Petri Wiklund, Xiaobo Zhang, Satu Pekkala, Reija Autio, Lingjia Kong, Yifan Yang, Sirkka

Transcript

1 Insulin resistance is associated with altered amino acid metabolism and adipose tissue dysfunction in normoglycemic women. Petri Wiklund, Xiaobo Zhang, Satu Pekkala, Reija Autio, Lingjia Kong, Yifan Yang, Sirkka Keinänen-Kiukaanniemi, Markku Alen, and Sulin Cheng Background information Background information including medical history and current health status was collected via self-administered questionnaires. Food consumption and intakes of total energy and energy yielding nutrients were assessed from three day food records and analyzed using Micro- Nutrica software developed by the Social Insurance Institution of Finland and updated with data for new foodstuffs by the study nutritionist. Leisure time physical activity (LTPA) of hours/week (participating in exercise such as walking, jogging, running, gym fitness, ball games, swimming, etc.) and physical inactivity hours per day (including lying down and sitting time) were evaluated using a validated self-administrated physical activity questionnaire described previously 1. Anthropometric, ectopic fat content and abdominal fat mass assessment All measurements were performed after an overnight fasting. Subjects were weighed with light clothes and without shoes. Weight was determined within 0.1 kg for each subject using an electronic scale and was calibrated before each measurement session. Height was determined using a fixed wall-scale measuring device to the nearest 0.1 cm. Body mass index (BMI) was calculated as weight (kilograms) per height (meters) 2. Whole body fat mass (FM) and fat free mass (FFM) was assessed by a Dual-energy X-ray absorptiometry (DXA

2 Prodigy, GE Lunar Corp., Madison, WI USA). Two repeated measurements of FM and FFM showed a coefficient of variation (CV) of 2.2% and 1.0% respectively in this study 2. Abdominal region and liver were scanned using a 1.5 Tesla MR-scanner (GE Sigma CV/i, General Electric Healthcare, Waukesha, WI, USA). Abdominal visceral adipose tissue (VAT) was quantified from a single slice image at the level of the L2-L3 intervertebral disc using the OsiriX software (OsiriX Foundation, Geneva, Switzerland). The results were converted into tissue fat mass in kilograms taking into account slice thickness and an adipose tissue density of g/ml 3. Liver fat content was assessed by 1HMRS with a PRESS sequence and was analyzed using the Linear Combination of Model spectra software which is generally considered to be the gold standard for in-vivo spectroscopy analysis 4. Muscle intra-myocellular lipid (IMCL) and extra-myocellular lipid (EMCL) from the tibialis anterior muscle were measured using a similar 1H MRS method with a surface coil placed over the middle part of the muscle 5. In order to obtain maximal IMCL and EMCL separation the tibialis anterior muscle was aligned as good as possible with the direction of the magnetic field and the voxel was placed parallel to the muscle fibers 5. Fitness test Maximum oxygen uptake (VO2max, ml/kg/min) was assessed by bicycle ergometer. During tests, heart rates were assessed using ECG and respiratory gases and ventilation was measured using respiratory gas analyzer VIASYS (Healthcare Inc. USA). A specialist physician was responsible for monitoring ECG and blood pressure responses during the test and recording subject s signs and symptoms throughout the test. Biochemical assessments

3 Blood samples were collected in the morning between 7:00 and 9:00 am after an overnight fasting. Plasma glucose and non-esterified fatty acids (NEFA) were assessed by KONELAB 20XTi analyzer (Thermo Fischer Scientific inc.waltham, MA, USA). Plasma insulin was assessed by chemiluminescent immunoassay using the IMMULITE analyzer (Diagnostic Products Corporation, Los Angeles). The intra- and inter-assay CVs were 3.4% and 2.0% for glucose, 11% and 3.4% for insulin, and 7.4% and 8.4% for NEFA, respectively. The HOMA- IR index (homeostatic model assessment of insulin resistance) was calculated as (fasting glucose x fasting insulin/22.5). Serum leptin was assessed using human leptin (ELISA; Diagnostic Systems Laboratories, Inc., Webster, TX). Total adiponectin was measured by an enzyme immunoassay method using the Quantikine human total adiponectin/acrp30 immunoassay (R&D Systems, Minneapolis, MN). Inter- and intra-assay coefficients of variation (CVs) were 2.2% and 2.7% for leptin, 3.3% and 4.3% for adiponectin, respectively Insulin sensitivity Whole-body insulin sensitivity was determined by the 75-g oral glucose tolerance test (OGTT). The test was performed for a subset of subjects (n=24) and insulin sensitivity index (Matsuda index) was calculated using the 0, 60 min and 120 min time points according to Matsuda and DeFronzo 6. Serum NMR spectroscopy All serum samples were analyzed using a high-throughput serum NMR metabonomics platform; the experimental protocols including sample preparation and NMR spectroscopy have been described in detail elsewhere 7. This methodology has recently been applied in various large-scale epidemiological and genetic studies 8,9. The NMR metabolomics methodology provides comprehensive quantitative information on various amino acids,

4 glycolysis intermediates, fatty acid composition and degree of saturation and lipoprotein subclass distributions. Altogether 130 metabolites were assessed. Subcutaneous adipose tissue biopsies Twenty-four participants agreed to donate subcutaneous adipose tissue biopsies, which were obtained under local anesthesia after overnight fasting. A region 5 cm lateral from the umbilicus either to the left side or right side was sterilized. A small intracutaneous injection was made, and 2 ml of a local anesthetic agent (lidocaine) was injected. After 5 min, anesthesia was confirmed, skin was sterilized again and 16 G, 40 mm needle, was then adapted to a 50-mL syringe and 10ml of 0.9% sodium-chloride was aspirated. Approximately two-third of the length of the needle was inserted into the subcutaneous fat, and 5 ml of 0.9% sodium chloride was injected. The needle piston was then pulled back maximally and released until it was locked by a stopper, thereby creating a vacuum. Tissue resistance was created by gripping the abdominal skin with one hand while the other hand rotated the needle throughout the tissue in back and forth motion. Once the tissue was aspirated by the syringe, the needle was withdrawn, and the piston was removed. The adipose tissue samples were washed with saline solution, and were immediately frozen in liquid nitrogen and stored at - 80 C. Skeletal muscle biopsies Twenty-four participants agreed to donate skeletal muscle biopsies, which were obtained under local anesthesia after overnight fasting. Biopsies were obtained from the vastus lateralis dx muscle with a 5-mm Bergström biopsy needle, midway between the patella and greater trochanter. A region and the optimum depth for muscle biopsy were confirmed by ultrasound imaging. The skin of the identified location was sterilized and 4 ml of local anesthetic agent (lidocaine) was injected in to the procedure area. A cooling pack was then

