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Dissecting the Genetic Architecture of Cystatin C in Diversity Outbred Mice

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Dissecting the Genetic Architecture of Cystatin C in Diversity Outbred Mice MULTIPARENTAL POPULATIONS Dissecting the Genetic Architecture of Cystatin C in Diversity Outbred Mice M. Nazmul Huda,*,† Melissa VerHague,‡ Jody Albright,§ Tangi Smallwood,§ Timothy A. Bell,§ Excel Que,* Darla R. Miller,§ Baback Roshanravan,** Hooman Allayee,†† Fernando Pardo Manuel de Villena,§ and Brian J. Bennett*,†,1 *Obesity and Metabolism Research Unit, Western Human Nutrition Research Center, USDA, ARS, Davis, California 95616, †Department of Nutrition, University of California Davis, California 95616, ‡Nutrition Research Institute, University of North § Carolina Kannapolis, North Carolina 28081, Department of Genetics, University of North Carolina at Chapel Hill, North Carolina 27599, **Department of Medicine, Division of Nephrology, University of California, Davis, Davis, California 95616, and ††Departments of Preventive Medicine and Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles California 90033 ORCID IDs: 0000-0003-2775-4470 (M.N.H.); 0000-0002-5738-5795 (F.P.M.d.V.); 0000-0002-0766-3195 (B.J.B.) ABSTRACT Plasma concentration of Cystatin C (CysC) level is a biomarker of glomerular filtration rate in the KEYWORDS kidney. We use a Systems Genetics approach to investigate the genetic determinants of plasma CysC Quantitative trait concentration. To do so we perform Quantitative Trait Loci (QTL) and expression QTL (eQTL) analysis of loci 120 Diversity Outbred (DO) female mice, 56 weeks of age. We performed network analysis of kidney gene Multi parental expression to determine if the gene modules with common functions are associated with kidney biomarkers models of chronic kidney diseases. Our data demonstrates that plasma concentrations and kidney mRNA levels Cystatin C of CysC are associated with genetic variation and are transcriptionally coregulated by immune genes. Kidney Specifically, Type-I interferon signaling genes are coexpressed with Cst3 mRNA levels and associated biomarkers with CysC concentrations in plasma. Our findings demonstrate the complex control of CysC by genetic Type-I interferon polymorphisms and inflammatory pathways. signalling pathway Multiparent Advanced Generation Inter-Cross (MAGIC) multiparental populations MPP The kidney is a complex organ responsible for excretion (Finco 1997), sex, and race, limiting its accuracy to represent true GFR (Stevens secretion (Davis et al. 1961), reabsorption (Lemann et al. 1970), and et al. 2006). An alternative to creatinine is Cystatin C (CysC), often activating vitamin D (Fraser and Kodicek 1973). The gold standard used in research as the basis for estimating glomerular filtration rate. for assessing kidney function is the glomerular filtration rate (GFR), CysC is produced by all mammalian cells, secreted into the blood, but it is difficult to measure with precision. Therefore, GFR is often filtered through the glomerulus, and catabolized by tubular cells estimated from circulating creatinine (Ferguson et al. 2015). Creat- (Inker and Okparavero 2011). Plasma CysC had been found to be inine is an amino acid derivative, released by muscle, and freely unaltered by age, sex, race, and metabolic disorders and was proposed filtered by the kidney glomerulus (Narayanan and Appleton 1980). as a clinical biomarker for GFR (Filler et al. 2005; Newman et al. However, the level of plasma creatinine is influenced by a number of 1995). Several clinical trials reported CysC as a superior marker factors, including: diet, muscle mass, medication, chronic illness, age, compared to creatinine (Plebani et al. 1998; Kyhse-Andersen et al. 1994; Volume 10 | July 2020 | 2529 Harmoinen et al. 1999) while a few others could not show a the manufacturer’s instructions. In brief, plasma samples were diluted significant difference between CysC and creatinine (Donadio et al. 200-fold and incubated in a 96 well microplate pre-coated with CysC 2001; Oddoze et al. 2001). Although CysC is not influenced by specific antibody and CysC concentration was determined from the physiological factors, several recent studies (Köttgen et al. 2010; color intensity of oxidized Tetramethylbenzidine (TMB) measured at Köttgen et al. 2009; Hwang et al. 2007) have found associations 450 nm. Urinary total protein, creatinine and plasma blood urea between SNPs near the Cystatin C gene (Cst3) and plasma CysC levels nitrogen were measured by COBAS INTEGRA 400 plus analyzer or CysC-based estimated glomerular filtration rate (eGFRcys). How (Roche Diagnostics, Rotkreuz, Switzerland). To measure urinary Na+, these genetic variants relate to plasma CysC protein level or its mRNA samples were diluted 1500-fold with 1.0% v/v trace metal free nitric level remains to be determined. acid and