SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT02133144

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Effects of Overfeeding Followed by Weight Loss on Liver Fat Content and Adipose Tissue Inflammation

A. BACKGROUND Accumulation of fat in the liver due to non-alcoholic causes (NAFLD) is associated with hepatic insulin resistance, which impairs the ability of insulin to inhibit the production of glucose and VLDL . This leads to increases in serum glucose, insulin and triglyceride concentrations as well as hyperinsulinemia. Recent epidemiologic studies have shown that a major reason for the metabolic syndrome as well as the accompanying increased risk of cardiovascular disease and type 2 diabetes is overconsumption of simple sugars. The investigators have recently shown that overeating simple sugars (1000 extra calories/day, "CANDY" diet) increases liver fat content by 30% within 3 weeks (4), and recapitulates features of the metabolic syndrome such as hypertriglyceridemia and a low HDL cholesterol concentration. The fatty acids in intrahepatocellular triglycerides may originate from peripheral lipolysis, de novo lipogenesis, uptake of chylomicron remnants by the liver and from hepatic uptake of fatty acids released during intravascular hydrolysis of triglyceride-rich lipoproteins (the spillover pathway). A classic study using stable isotope methodology by the group of Elisabeth Parks showed that in subjects with NAFLD, the excess intrahepatocellular triglycerides originate from peripheral lipolysis and de novo lipogenesis. It is well-established that ingestion of a high carbohydrate as compared to high fat diet stimulates de novo lipogenesis in humans. Meta-analyses comparing isocaloric high fat and high carbohydrate diets have shown that high carbohydrate but not high fat diets increase increase serum triglycerides and lower HDL cholesterol. Since hypertriglyceridemia results from overproduction of VLDL from the liver, these data suggest the composition of the diet influences hepatic lipid metabolism. Whether this is because overfeeding fat leads to preferential deposition of fat in adipose tissue while high carbohydrate diets induce a relative greater increase in liver fat is unknown. There are no previous studies comparing effects of chronic overfeeding of fat as compared to carbohydrate on liver fat or and the sources of intrahepatic fatty acids. A common polymorphism in PNPLA3 at rs738409 (adiponutrin) gene is associated with a markedly increase liver fat content. This finding has been replicated in at least 20 studies across the world. The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. B. HYPOTHESIS The investigators hypothesize that overfeeding a high fat as compared to an isocaloric high carbohydrate diet influences the source of intrahepatocellular triglycerides. During a high fat diet, relatively more of intrahepatocellular triglycerides originate from peripheral lipolysis and less from DNL than during a high carbohydrate diet in the face of a similar increase in liver fat. It is also possible given the lack of previous overfeeding data comparing 2 different overfeeding diets that the high fat diet induces a smaller increase in liver fat than a high carbohydrate diet even in the face of an identical increase in caloric intake because a greater fraction of ingested fat is channeled to adipose tissue than the liver. The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. C. SPECIFIC AIMS The investigators wish to randomize, using the method of minimization (considers baseline age, BMI, gender, liver fat, PNPLA3 genotype) 40 non-diabetic subjects with NAFLD as determined by the non-invasive score developed in our laboratory or previous knowledge of liver fat content based on MRS to overeat either a high carbohydrate or high fat diet (1000 extra calories per day) for 3 weeks. Before and after the overfeeding diets, will measure liver fat content by 1H-MRS and the rate of adipose tissue lipolysis using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol as described in detail below. The investigators also wish to characterize glucose, insulin, fatty acid and triacylglyceride profiles before and while on the experimental diet. An adipose tissue biopsy is taken to determine whether expression of genes involved in lipogenesis or lipolysis, or those involved in adipose tissue inflammation change in response to overfeeding, and for measurement of LPL activity. After overfeeding, both groups will undergo weight loss to restore normal weight as described in our recent study. The metabolic study is repeated after weight loss.