5 applied on the location. After 10 minutes, anesthesia was confirmed, skin was sterilized again and small stab incision was made with surgical scalpel. Subsequently, the biopsy needle attached to a syringe was introduced perpendicularly into the incision. The piston was then pulled back maximally creating a vacuum and sample was obtained. After the muscle biopsy was obtained, pressure was applied to the incision site for hemostasis. The muscle sample was cleaned of any visible connective and adipose tissue as well as blood and was frozen immediately in liquid nitrogen ( 180 C) and stored at 80 C. RNA extraction Total RNA was extracted from biopsies using the FastPrep system (MP Biomedicals, France) and the RNeasy Lipid Tissue Mini Kit (QIAGEN, Gaithersburg, MD, USA) according to manufacturer s instructions. Total RNA was digested on column with the RNase-free DNase set (QIAGEN) during RNA isolation. The quality of the total RNA was studied using a 2100 Bioanalyzer (Agilent, Santa Clara, CA, USA) and Experion Automated Electrophoresis Station (BioRad, Hercules, CA, USA). The total RNA was amplified and processed using the Gene Chip 3 IVT Express Kit (Affymetrix, Santa Clara, CA, USA) and hybridized on Affymetrix Human Genome U219 Array Plates. The samples of this study have been submitted to Array Express. Array Express data are fully accessible in E-MTAB Microarray analysis The total RNA was amplified and processed using the GeneChip 3 IVT Express Kit (Affymetrix, Santa Clara, CA, USA) and hybridized on Affymetrix Human Genome U219 Array Plates as described previously 10. Microarray data was pre-processed by the Robust Multiarray Averaging (RMA) algorithm in the R package affy Differentially expressed genes (DEG) were identified with the limma R package utilizing linear modeling and

6 empirical Bayes methods. Raw p-values were adjusted using the Benjamini and Hochberg multiple adjustment method 14. Gene enrichment analysis The enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for a given gene set were calculated using the R packages GOStats and KEGG.db. In the enrichment analysis, all human ENSEMBL genes were used as a background gene group and categories with a p-value lower than 0.05 were considered significantly enriched. Genes related to HOMA-IR were identified using the following two criteria: Genes were differentially expressed in our DEG analysis between the low HOMA- IR and high HOMA-IR groups with adjusted p-value <0.05 or genes fold change >= 2 between the low and high HOMA-IR groups. For the gene pathways derived from KEGG enrichment analysis, the mean-centroid value representing the activity of the regulated part of the pathway was computed by normalizing the expression levels of all subset genes to a mean of zero and a variance of 1 across all individuals. The mean centroids have previously been shown to correlate with various metabolic and physiologic parameters 15,16, and may therefore be used to assess gene expression patterns that are associated with metabolic diseases. Protein extraction from skeletal muscle biopsies and Western blot analysis Muscle biopsies were homogenized in ice-cold lysis buffer [20 mm Tris-HCl (ph 7.4), 1 mm EDTA, 150mM NaCl, 100 mm β-glycerophosphate, 1 mm Na3VO4, 1 mm DTT, 1% Triton- X-100], supplemented with protease and phosphatase inhibitors inhibitors (Sigma Aldrich, St Louis, MO, USA). Thirty to sixty micrograms of muscle lysate samples were separated by SDS-Page using 4-20% gradient gels on Criterion electrophoresis cell (Bio-Rad Laboratories,

7 Richmond, CA). Proteins were transferred to nitrocellulose membranes at 300-mA constant current on ice at 4ºC. Membranes were blocked in TBS containing 5% nonfat dry milk for 1 hour at room temperature (RT), and then probed overnight at 4ºC with primary antibodies purchased from Cell Signaling Technology (Danvers, MA, USA) (p-akt, p-irβ and p- AS160), Sigma-Aldrich (anti-gapdh) and Abcam (MitoProfile Total OXPHOS Rodent WB Antibody Cocktail, Abcam, Cambridge, MA, USA). All antibodies were diluted 1:1.000 (except anti-gapdh (housekeeping, which was diluted 1:40.000) in TBS containing 5% nonfat dry milk. Membranes were then washed with TBS containing 0.1% Tween-20 (TBS- T) followed by 1 hour incubation with the secondary antibody. Odyssey anti-rabbit IRDye 800 and Odyssey anti-mouse IRDye 600 (LI-COR Biosciences, Lincoln, NE, USA) were used as a secondary antibody. Blots were visualized and quantified using Odyssey CLX Infrared Imager of Li-COR and manufacturer's software. When reprobing was needed, the membranes were incubated in 0.2 M NaOH for 10 min at RT, washed with TBS and reprobed with appropriate antibodies. All samples were run in the same gel to minimize the variability and the quantitative results for each protein were normalized to GAPDH. References 1 Volgyi, E. et al. Effect of long-term leisure time physical activity on lean mass and fat mass in girls during adolescence. J Appl Physiol (1985) 110, , doi: /japplphysiol (2011). 2 Cheng, S. et al. Trait-specific tracking and determinants of body composition: a 7- year follow-up study of pubertal growth in girls. BMC medicine 7, 5, doi: / (2009). 3 Ojanen, X. et al. Comparison of vertebral bone marrow fat assessed by 1H MRS and inphase and out-of-phase MRI among family members. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 25, , doi: /s (2014). 4 Borra, R. J. et al. Nonalcoholic fatty liver disease: rapid evaluation of liver fat content with in-phase and out-of-phase MR imaging. Radiology 250, , doi: /radiol (2009). 5 Furuyama, J. K. et al. A pilot validation of multi-echo based echo-planar correlated spectroscopic imaging in human calf muscles. NMR in biomedicine 27, , doi: /nbm.3171 (2014).

8 6 Matsuda, M. & DeFronzo, R. A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes care 22, (1999). 7 Soininen, P. et al. High-throughput serum NMR metabonomics for cost-effective holistic studies on systemic metabolism. The Analyst 134, , doi: /b910205a (2009). 8 Stancakova, A. et al. Effects of 34 risk loci for type 2 diabetes or hyperglycemia on lipoprotein subclasses and their composition in 6,580 nondiabetic Finnish men. Diabetes 60, , doi: /db (2011). 9 Wurtz, P. et al. Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes 61, , doi: /db (2012). 10 Munukka, E. et al. Gut-adipose tissue axis in hepatic fat accumulation in humans. Journal of hepatology 61, , doi: /j.jhep (2014). 11 Gautier, L., Cope, L., Bolstad, B. M. & Irizarry, R. A. affy--analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 20, , doi: /bioinformatics/btg405 (2004). 12 Bolstad, B. M., Irizarry, R. A., Astrand, M. & Speed, T. P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, (2003). 13 Gentleman, R. C. et al. Bioconductor: open software development for computational biology and bioinformatics. Genome biology 5, R80, doi: /gb r80 (2004). 14 Benjamini Y, H. Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. Journal of the Royal Statistical Society Series B 57, (1995). 15 Mootha, V. K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nature genetics 34, , doi: /ng1180 (2003). 16 Pietilainen, K. H. et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS medicine 5, e51, doi: /journal.pmed (2008).