analyzed by using a Varian VISTA AX CCD Simultaneous In the current study, we focus on the genetic determination of CysC Inductively Coupled Plasma Atomic Emission Spectroscopy (Varian, protein and mRNA levels using a “Systems Genetics” approach, which is CA, USA). Standards Na+ for Inductively Coupled Plasma Mass useful for the discovery of genes and pathways associated with a reduced Spectrometry (Spex CertiPrep, NJ, USA) was used to make standards kidney function (Keller et al. 2012). We also perform co-expression ranging from 0.05 ppm to 5.0 ppm. Certified urine controls analysis and expression QTL (eQTL) analysis to further investigate the (Seronorm, Stasjonsveien, Norway) and sample pool controls were control of CysC levels using the Diversity Outbred (DO) population, used to check the accuracy of the assay. which are derived from eight founder strains (A/J, C57BL/6J, 129S1/ SvImJ, NOD/ShiLtJ, NZO/HiLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Kidney mRNA microarray Since the DO is a highly recombinant population with immense genetic Total RNA was extracted from about 25 mg of kidney tissue using and phenotypic variation (Svenson et al. 2012; Smallwood et al. 2014), automated instrumentation (Maxwell 16 Tissue LEV Total RNA DO mice have been successfully used in studies focused on the genetic Purification Kit, Promega). RNA concentration was measured by response to environmental toxin exposure and diseases (French et al. fluorometry (Picogreen Life Technologies), and RNA quality was 2015; Tyler et al. 2017).TheDOmicecapturethesamesetofallelic verified using a microfluidics platform (Bioanalyzer, Agilent Tech- variants as the eight founder strains, and their genetic backgrounds are nologies). 95 RNA samples were chosen for microarray analysis and well-studied, which make them an excellent model for researching the 1 sample was run in duplicate as a control. RNA was hybridized to genetic susceptibility to disease. In this study, we focus on the genetic Affymetrix Mouse Gene 2.1 ST 96-Array Plate using a GeneTitan variation associated with CysC gene expression and plasma CysC instrument from Affymetrix according to the manufacturer’s proto- concentration in DO mice. We then performed co-expression network cols. We used the robust multiarray average method (RMA) imple- analysis to identify gene modules associated with CysC and identified mented in the Affymetrix gene expression console with default two gene modules associated with CysC levels. settings (median polish and sketch-quantile normalization) to esti- mate the normalized expression levels of transcripts. All probes MATERIALS AND METHODS containing known single nucleotide polymorphisms (SNPs) from the eight founder inbred mouse strains of the DO mouse population Study design and sample collection were masked (165,204 probes) during normalization by downloading Female diversity outbred (DO) mice (n = 120; J: DO; G16; stock theSNPsfromtheSangersequencingwebsite(http://www.sanger.ac.uk/ number 009376) were obtained from the Jackson Laboratory (Bar science/data/mouse-genomes-project) and overlapping them with Harbor, ME) at 4 weeks of age. These mice were used to generate probe sequences. The data are available at NCBI Gene Expression progeny for another study (Didion et al. 2015) and then aged. At Omnibus (GEO) database under the accession ID GSE122061. 56 weeks of age, all mice were injected intraperitoneally with a volume of sterile isotonic saline equivalent to 10% of their body weight and Genotyping urine was collected in a chilled metabolic cage system (Hatteras Inc, DNA was extracted and purified from tail samples using Qiagen NC). On the following day, mice were fasted for 4 hr, plasma was DNeasy kit (Qiagen, MD, USA) according to the manufacturer’s collected from the retro-orbital sinus into EDTA-containing micro- instructions. Genotyping was performed using the Mega Mouse tubes and centrifuged. Mice were euthanized, dissected, and tissue Universal Genotyping Array (MegaMUGA) by GeneSeek (Neogen, samples were snap frozen in liquid nitrogen. Biological samples were Lansing, MI) (Welsh et al. 2012). The MegaMUGA array is built on ° stored at -80 until assayed. All procedures were approved by the the Illumina Infinium platform and contains 77,800 SNP markers IACUC at UNC, Chapel Hill (IACUC Protocol Number 13-103). that are distributed throughout the genome at an average spacing of 33 Kb. Genotypes of DO mice are accessible through UNC’s Plasma and urine biochemical assays Mutant Mouse Resource and Research Centers website (https:// Plasma CysC was measured by a commercially available quantitative www.med.unc.edu/mmrrc/genotypes/). We estimated heritability sandwich ELISA kit (R&D Systems, MN, USA) for mice according to (h2) from allele probability using a linear mixed model in R package QTL2 version 0.18 (Broman et al. 2019). Copyright
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