NCT02133144 NAFLD
MeSH: Inflammation Weight Loss
HPO: Decreased body weight Weight loss

2 Interventions

Name: overeating fat

Type: Behavioral

High fat diet High carbohydrate diet

Name: overeating carbohydrate

Type: Behavioral

High fat diet High carbohydrate diet


Primary Outcomes

Measure: Liver fat content (1H-MRS) and intra-abdominal and subcutaneous fat (MRI)

Time: 3 weeks

Description: the rate of DNL and adipose tissue lipolysis is measured using doubly labeled water (DDW) and [1,1,2,3,3-2H5] glycerol

Measure: De novo lipogenesis (DNL) and measurement of lipolysis

Time: 3 weeks

Secondary Outcomes

Description: Laboratory tests including fasting glucose, insulin, C-peptide, liver enzymes, total, LDL and HDL cholesterol and TG concentrations PNPLA3 genotyping is performed also

Measure: Analytical procedures

Time: 3 weeks

Other Outcomes

Description: Needle biopsies of abdominal subcutaneus tissue will be taken for subsequent isolation of RNA for measurements of gene expression (by quantitative PCR). Fat cell size is also measured.

Measure: Biopsies and analysis of subcutaneus adipose tissue

Time: 3 weeks

Description: Indirect calorimetry is the method by which metabolic rate is estimated from measurements of oxygen (O2) consumption and carbon dioxide (CO2) production.

Measure: Indirect calorimetry

Time: 3 week

Purpose: Prevention

Allocation: Randomized

Parallel Assignment


There is one SNP

SNPs


1 I148M

The investigators have shown that PNPLA3 is regulated by the carbohydrate response element binding protein 1. Mice overexpressing the human I148M PNPLA3 variant in the liver exhibit an increase in liver triglycerides and cholesteryl esters on a high sucrose but not high fat diet. --- I148M ---

These data suggest that overfeeding a high carbohydrate as compared to a high fat diet may increase liver fat more in subjects carrying the I148M allele than in non-carriers. --- I148M ---

The investigators also hypothesize that liver fat may increase more in carriers than non-carriers of the I148M variant in PNPLA3 during a high carbohydrate than a high fat diet. --- I148M ---