9 Table S2. General characteristics and serum metabolites in normal weight individuals stratified by low and high HOMA-IR groups (MIXED model estimated marginal means with 95% confidence intervals are given taking into account genetic similarity and shared environment (daughter and mother) and contrast estimates p-values were used to localize the significant differences between the two groups and group by generation interaction). Low HOMA-IR n=20 Mean 95% CI High HOMA-IR n=20 Mean 95% CI p-value Group by generation Age 35.6 (34.2, 37.1) 36.9 (35.3, 38.5) Height (cm) (165.4, 170.8) (163.1, 168.8) Weight (kg) 59.2 (56.3, 62.2) 58.8 (55.7, 61.9) BMI (kg/height 2 ) 21.0 (20.2, 21.8) 21.3 (20.4, 22.1) Percent body fat 23.5 (21.4, 25.2) 25.7 (23.7, 27.7) FM (kg) 16.9 (14.8, 19.0) 21.2 (19.1, 23.3) FFM (kg) 40.9 (39.5, 42.3) 40.5 (39.1, 42.0) VAT (kg) 0.55 (0.47, 0.62) 0.60 (0.53, 0.67) Liver fat (%) 2.5 (1.0, 4,0) 1.9 (0.4, 3.4) HOMA-IR 0.9 (0.7, 1.2) 2.4 (2.1, 2.7) < Metabolites (mmol/l) Betahydroxybutyrate (0.028, 0.069) (0.053, 0.089) Acetate (0.036, (0.038, 0.045) Acetoacetate (0.031, 0.045) (0.029, 0.042) Alanine (0.355, 0.405) (0.377, 0.423) Citrate (0.093, 0.107) (0.097, 0.111) Creatinine (0.045, 0.054) (0.047, 0.055) Glutamine (0.492, 0.532) (0.522, 0.557) Glycerol (0.048, 0.068) (0.060, 0.078) Glycine (0.237, 0.276) (0.261, 0.296) Orosomucoid (1.155, 1.288) (1.238, 1.360) Histidine (0.040, 0.054) (0.053, 0.059) Isoleucine (0.032, 0.045) (0.038, 0.044) Leucine (0.056, 0.065) (0.063, 0.071) Valine (0.145, 0.168) (0.160, 0.181) BCAA_sum (0.236, (0.262, 0.298) Tyrosine (0.038, 0.046) (0.042, 0.049) Phenylalanine (0.058, 0.065) (0.061, 0.067) Pyruvate (0.060, 0.075) (0.067, 0.081) Lactate (0.796, 0.980) (0.850, 1.022) Urea (0.045, 0.060) (0.043, 0.057)

10 FM = fat mass; FFF = fat-free mass; VAT = visceral adipose tissue; HOMA-IR = homeostatic model assessment of insulin resistance.

11 Table S3. General characteristics of the participants with adipose tissue biopsies Low HOMA-IR n= 12 High HOMA-IR n=12 Group by generation Mean 95% CI Mean 95% CI p-value Anthropometry Age (years) 34.5 (31.8, 37.3) 36.5 (34.2, 38.9 ) Height (cm) (158.2, 166.6) (160.7, 168.0) Weight (kg) 59.4 (51.3, 67.6) 66.2 (59.1, 73.3) BMI (kg/height(m) 2 ) 22.5 (19.8, 25.2) 24.5 (22.2, 28.7) Percent body fat 34.8 (29.2, 40.4) 37.1 (30.8, 43,4) Body composition FM (kg) 19.6 (13.0, 26.2) 24.7 (18.9, 30.5) FFM (kg) 37.4 (34.8, 40.0) 38.6 (36.3, 40.8) VAT (kg) 0.51 (0.34, 0.67) 0.67 (0.52, 0.81) Liver fat (%) 4.3 (-5.6, 14.2) 4.9 (-2.1, 11.9) Metabolic biomarkers Glucose (mmol/l) 5.3 (4.8, 5.8) 6.2 (5.7, 6.6) Insulin (IU/l) 3.3 (-1.9, 6.9) 11.0 (7.9, 14.0) HOMA-IR 0.8 (-0.4, 1.9) 3.1 (2.2, 4.1) Matsuda index 155 (63, 248) 134 (63, 204) Lipids FFA (mmol/l) 5.2 (4.1, 6.3) 3.8 (2.6, 4.8) Triglyceride (mmol/l) 1.3 (0.8, 1.8) 1.1 (0.7, 1.6) Adipokines Leptin (ng/ml) 18.2 (3.4, 33.0) 31.5 (18.8, 44.2) Adiponectin (μg/ml) 12.9 (7.1, 18.7) 15.0 (9.9, 20.1) Diet Energy (kcal) 1490 (1121, 1860) 1717 (1342, 2091) Protein (E%) 17.7 (14.9, 20.7) 18.8 (15.8, 21.8 ) Fat (E%) 36.5 (30.6, 42.5) 34.4 (28.4, 40.4) Carbohydrates (E%) 45.8 (44.5, 49.6) 46.8 (45.6, 50.5) Aerobic fitness LTPA (hours/week) 4.8 (3.4, 6.3) 4.0 (2.7, 5.2) VO2max (ml/kg/min) 38.9 (32.8, 44.9) 37.7 (31.5, 43.8) Data are given as mean ± SD. FM = fat mass; VAT = visceral adipose tissue; HOMA-IR = homeostatic model assessment of insulin resistance; Matsuda index = insulin sensitivity index; FFA = free fatty acids; E% = percentage of total energy intake.

