholesterolN=1183
DDX46
![Page 53: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/53.jpg)
53
Fibrate-all races
Placebo-all races
Rare Variant Analysis-Cholesterol
ASIC5
NMUFAM110B
KRTAP10-1
ALDH1A2
NKAIN4
MUC3A
TMEM210
ZNF469
PAQR8
RBM15B
![Page 54: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/54.jpg)
54
Fibrate-HDLBlack
White
N=779
N=137
![Page 55: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/55.jpg)
55
Fibrate-HDLBlack White
N=779
N=137
![Page 56: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/56.jpg)
56
Fibrate-HDLBlack
N=137
MSH3
LOC101927640
LOC102723892, CARD11
KMT2C
LOC101928077
SORBS1
STX8
LOC101927369, CCL3
CELSR1
CARD10
![Page 57: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/57.jpg)
57
Fibrate-HDLWhite
N=779
ASTN2
![Page 58: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/58.jpg)
White-Fibrate
Black-Fibrate
Rare Variant Analysis by Race-HDL HSD17B13
RAE1PTPN3
HARS2
![Page 59: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/59.jpg)
59
Fibrate-LDLBlack
White
N=779
N=137
![Page 60: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/60.jpg)
60
Fibrate-LDLBlack White
N=779
N=137
![Page 61: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/61.jpg)
White-Fibrate
Black-Fibrate
Rare Variant Analysis by Race-LDL
![Page 62: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/62.jpg)
62
Fibrate-Triglycerides Black
White
N=779
N=137
![Page 63: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/63.jpg)
63
Fibrate-Triglycerides
Black White
N=779
N=137
![Page 64: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/64.jpg)
64
Fibrate-Triglycerides
Black
N=137
PARVB
ZYG11BLINC00624
SYT14
BCL9
LOC100507073
HECW2
ADAMTS9, ROBO2
LINC01182CCDC149
LOC101927145, ADGRL3-AS1
ARHGAP26
BLOC1S5-TXNDC5, EEF1E1-BLOC1S5, BLOC1S5
LRFN2
GLIS3LINGO2
BPIFA1
SNHG17, LOC101928356
![Page 65: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/65.jpg)
65
Fibrate-TriglyceridesWhite
N=779
CSMD3
RPGRIP1L
![Page 66: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/66.jpg)
White-Fibrate
Black-Fibrate
Rare Variant Analysis by Race-Triglycerides
HSD17B13
MARCH3
OCSTAMP
POGZ
HARS2
![Page 67: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/67.jpg)
67
Fibrate-Cholesterol Black
White
N=137
N=779
![Page 68: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/68.jpg)
68
Fibrate-Cholesterol
Black White
N=137
N=779
![Page 69: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/69.jpg)
69
Fibrate-Cholesterol
Black
N=137
NRXN1LRRFIP1
NLGN1, PEX5L
SCGN
CLN8 BICC1
RBM19 SMAD3
![Page 70: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/70.jpg)
70
Fibrate-Cholesterol
White
N=779
PBX4
![Page 71: Baseline genetics and fenofibrate response in the ACCORD clinical trial Daniel Rotroff PhD, MSPH September 18, 2015 Postdoctoral Research Fellow, Bioinformatics.](https://reader035.fdocuments.us/reader035/viewer/2022062517/56649ef65503460f94c0a90f/html5/thumbnails/71.jpg)
White-Fibrate
Black-Fibrate
Rare Variant Analysis by Race-Cholesterol
C9orf92DNAJB9
COL14A1
AKR7A3