HPO Nodes


HPO:
Decreased body weight
Genes 1050
MKKS EPHX1 TACO1 UBA5 EPRS NAT8L AARS CCDC8 ERCC1 ERCC2 ABCA3 AMER1 ERCC3 BRIP1 ERCC4 ABL1 ERCC5 ERCC6 RNF168 ZMPSTE24 ACADS ACAT1 MARS RBM10 ACO2 SMC1A ACOX1 ESR2 TRAIP MAX RPS6KA3 ACTA1 TMEM216 ACTB LRRK2 ZFP57 MC2R ACTG1 TCIRG1 EVC DHDDS MCM5 RPS19 IKZF1 RPS20 EWSR1 EXT1 TRAC KLHL41 EXT2 TMEM173 ACVR1 MDH2 RREB1 SGO1 ADA TIMMDC1 ADAR F5 MECP2 KLRC4 MEFV RYR1 CDC45 FANCA FANCC FANCD2 FZD4 FANCE ADK FAH BPTF FANCB DACT1 FANCF FANCG TUBB4A ARID1B MGAT2 FBN1 PANK2 FBN2 SALL1 OTULIN SARS ATRIP MBTPS2 AARS2 MSMO1 CIITA SC5D COG6 ARHGAP31 ATXN7 POMP STRADA JAG1 SCN3A AGXT MIPEP NR0B1 SCN8A AHCY SCNN1A SCNN1B EMG1 MLH1 SCNN1G FGD1 SCO1 KMT2A AK2 FGF8 PLA2G6 AKT1 FGF12 ALAD NR3C2 FGFR1 PWAR1 MAD2L2 FH TRMT5 DOCK6 ALDOB SLC9A6 ALOX12B SEC23B SDHA SDHB SDHC SDHD ALPL GNPAT MPI MPL CUL4B MPV17 FLI1 FLII FLNA AMPD2 SEMA3C FOXRED1 VPS37A DEAF1 FMR1 OFD1 SLC25A4 SFTPB SFTPC PTF1A NACC1 PUF60 HIKESHI ACAD9 FOS UFC1 PEX3 CNTNAP1 AGPAT2 DOLK LARS KCNAB2 ARFGEF2 TRMT1 BIRC3 NLRP1 SLC39A4 CNKSR2 MSH2 CHD7 FASTKD2 ZSWIM6 TXNRD2 AGPS OSGEP FANCM SKI FAS SKIV2L TMEM127 AQP2 SLC1A2 CDK10 COA8 SLC2A2 ARCN1 LARP7 PEX26 CYFIP2 SLC3A1 RBCK1 STAMBP SLC4A1 TRAK1 SLC5A1 EPG5 CASK FAN1 MTFMT MST1 SLC6A8 HSD3B7 LIPT1 VAC14 RAB3GAP1 MLH3 NDUFAF4 VIPAS39 PIEZO2 SLC10A2 ATP6 SLC11A1 GPIHBP1 FAM111A SLC12A1 SLC12A3 LAT COX1 COX2 UBE2T G6PC3 COX3 ARVCF WDR11 SLC34A1 DYNC2LI1 ASAH1 ELMO2 ASCL1 PDE8B RFXANK OTUD6B ASL ZNF335 ND1 ASNS ND2 SLC22A5 MCM9 ND3 VPS35 EBP ND4 MRPS14 ND5 ASS1 ND6 CLDN16 TIMM50 PTRH2 SMARCA2 MTR PUS1 ABCB11 FLCN MTRR SMARCC2 SMARCD2 FOXP1 TRNF NDUFAF6 SMPD1 CEP152 TRNH FUCA1 TRNK TRNL1 ATM NGLY1 RERE TRNN TBR1 TRNQ TBC1D23 TRNS1 SNCA TRNS2 OCLN TRNV FUT8 TRNW KDSR ERMARD SPATA5 MCTP2 PRDM16 LMBRD1 PLK4 SNRPN PALLD STAG2 TRIM37 SIX2 SLX4 MUSK ATP5F1A MMUT MEGF10 UNC80 H19 MVK RAI1 SON GABRA3 LYRM7 GABRB2 GABRD SNORD115-1 SOX9 UBR1 ATP6V1A MYH3 INTU ATP6V1E1 MYH7 GALC GALE EOGT MYL2 DIS3L2 