12 Table S4. Differentially expressed genes in adipose tissue in high HOMA-IR subjects Ensembl Name HGNC Name Entrez logfc AveExpr adj.p.value ID ENSG MMP e-05 ENSG SPP e-04 ENSG EGFL e-02 ENSG CHI3L e-04 ENSG TREM e-04 ENSG FCGBP e-04 ENSG CD e-04 ENSG IFI e-05 ENSG ACP e-04 ENSG CCL e-04 ENSG TM4SF e-03 ENSG ITGB e-04 ENSG LYZ e-02 ENSG IL1RN e-03 ENSG LCP e-04 ENSG FCGR3A e-03 ENSG C1orf e-05 ENSG CHIT e-04 ENSG MNDA e-04 ENSG LAPTM e-05 ENSG CD e-05 ENSG C3AR e-03 ENSG CD300A e-04 ENSG GRAPL e-02 ENSG UCHL e-02 ENSG CCL e-05 ENSG HCST e-05 ENSG MSR e-05 ENSG TYROBP e-04 ENSG DHRS e-03 ENSG CCL e-04 ENSG MARCO e-02 ENSG EMILIN e-04 ENSG CD e-03 ENSG CTSS e-03 ENSG BCL2A e-03 ENSG CD e-03 ENSG PLEK e-04 ENSG NCKAP1L e-04 ENSG VSIG e-03 ENSG TNMD e-03

13 ENSG FERMT e-04 ENSG MYEOV e-03 ENSG FCER1G e-03 ENSG GPR e-04 ENSG RNASE e-03 ENSG ABCC e-05 ENSG ITGAX e-04 ENSG SFRP e-03 ENSG FCGR2A e-03 ENSG RAC e-03 ENSG C1QB e-03 ENSG C1QC e-03 ENSG ADAP e-04 ENSG RGS e-04 ENSG NCF e-04 ENSG GLIPR e-03 ENSG FGR e-04 ENSG SLC15A e-04 ENSG PALLD e-02 ENSG NPL e-03 ENSG SRPX e-03 ENSG SYK e-04 ENSG CPVL e-03 ENSG PLEKHO e-05 ENSG CCL e-03 ENSG VAMP e-05 ENSG SLC7A e-03 ENSG TIMP e-05 ENSG SCIN e-02 ENSG GLIPR e-03 ENSG PYCARD e-05 ENSG CTSH e-03 ENSG FABP e-03 ENSG BASP e-03 ENSG PRG e-02 ENSG CD e-03 ENSG CXCL e-05 ENSG SH3BGRL e-03 ENSG CD e-04 ENSG CCL e-03 ENSG CD e-04 ENSG NPR e-02 ENSG PTPRC e-03 ENSG C1QA e-03

14 ENSG EVI2B e-03 ENSG CTSG e-02 ENSG MAP1B e-02 ENSG DNASE2B e-04 ENSG FYB e-04 ENSG PTPN e-05 ENSG MS4A6E e-03 ENSG DPEP e-05 ENSG SLIT e-03 ENSG SIGLEC e-03 ENSG S100A e-02 ENSG TUBB2B e-04 ENSG LGALS e-02 ENSG IGHM e-03 ENSG FCN e-02 ENSG LTBP e-02 ENSG PIK3AP e-05 ENSG ATP1B e-03 ENSG FOLR e-02 ENSG MS4A6A e-02 ENSG ARHGAP e-04 ENSG SLA e-05 ENSG TNC e-03 ENSG LBP e-03 ENSG MS4A4A e-02 ENSG IGJ e-02 ENSG NCF e-02 ENSG TUBA1C e-03 ENSG MICAL e-03 ENSG S100A e-03 ENSG TBC1D e-04 ENSG BLNK e-04 ENSG CXorf e-03 ENSG MATK e-03 ENSG TUBB2A e-02 ENSG CYBA e-04 ENSG ST e-05 ENSG AOAH e-03 ENSG THY e-02 ENSG SPAG e-03 ENSG DOK e-04 ENSG LY e-03 ENSG GPC e-02 ENSG EVI2A e-04

15 ENSG RAB e-03 ENSG LPXN e-03 ENSG PNMAL e-02 ENSG SAMHD e-03 ENSG SAMSN e-02 ENSG CTSZ e-05 ENSG GSTM e-02 ENSG F13A e-02 ENSG HK e-04 ENSG ALOX5AP e-02 ENSG TMEM e-04 ENSG MYO1F e-05 ENSG EMP e-03 ENSG ITGB e-04 ENSG CAPG e-03 ENSG CCR e-03 ENSG CYP27A e-03 ENSG MAN2B e-05 ENSG TCIRG e-04 ENSG CCL e-03 ENSG ANPEP e-04 ENSG PEMT e-02 ENSG FPR e-02 ENSG C22orf e-05 ENSG GLB e-03 ENSG GAA e-03 ENSG ARRB e-05 ENSG SPOCD e-02 ENSG PLAUR e-03 ENSG EFHD e-05 ENSG FCGR2B e-03 ENSG TBC1D e-03 ENSG C3orf e-03 ENSG C11orf e-05 ENSG CD e-03 ENSG NUP e-03 ENSG TMEM e-04 ENSG CCL e-02 ENSG CTSB e-04 ENSG CD e-03 ENSG RGS e-04 ENSG ALCAM e-02 ENSG GPR e-03 ENSG FPR e-02

16 ENSG SDSL e-03 ENSG KCNN e-05 ENSG ODZ e-03 ENSG NAGA e-03 ENSG FICD e-02 ENSG HCK e-03 ENSG LGMN e-02 ENSG VASN e-02 ENSG TNFRSF12A e-02 ENSG FXYD e-03 ENSG C1R e-03 ENSG LILRB e-03 ENSG GM2A e-04 ENSG FTH e-03 ENSG TM6SF e-03 ENSG PTPRE e-04 ENSG SLC38A e-02 ENSG LSP e-04 ENSG HN e-03 ENSG VMO e-03 ENSG CXCR e-03 ENSG FLNA e-02 ENSG P2RX e-03 ENSG RFFL e-02 ENSG VCAN e-03 ENSG CMTM e-04 ENSG GPSM e-04 ENSG CSF2RB e-05 ENSG TLR e-03 ENSG PHACTR e-02 ENSG DOCK e-05 ENSG MARCH e-04 ENSG GRN e-03 ENSG SDF2L e-03 ENSG MSC e-03 ENSG GPNMB e-02 ENSG MAFB e-02 ENSG BAG e-02 ENSG RASSF e-04 ENSG PENK e-02 ENSG IRAK e-02 ENSG GFRA e-03 ENSG CORO1A e-03 ENSG ARHGDIB e-04

17 ENSG UBE2C e-02 ENSG COL16A e-02 ENSG TMEM e-02 ENSG IQGAP e-03 ENSG DOPEY e-03 ENSG KIAA e-03 ENSG CD e-03 ENSG IL4I e-03 ENSG MVP e-03 ENSG RARRES e-03 ENSG TGFBI e-02 ENSG CCDC e-03 ENSG TNFAIP8L e-03 ENSG COL6A e-03 ENSG MYO5A e-04 ENSG OLFML2B e-03 ENSG CD e-03 ENSG HPGDS e-02 ENSG ITIH e-03 ENSG PTTG e-03 ENSG CCDC109B e-03 ENSG MFHAS e-05 ENSG GZMA e-02 ENSG MICALL e-04 ENSG GPC e-04 ENSG C6orf e-02 ENSG CCND e-02 ENSG RAB e-03 ENSG C6orf e-04 ENSG TNFSF13B e-04 ENSG TMED e-04 ENSG C6orf e-03 ENSG PLD e-03 ENSG FAR e-02 ENSG SIGLEC e-05 ENSG CKS e-02 ENSG CD e-04 ENSG CCNB e-02 ENSG CD e-04 ENSG PIK3R e-04 ENSG BST e-02 ENSG TLR e-02 ENSG MPP e-04 ENSG PTGFRN e-03

18 ENSG SLIT e-02 ENSG SLC16A e-05 ENSG PREX e-03 ENSG EXT e-03 ENSG TNFAIP e-03 ENSG CCDC88A e-02 ENSG DZIP1L e-02 ENSG MMP e-03 ENSG KYNU e-02 ENSG PDLIM e-03 ENSG SFT2D e-03 ENSG VAV e-05 ENSG STAB e-03 ENSG CD e-02 ENSG CHST e-04 ENSG PILRA e-05 ENSG CCL e-03 ENSG TOP2A e-02 ENSG FRMD4B e-03 ENSG FZD e-03 ENSG PLEKHA e-04 ENSG PHLDA e-02 ENSG DOCK e-02 ENSG ABCC e-04 ENSG ACTB e-02 ENSG TSHZ e-02 ENSG CLN e-03 ENSG TMEM e-02 ENSG BCAT e-04 ENSG IGSF e-03 ENSG RPS6KA e-04 ENSG MMP e-03 ENSG HEXB e-05 ENSG FAM171A e-03 ENSG CLU e-03 ENSG C1RL e-02 ENSG SDS e-03 ENSG HOMER e-03 ENSG TAGLN e-02 ENSG ATP6V0B e-04 ENSG WDFY e-03 ENSG CYP1B e-02 ENSG TRBC e-03 ENSG HSPA e-04

19 ENSG HSPA e-04 ENSG CD e-03 ENSG KCND e-02 ENSG BIRC e-04 ENSG FUCA e-02 ENSG KCNQ e-03 ENSG SLC4A e-03 ENSG NCEH e-03 ENSG LHFPL e-03 ENSG FAM105A e-03 ENSG GLA e-04 ENSG CD163L e-02 ENSG MAP2K e-02 ENSG ARHGAP e-02 ENSG MFSD e-02 ENSG GPR172A e-03 ENSG MCOLN e-03 ENSG SERPINE e-03 ENSG RBM e-03 ENSG C11orf e-02 ENSG YWHAH e-03 ENSG FAM129B e-03 ENSG ENO e-02 ENSG PSAP e-05 ENSG TMEM e-02 ENSG RHOG e-02 ENSG AURKA e-02 ENSG COL6A e-03 ENSG CXCL e-02 ENSG NEK e-03 ENSG COL12A e-02 ENSG ZYX e-04 ENSG TRPV e-04 ENSG FAM26F e-03 ENSG DNMT e-03 ENSG HRH e-02 ENSG C6orf e-02 ENSG AQP e-05 ENSG CSTA e-02 ENSG MYL e-02 ENSG SLCO2B e-03 ENSG NCAPH e-02 ENSG C16orf e-05 ENSG RGS e-02

20 ENSG TLR e-03 ENSG ARRDC e-04 ENSG NPC e-04 ENSG FAM46A e-03 ENSG PEA e-03 ENSG PARP e-02 ENSG ANKDD1A e-02 ENSG HPRT e-03 ENSG ACTR e-02 ENSG ACTN e-02 ENSG LAMB e-02 ENSG CYP7B e-02 ENSG TLR e-03 ENSG TFEC e-03 ENSG METRNL e-03 ENSG C1orf e-03 ENSG LPCAT e-02 ENSG PFKP e-02 ENSG NFKBIE e-03 ENSG BID e-03 ENSG GALM e-02 ENSG FAM129A e-04 ENSG METTL e-02 ENSG TRIM e-03 ENSG CA e-02 ENSG IL10RA e-03 ENSG MMP e-02 ENSG DRAM e-04 ENSG PPT e-02 ENSG TFPT e-02 ENSG DEF e-03 ENSG ACOT e-02 ENSG TRAM e-03 ENSG KCTD e-02 ENSG ATP6V1B e-02 ENSG C1S e-03 ENSG CSF1R e-03 ENSG MAN1B e-03 ENSG LGI e-03 ENSG NRIP e-03 ENSG ATP6AP e-02 ENSG FCGRT e-04 ENSG RPN e-02 ENSG HPCAL e-03

21 ENSG CUEDC e-02 ENSG GNG e-03 ENSG SLC11A e-03 ENSG RAB e-02 ENSG ARL4C e-03 ENSG SLC39A e-02 ENSG MIF e-02 ENSG SNCA e-03 ENSG TAX1BP e-02 ENSG NAGK e-02 ENSG CLECL e-04 ENSG HIVEP e-02 ENSG SLC29A e-04 ENSG PTPLAD e-04 ENSG EZR e-03 ENSG LILRB e-04 ENSG PI4K2A e-03 ENSG TCEAL e-02 ENSG OSBPL e-04 ENSG PSMB e-03 ENSG IKZF e-04 ENSG PDIA e-02 ENSG FAM118B e-02 ENSG CEP e-02 ENSG SMPD e-02 ENSG DLGAP e-02 ENSG LAMP e-04 ENSG TIAM e-03 ENSG ZDHHC e-02 ENSG H2AFY e-04 ENSG COMT e-03 ENSG MAF e-03 ENSG C13orf e-03 ENSG TBXAS e-03 ENSG FGF e-02 ENSG ARF e-02 ENSG PLEKHM e-02 ENSG GSR e-04 ENSG AMPD e-03 ENSG SCUBE e-02 ENSG FAM177A e-03 ENSG IER5L e-04 ENSG PTAFR e-03 ENSG CECR e-03