ADAT3 CENPJ ATP7B WWOX GALT ATR RIPK1 WDR4 ATRX AUH TNFSF12 RTEL1 AVP ERAP1 SPR AVPR2 JAGN1 GJB4 NEXMIF TMEM165 NADK2 B2M KIF1B TMEM126B IQSEC2 BAAT HDAC8 AKR1D1 CPLX1 MAP3K20 GATA2 GATA4 GATA6 GATM GBA PWRN1 GBE1 CDH23 SRP54 FGFRL1 NFASC NBN GCDH SLC46A1 CCND1 BCL2 NDN GCK NDP NDUFA2 MCCC2 NDUFA4 BCL6 SSR4 SMOC1 PEX11B NEB NDUFA9 NDUFA10 SUCLG1 SUCLA2 NDUFB3 ANKLE2 BCS1L NDUFB8 GDNF DPM1 AHDC1 BANF1 NFU1 NDUFS1 NDUFS2 MMADHC NDUFS3 STAR NDUFV1 NAGS HESX1 NDUFS4 FGF17 STAT3 STAT4 NDUFS8 NDUFV2 STAT5B SYNGAP1 SLC52A3 XYLT2 GHSR IFIH1 BMP1 GJA1 BMP4 MALT1 BMPR1A GJB3 GK KISS1R PNPLA6 STXBP1 GPC3 NDUFA12 BRCA1 BRAF BRCA2 SYNJ1 ST3GAL5 KLHL7 NFE2L2 GLI1 NFIX ABCC8 SURF1 NFKB1 BTK NFKB2 MYPN BUB1B VPS13A MYMK ACSF3 C4A TAC3 BCL10 MCEE TACR3 GNAS SEMA4A HERC2 COX4I2 STRA6 GNB1 NME1 PHOX2B GPT2 TAF13 MAP3K7 TALDO1 NONO GNRH1 GNRHR NOTCH1 TBX1 NOTCH2 TAZ AGTPBP1 CA2 GP1BB PNP SPINK5 CA12 NPHS1 CACNA1A NPM1 CACNA1S TCF4 NIPAL4 TCF3 DNAJC13 CARMIL2 MLX TCN2 TCOF1 NRTN SZT2 CALR GPR35 HCN1 NTRK2 PCLO NUMA1 SLC19A3 OBSL1 BAZ1B CASP8 OAS1 TWIST2 GRIA3 GRIA4 CASR OCRL CAV1 GRIN2D SLC7A7 NSMCE3 TERT CIT CBS TFAM CREB3L1 SIL1 POLR3A STT3B TFRC TGFB1 MMAA TGFB3 HAVCR2 ORC1 ORC4 TGFBR2 GPR161 TGM1 MSH6 USP8 ORAI1 GTF2E2 OTC CD3D KLLN CD3G GTF2I THPO THRB CD19 MS4A1 DCLRE1C SMC3 IL12A-AS1 TK2 ASXL3 ETHE1 BTNL2 GYS2 PPP1R15B MRAP TGDS TLR4 PRDX1 CHEK2 TNFRSF13C CKAP2L LRRC8A TNFRSF13B CD79A CD79B CD81 WDR73 PARN SERAC1 HADHA MRPL3 HADHB HADH LRBA KCNJ18 CDC6 HBA1 HBA2 POLG2 KAT6B MMAB PCCA PCCB NNT HCCS HCFC1 HACD1 TOP3A TP53 HTT ATP6V0A2 COX14 PCNT TPM2 PCSK1 TPM3 CDKN2A SDHAF1 ASXL1 POU6F2 B4GALT7 PDE6D HLA-B MICOS13 CENPE AIMP1 PDHA1 LEMD3 HLA-DPA1 ORC6 HLA-DPB1 HLA-DQB1 VPS45 AMACR HLA-DRB1 CFTR COPB2 GLYCTK BLNK HLCS PEX1 PEX6 PEX7 DNAJC21 PEX10 HMBS PEX12 PEX13 PEX14 EXOSC8 RNF13 HMGCL NUP62 ATP8B1 TSHR TRIP13 TTN CHRM3 TTR ELAC2 NLRC4 HNRNPH2 SLC39A13 CHRNG HIRA RNU4ATAC SNAP29 SLC25A3 UBA1 ICOS PNPLA1 PLAA CLCNKA NALCN CLCNKB COG1 HPD PIK3CA