22 ENSG NUDT e-02 ENSG CALM e-03 ENSG APOC e-02 ENSG GARS e-02 ENSG CORO1C e-02 ENSG DYRK e-02 ENSG MYO1D e-03 ENSG ABCC e-02 ENSG TNFRSF1B e-02 ENSG GGT e-02 ENSG PHLDA e-03 ENSG C1orf e-02 ENSG ACTG e-03 ENSG C5AR e-04 ENSG ADCY e-03 ENSG HMG20B e-03 ENSG ZNF e-02 ENSG PPP1CA e-02 ENSG FAT e-02 ENSG GLG e-02 ENSG CD300LB e-04 ENSG CHPF e-03 ENSG GAS2L e-02 ENSG TMEM e-02 ENSG C13orf e-03 ENSG SYNGR e-02 ENSG GUSB e-02 ENSG NLN e-02 ENSG SLAMF e-04 ENSG MOXD e-02 ENSG MGAT e-03 ENSG GNPDA e-04 ENSG RAP2B e-02 ENSG SERPINA e-03 ENSG HVCN e-02 ENSG ANXA e-02 ENSG GRB e-03 ENSG QSOX e-02 ENSG DUSP e-02 ENSG PRKX e-03 ENSG ATP2B e-02 ENSG CREB e-02 ENSG SIPA1L e-02 ENSG TSHZ e-02

23 ENSG FEN e-02 ENSG SCARB e-03 ENSG GMFG e-02 ENSG CMKLR e-03 ENSG NUP e-02 ENSG GZMK e-03 ENSG SECTM e-02 ENSG BAX e-03 ENSG NTAN e-02 ENSG CNPY e-02 ENSG SYNPO e-02 ENSG SLAMF e-03 ENSG PLBD e-02 ENSG AP2S e-02 ENSG SERPINE e-04 ENSG TNFRSF11A e-02 ENSG C10orf e-02 ENSG CD e-02 ENSG OSCAR e-03 ENSG GIPC e-02 ENSG CORO e-03 ENSG MPEG e-02 ENSG SPRED e-02 ENSG PDGFA e-04 ENSG LMNA e-02 ENSG PLEKHM e-02 ENSG TTC7A e-02 ENSG HOOK e-02 ENSG PRKCB e-03 ENSG MAP3K e-02 ENSG ARHGEF10L e-03 ENSG GLT25D e-02 ENSG MSN e-02 ENSG NLRP e-03 ENSG MIDN e-03 ENSG RGL e-02 ENSG SEC61A e-02 ENSG TPD e-02 ENSG RGS e-02 ENSG FOXRED e-02 ENSG STK e-02 ENSG SLC1A e-03 ENSG CPT1A e-02 ENSG RCSD e-03

24 ENSG SASH e-04 ENSG CTSA e-02 ENSG PLA2G e-03 ENSG HAVCR e-03 ENSG RRP e-02 ENSG CENPF e-02 ENSG ICAM e-03 ENSG AP1B e-02 ENSG UPP e-03 ENSG STAT e-03 ENSG FKBP e-02 ENSG FUCA e-02 ENSG PPP1R15A e-02 ENSG PTDSS e-02 ENSG RHOC e-02 ENSG FBLIM e-03 ENSG LYPLA e-02 ENSG HPSE e-03 ENSG ITPA e-02 ENSG CKAP e-02 ENSG SNX e-03 ENSG TRIM e-03 ENSG FAM176B e-02 ENSG TK e-02 ENSG PSD e-03 ENSG AMDHD e-02 ENSG ABHD e-02 ENSG TES e-02 ENSG SH3BP e-02 ENSG LAT e-02 ENSG WDR e-03 ENSG TMEM e-02 ENSG ALDH3B e-02 ENSG DEM e-03 ENSG P2RX e-04 ENSG YIPF e-02 ENSG C17orf e-02 ENSG AMICA e-02 ENSG TP53I e-02 ENSG PTGFR e-02 ENSG PLXNB e-02 ENSG TAOK e-02 ENSG EHBP1L e-02 ENSG PTGES e-02

25 ENSG HCLS e-02 ENSG TPX e-02 ENSG DNAJC e-02 ENSG ETV e-02 ENSG TMED e-03 ENSG CADM e-02 ENSG SQSTM e-02 ENSG SIGLEC14 1E e-02 ENSG SIGLEC e-02 ENSG C19orf e-02 ENSG NAAA e-02 ENSG TGOLN e-02 ENSG CYB e-03 ENSG EHD e-02 ENSG SELPLG e-02 ENSG CDR2L e-02 ENSG GBA e-02 ENSG FAM20A e-02 ENSG STMN e-02 ENSG STK e-02 ENSG PLAU e-02 ENSG MEGF e-02 ENSG HOXD e-02 ENSG TTC e-02 ENSG BICC e-02 ENSG TBC1D10C e-03 ENSG SLAMF e-02 ENSG ADORA2B e-02 ENSG DENND1C e-02 ENSG CRYBB e-03 ENSG SH2B e-02 ENSG ATP6V0D e-03 ENSG LOXL e-03 ENSG UBP e-02 ENSG C13orf e-02 ENSG FAIM e-03 ENSG KMO e-02 ENSG DGCR e-02 ENSG SPTAN e-02 ENSG GNA e-02 ENSG ITGAL e-02 ENSG EGR e-02 ENSG SEPT e-03 ENSG CDK e-02

26 ENSG ACOT e-02 ENSG UGGT e-02 ENSG MAP3K e-02 ENSG MTHFR e-02 ENSG COL14A e-02 ENSG FARP e-02 ENSG TMEM e-02 ENSG PTGS e-02 ENSG HEATR e-02 ENSG PTPRJ e-03 ENSG EXO e-02 ENSG HS3ST e-03 ENSG SLC37A e-02 ENSG PITPNA e-02 ENSG TM7SF e-03 ENSG SLC37A e-02 ENSG SMAP e-02 ENSG SLC39A e-02 ENSG TIMP e-02 ENSG STX e-02 ENSG STK32C e-02 ENSG KIAA e-02 ENSG PLEKHA e-02 ENSG TNFAIP e-02 ENSG C19orf e-02 ENSG ARSB e-03 ENSG DACT e-02 ENSG UBE2Z e-02 ENSG WIPF e-02 ENSG FBXO e-02 ENSG BACH e-02 ENSG GCNT e-03 ENSG GALNT e-02 ENSG NUMBL e-02 ENSG NRP e-02 ENSG ADPRH e-02 ENSG KIAA e-03 ENSG FAM78A e-02 ENSG PSMA e-02 ENSG CRTAM e-03 ENSG DGKZ e-02 ENSG DAPP e-02 ENSG GMIP e-02 ENSG P2RY e-02

27 ENSG PAPLN e-02 ENSG CDC25B e-02 ENSG F11R e-02 ENSG KIAA e-02 ENSG TOMM40L e-02 ENSG SCARA e-02 ENSG MAFG e-02 ENSG SYNPO e-02 ENSG CYP2S e-02 ENSG HS3ST e-02 ENSG HMHA e-02 ENSG CYTH e-02 ENSG ZNF780B e-02 ENSG TTYH e-02 ENSG RPS6KA e-02 ENSG GIT e-02 ENSG DLG e-02 ENSG CD e-02 ENSG ANKRD e-02 ENSG SDF e-02 ENSG JARID e-02 ENSG GNB e-02 ENSG FZD e-02 ENSG TFCP2L e-02 ENSG SLC36A e-02 ENSG ZNF e-02 ENSG PDE6B e-02 ENSG STAT e-02 ENSG PIP4K2A e-03 ENSG BIRC e-02 ENSG CLEC7A e-02 ENSG WDR e-02 ENSG GNE e-02 ENSG RSRC e-02 ENSG ST3GAL e-02 ENSG EPB41L e-02 ENSG FBXO e-02 ENSG GOLPH3L e-02 ENSG RBM e-02 ENSG WDR e-02 ENSG PPARGC1A e-02 ENSG C3orf e-02 ENSG MRPL e-02 ENSG STOML e-02

28 ENSG UBE4A e-02 ENSG PECI e-03 ENSG APEX e-02 ENSG PGPEP1L e-02 ENSG GEMIN e-02 ENSG BEND e-02 ENSG SRI e-02 ENSG PMPCB e-02 ENSG RPS e-02 ENSG TMEM e-02 ENSG ZSCAN e-02 ENSG NEK e-02 ENSG DERL e-02 ENSG RMND5A e-02 ENSG MED e-02 ENSG LPL e-02 ENSG CAPRIN e-02 ENSG PKIG e-03 ENSG SLC25A e-02 ENSG IPO e-02 ENSG ZC3H e-02 ENSG PFDN e-02 ENSG KIAA e-03 ENSG ADIPOR e-02 ENSG PTPRG e-02 ENSG MUM1L e-02 ENSG MYNN e-02 ENSG FAM120AOS e-03 ENSG DDHD e-02 ENSG VAMP e-02 ENSG RPL e-02 ENSG LRRIQ e-02 ENSG PRKAG e-02 ENSG COX e-03 ENSG PHF e-03 ENSG NARG e-03 ENSG BRD e-02 ENSG PPARA e-02 ENSG BAZ2B e-02 ENSG ATP5L e-02 ENSG ARIH e-02 ENSG RPL e-02 ENSG SMURF e-02 ENSG HBS1L e-02

29 ENSG BTF e-02 ENSG FXR e-03 ENSG TMTC e-02 ENSG ASH2L e-02 ENSG C19orf e-02 ENSG SNRK e-02 ENSG ESD e-02 ENSG SPATA e-02 ENSG PTCD e-02 ENSG ADCY e-02 ENSG PRKRA e-02 ENSG PRKRAP e-02 ENSG TJP e-02 ENSG GNPAT e-02 ENSG CECR e-02 ENSG TMEM e-02 ENSG MRPS e-02 ENSG NIT e-02 ENSG YIPF e-02 ENSG PAAF e-02 ENSG AZI e-03 ENSG GBAS e-02 ENSG CCDC e-02 ENSG USP e-02 ENSG ANKRD e-03 ENSG CNOT e-02 ENSG KLHL e-02 ENSG ANAPC e-02 ENSG LONP e-02 ENSG PDHB e-02 ENSG MRPS e-02 ENSG CLDND e-03 ENSG HMGN e-02 ENSG MOSC e-02 ENSG ORC4L e-03 ENSG C16orf e-02 ENSG NDUFA e-04 ENSG MIB e-02 ENSG TYW e-03 ENSG WRB e-02 ENSG MRPS e-02 ENSG PRDX e-03 ENSG SNAPIN e-02 ENSG MRPL e-02

30 ENSG PEX e-03 ENSG PRMT e-02 ENSG ACTR e-02 ENSG HSDL e-02 ENSG ALDH7A e-03 ENSG RSL1D e-02 ENSG SLC25A e-02 ENSG RMND e-02 ENSG PHKA e-02 ENSG AMZ e-02 ENSG PHYH e-02 ENSG EAPP e-02 ENSG CFL e-03 ENSG MRPL e-02 ENSG GATAD e-02 ENSG ZDHHC e-02 ENSG DRG e-02 ENSG METTL e-02 ENSG PTCD e-03 ENSG SIRT e-02 ENSG NDUFS e-02 ENSG ACOT e-02 ENSG DPY19L e-02 ENSG LTBP e-02 ENSG MAOB e-02 ENSG C16orf e-02 ENSG HTRA e-02 ENSG LASS e-02 ENSG STYX e-03 ENSG RPL36AL e-03 ENSG SFRS e-02 ENSG DCUN1D e-02 ENSG PPP2R5A e-02 ENSG ZC3H e-02 ENSG RANBP e-02 ENSG PTPN e-03 ENSG PCYOX e-02 ENSG IDH3B e-03 ENSG MRPL e-02 ENSG SPRY e-02 ENSG RCOR e-02 ENSG SLC35F e-02 ENSG TOR1AIP e-03 ENSG ARL e-02

31 ENSG ZNF e-03 ENSG TTC21B e-02 ENSG LRRC8B e-02 ENSG NUP e-02 ENSG SUCLG e-03 ENSG VPS e-03 ENSG CIRH1A e-02 ENSG OXNAD e-02 ENSG RFC e-03 ENSG MLX e-02 ENSG DALRD e-02 ENSG MUT e-03 ENSG RTCD e-02 ENSG MORC e-02 ENSG STAU e-03 ENSG ABHD e-02 ENSG NCRNA e-03 ENSG PPAP2B e-02 ENSG KLF e-02 ENSG UBR e-02 ENSG HOXA e-02 ENSG HOXA e-02 ENSG HSCB e-02 ENSG TJP e-02 ENSG RBM e-02 ENSG BTF3L e-02 ENSG LRP e-02 ENSG EIF4EBP e-02 ENSG UBE2W e-02 ENSG DHRS e-02 ENSG ALDH e-03 ENSG OXA1L e-03 ENSG ANO e-03 ENSG C1orf e-02 ENSG C11orf e-02 ENSG PKN e-02 ENSG SLC25A e-02 ENSG ZCCHC e-02 ENSG NFU e-02 ENSG DHX e-02 ENSG PEX11A e-02 ENSG TMEM e-03 ENSG HEATR5B e-02 ENSG FBXL e-02