PIK3R1 UBTF HS6ST1 RIN2 RECQL4 UFD1 CLTC NPAP1 SNX10 PEX16 HRAS PKP1 TJP2 CRIPT CYP7B1 ALG8 UMPS PLAGL1 CCR1 HSD11B2 PLEC MTO1 FTO HSD17B4 MED17 PYCR2 PLP1 EIF2AK3 KDM6A NIPBL ALG12 COG4 PUS7 CNTN1 PML COL1A1 PMM2 VDR COL1A2 PMS1 PROK2 VHL SLC25A24 COL5A1 COL5A2 COL6A1 HSPG2 NDUFB11 COL6A2 COL6A3 COL7A1 EXOSC9 PMS2 COL12A1 MAGEL2 TBX4 NDUFAF5 POLR1A POC1A COMT TAPT1 ARV1 CLIP2 DLL4 PMPCB WHCR NSD2 NELFA POLA1 IARS POLE RRM2B POLG MPDU1 GNPTAB RTTN WNT2B NDUFAF3 COX6B1 POLR1C WRN WT1 POMC COX7B COX8A POR COX10 COX15 TWNK XPA XPC SIN3A SLC34A3 NABP1 PPARG XRCC2 CPS1 GTF2IRD1 CR2 SP110 CREBBP YWHAG PREPL ZAP70 MMACHC PPM1B NECAP1 ZIC3 PPP1CB IFNGR1 GTPBP2 IGF1 IGF1R IGF2 PPP3CA NSMF CSF2RA KANSL1 CSF2RB SEC24C CYP2R1 IGH PRF1 CSNK2A1 IGHM TTC37 IGHMBP2 NUS1 C12ORF65 IL21R SETBP1 CERS3 ATP6V0A4 RBPJ PRKACA LPIN2 AUTS2 PRKAR1A KBTBD13 GIGYF2 SLC13A5 PRKCD CTBP1 CAVIN1 CTLA4 IGLL1 CTNS IKBKB MAP2K1 MAP2K2 CEP57 IL2RG DNAJC3 NEUROG3 PRNP IL7R CYB5A RAB33B ATPAF2 MKRN3 IL10 COX20 TET2 IL12A IL12B TCTN3 PRSS1 TRIT1 TMPRSS15 NDUFS7 ZBTB16 SAMD9 PRTN3 ACD EARS2 ABCA12 PET100 INS CYP11A1 CYP11B2 CYP17A1 CYP19A1 CYP24A1 CYP27B1 KIAA0586 INSR PSMB4 PTDSS1 PSMB8 PSMB9 PDX1 IPW PTPN22 DAXX PSMD12 NHLRC2 MCCC1 CUL7 ITGA7 PTEN BCOR DCTN1 NSUN2 DDB2 ITGB4 DDOST PHGDH SNORD116-1 DDX3X STT3A KIAA0753 FBXL4 NSDHL BSND JAK2 JAK3 ANOS1 TRMT10C PTPN11 KCNA2 SARS2 KCNA4 ANTXR2 PTPRC KCNB1 MOGS PROKR2 VPS33B TINF2 SDHAF2 FIG4 CCDC47 PTS KCNJ1 KCNJ6 DGUOK DHCR7 DHCR24 KCNJ10 KCNJ11 TMEM70 IL21 PEX19 PEX2 PEX5 PYCR1 DKC1 ALDH18A1 FIP1L1 DLD PYGL RARS2 MAFB CDT1 CDC73 RFT1 SLC52A2 DNM1 CARS2 CPLANE1 DNA2 HYMAI KISS1 MED12 NR1H4 IL23R CDON DNM2 PDE11A DNMT3B RAD21 FOXP3 RAD51 RAD51C KRAS KRT1 RAG1 RAG2 DPP6 KRT5 SCO2 DPYD EFL1 KRT10 RAP1A SLC26A3 RAP1B KRT14 EVC2 B3GLCT RARA RARB LHX4 RHBDF2 RB1 NDUFAF2 DSP LYRM4 COG7 RBBP8 UBE3B DUSP6 DYRK1A LAMA2 LAMA3 FARSB WDR60 B3GALT6 LAMB3 DNM1L MRPS16 LAMC2 FANCL PAM16 RELB LBR REST RET LCK RFC2 ECE1 TYMP CCNQ ECHS1 