32 ENSG RPAP e-02 ENSG RPS15A e-02 ENSG C5orf e-02 ENSG MRPS e-03 ENSG PJA e-02 ENSG ARG e-02 ENSG DCTN e-02 ENSG FOXJ e-02 ENSG NACA e-04 ENSG NACA e-04 ENSG NACAP e-04 ENSG EIF2A e-02 ENSG C4orf e-03 ENSG RAD e-03 ENSG SPRY e-02 ENSG TAF9B e-02 ENSG PHB e-03 ENSG LRRC e-02 ENSG MBIP e-02 ENSG PPME e-02 ENSG LRRC e-02 ENSG ZCCHC e-02 ENSG BRPF e-02 ENSG MRPS e-03 ENSG C20orf e-02 ENSG AKAP e-02 ENSG MRPS e-03 ENSG GYG e-03 ENSG BAG e-02 ENSG FDFT e-02 ENSG EFHA e-02 ENSG TOM1L e-02 ENSG FAM200A e-02 ENSG MID e-02 ENSG ORC3L e-02 ENSG AKAP e-02 ENSG DLST e-02 ENSG ADNP e-02 ENSG FAHD2A e-03 ENSG CD e-02 ENSG CCNG e-02 ENSG PTPN e-02 ENSG CETN e-02 ENSG C6orf e-02

33 ENSG SAV e-02 ENSG ORC2L e-02 ENSG MSH e-02 ENSG EIF1B e-02 ENSG SMARCA e-02 ENSG WDSUB e-02 ENSG CASD e-02 ENSG HYI e-02 ENSG DHTKD e-02 ENSG EIF4B e-02 ENSG C2orf e-02 ENSG SDHB e-03 ENSG SYNE e-03 ENSG C16orf e-02 ENSG GHR e-02 ENSG C3orf e-02 ENSG POLI e-02 ENSG MCCC e-02 ENSG RRAGB e-02 ENSG CTTNBP e-02 ENSG TCEB e-02 ENSG ACADL e-03 ENSG SCAI e-02 ENSG METAP e-02 ENSG PGAM e-02 ENSG PXMP e-02 ENSG CRYBG e-02 ENSG CSAD e-02 ENSG SLC25A e-02 ENSG VEGFA e-03 ENSG KIAA e-03 ENSG APPBP e-03 ENSG PCCA e-03 ENSG ETFDH e-02 ENSG ABHD e-02 ENSG NKIRAS e-02 ENSG NDUFB e-02 ENSG COPS e-03 ENSG NDFIP e-02 ENSG ECHDC e-02 ENSG HOXD e-02 ENSG ADIPOQ e-02 ENSG PCCB e-02 ENSG MTHFD e-03

34 ENSG C13orf e-02 ENSG CNBP e-02 ENSG ZFPM e-02 ENSG LSM e-03 ENSG OXCT e-02 ENSG NR3C e-02 ENSG TAF1D e-04 ENSG HOXB e-02 ENSG TMEM e-02 ENSG BNIP3L e-03 ENSG BCKDHB e-03 ENSG PCBD e-03 ENSG BRP44L e-02 ENSG HNRPDL e-02 ENSG MRPL e-03 ENSG YPEL e-03 ENSG C11orf e-02 ENSG RNASE e-03 ENSG ATP5S e-03 ENSG PTP4A e-02 ENSG GNAI e-03 ENSG GLRB e-02 ENSG LGALS e-02 ENSG NRIP e-02 ENSG FAM10A e-02 ENSG ST e-02 ENSG BTG e-02 ENSG COQ e-02 ENSG HRSP e-03 ENSG DCXR e-03 ENSG PCDH e-02 ENSG NDUFA e-04 ENSG PTEN e-02 ENSG ATPAF e-04 ENSG PIGP e-02 ENSG NEDD4L e-02 ENSG ZFYVE e-02 ENSG ZNHIT e-03 ENSG AUH e-02 ENSG UQCRC e-03 ENSG NPHP e-02 ENSG GINS e-02 ENSG FAM89A e-02 ENSG CDKN1B e-02

35 ENSG MATN e-02 ENSG CYB5A e-02 ENSG HADH e-04 ENSG SCO e-02 ENSG AQP e-02 ENSG ADH1B e-02 ENSG CDKN2C e-03 ENSG LETMD e-03 ENSG DRAM e-02 ENSG RABL2B e-02 ENSG TARSL e-02 ENSG PC e-02 ENSG AASS e-02 ENSG ZFAND e-02 ENSG ANKRA e-02 ENSG MPDZ e-02 ENSG MOSC e-03 ENSG HIBADH e-03 ENSG CTH e-02 ENSG LACTB e-02 ENSG SLC25A e-02 ENSG MAP3K e-02 ENSG ALPK e-02 ENSG GLUL e-04 ENSG FAM13A e-02 ENSG ZNF204P e-03 ENSG TMEM e-02 ENSG ZBTB e-02 ENSG ACVR1C e-03 ENSG ETFA e-03 ENSG HSD17B e-03 ENSG PMM e-02 ENSG HMGN e-02 ENSG PFKFB e-02 ENSG ACACB e-03 ENSG ECHDC e-03 ENSG LRIG e-03 ENSG AGTR e-02 ENSG GPD1L e-03 ENSG ADRBK e-02 ENSG GMCL e-02 ENSG GMCL1L e-02 ENSG MAPK e-03 ENSG PRKAR2B e-02

36 ENSG ZC3H e-02 ENSG GPN e-02 ENSG SLC25A e-02 ENSG SLC19A e-02 ENSG PPP1R16A e-02 ENSG SYT e-02 ENSG RAI e-03 ENSG BBS e-03 ENSG MAB21L e-02 ENSG CALCRL e-03 ENSG ORMDL e-03 ENSG DAPK e-02 ENSG NUDT e-02 ENSG TWIST e-03 ENSG LPIN e-02 ENSG RGS e-02 ENSG GPHN e-02 ENSG NAALAD e-02 ENSG CMTM e-02 ENSG PECR e-04 ENSG FAM162B e-02 ENSG TTLL e-02 ENSG ACSS e-03 ENSG CIDEA e-03 ENSG ABHD e-02 ENSG PGAM e-02 ENSG DBP e-02 ENSG SC5DL e-02 ENSG GSDMB e-02 ENSG SERPINI e-02 ENSG CASQ e-02 ENSG DMRT e-02 ENSG NIPSNAP3B e-02 ENSG ADSSL e-02 ENSG AZGP e-02 ENSG STOX e-03 ENSG COL6A e-02 ENSG APOB e-03 ENSG C12orf e-02 ENSG CA e-02

37 Figure S1. Protein expression in the skeletal muscle related to mitochondrial energy metabolism, glucose uptake and insulin signaling. Values are reported as mean and the error bars represent standard deviation.