SELENON TBL1XR1 RFX5 RFXAP GMNN JMJD1C ARPC1B PALB2 LETM1 EDN3 EDNRB RFWD3 YARS2 KIF7 PNPO MKRN3-AS1 EEF1A2 RIT1 NDUFA13 SLC17A5 RMRP MRPS7 POLR1D MLXIPL LIG4 SEMA3D LRPPRC LIMK1 LIPA KMT2D BCAP31 HMGA2 NDUFAF1 LMNA EGFR SUGCT SETD5 TRIM28 MRPS2 SBDS FANCI EIF2S3 SLC25A13 ALG9 SLC25A15 ARMC5 SAR1B AP3B2 SPRY4 EIF4G1 EHMT1 LRP5 ROBO1 TRPV4 UBAC2 CAMKMT ALOXE3 YY1AP1 CLMP ALG3 BSCL2 ELN LTC4S SPRTN EPCAM CSPP1 RPL5 TBL2 CD96 EP300 VPS13B COQ7 SMAD4 JPH3 ALG13
Weight loss
Genes 254
IL10 CDKN2A TET2 IL12A IL12B SDHAF1 POU6F2 ERCC2 ERCC3 BRIP1 ERCC4 ZBTB16 ERCC5 PRTN3 DIS3L2 CENPJ ATP7B RNF168 GALT ATR ATRX HLA-B ACAT1 CENPE AVP ERAP1 HLA-DPA1 HLA-DPB1 INS HLA-DQB1 GJB4 HLA-DRB1 TRAIP MAX B2M CYP24A1 KIF1B CFTR INSR LRRK2 ZFP57 MC2R GATA2 GATA4 PDX1 GBA HLCS CDH23 HMBS NBN PTPN22 DAXX IKZF1 RPS20 EWSR1 CCND1 HMGCL BCL2 GCK NDP TSHR BCL6 MDH2 PTEN SUCLA2 TRIP13 DCTN1 F5 GDNF MECP2 TTR KLRC4 MEFV STAR STAT3 STAT4 STAT5B FANCA SLC52A3 FANCC FANCD2 FANCE JAK2 GJA1 FANCB FANCF MALT1 FANCG BMPR1A GJB3 PANK2 ATRIP GPC3 BRCA1 BRCA2 SDHAF2 PIK3CA PIK3R1 ABCC8 BTK KCNJ11 VPS13A SCNN1A SCNN1B MLH1 SCNN1G FIP1L1 AK2 PLAGL1 PLA2G6 CCR1 AKT1 MAFB C4A BCL10 CDC73 SEMA4A MAD2L2 SLC52A2 NME1 FH HYMAI EIF2AK3 SLC9A6 IL23R SDHA SDHB SDHC SDHD PML COL1A1 FOXP3 MPL RAD51 RAD51C CUL4B PMS1 VHL KRAS NPM1 KRT1 COL5A1 FLI1 COL5A2 CACNA1S COL6A1 HSPG2 COL6A2 COL6A3 TCF4 SEMA3C KRT10 PMS2 DNAJC13 COL12A1 RARA MLX RHBDF2 RB1 NRTN CALR GPR35 RBBP8 RRM2B POLG GNPTAB CNTNAP1 NUMA1 WT1 BIRC3 SLC39A4 FANCL MSH2 REST TXNRD2 RET NABP1 XRCC2 FANCM ECE1 TYMP FAS TMEM127 TBL1XR1 PALB2 EDN3 EDNRB RFWD3 FAN1 TGFB1 IFNGR1 HAVCR2 MST1 SLC6A8 TGFBR2 MSH6 SEMA3D LIPA MLH3 THPO SLC11A1 LMNA COX1 COX2 UBE2T COX3 IGH TRIM28 IL12A-AS1 FANCI BTNL2 MRAP ND1 VPS35 ND4 TLR4 ND5 EIF4G1 ND6 LPIN2 CHEK2 PRKAR1A GIGYF2 TRPV4 UBAC2 FOXP1 TRNF CEP152 TRNH CTLA4 TRNL1 ATM KCNJ18 TRNQ TRNS1 SNCA TRNS2 TRNW KDSR EPCAM NNT PLK4 PALLD TRIM37 SLX4 UNC80 H19 PRNP TP53 HTT SMAD4 JPH3 GABRA3 PCNT