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View of Epidermal Growth Factor Receptor/HER2 In- 11 CLINICAL RESEARCH www.jasn.org Blood HER2 and Uromodulin as Causal Mediators of CKD Jennifer Sjaarda,1,2,3 Hertzel C. Gerstein,1,2 Salim Yusuf,1 Darin Treleaven,4 Michael Walsh,1,4,5 Johannes F.E. Mann,6,7 Sibylle Hess,8 and Guillaume Paré1,2,9,10 1Population Health Research Institute and 2Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, Ontario, Canada; 3Departments of Medical Sciences, 4Medicine, 5Health Research Methods, Evaluation and Impact, and 10Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; 6Department of Nephrology and Hypertension, University Hospital, Friedrich- Alexander University, Erlangen-Nuremberg, Germany; 7Department of Medicine IV, University of Erlangen-Nurnberg, Erlangen, Germany; 8Sanofi Aventis Deutschland GmbH, Research and Development Division, Translational Medicine and Early Development, Biomarkers and Clinical Bioanalyses, Frankfurt, Germany; and 9Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, Ontario, Canada ABSTRACT Many biomarkers have been epidemiologically linked with CKD; however, the possibility that such asso- ciations are due to reverse causation or confounding limits the utility of these biomarkers. To overcome this limitation, we used a Mendelian randomization (MR) approach to identify causal mediators of CKD. We performedMRbyfirst identifying genetic determinants of 227 serum protein biomarkers assayed in 4147 participants of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial who had early or pre- diabetes, and assessing the effects of these biomarkers on CKD in the CKD genetics consortium (n=117,165; 12,385 cases) using the inverse-variance weighted (fixed-effects)method.Wethenestimatedtherelationship between the serum concentration of each biomarker identified and incident CKD in ORIGIN participants. MR identified uromodulin (UMOD) and human EGF receptor 2 (HER2)asnovel,causalmediatorsofCKD(UMOD: 2 odds ratio [OR], 1.30 per SD; 95% confidence interval [95% CI], 1.25 to 1.35; P,5310 20; HER2: OR, 1.30 per SD; 2 95% CI, 1.14 to 1.48; P=8.0310 5). Consistent with these findings, blood HER2 concentration associated with CKDeventsinORIGINparticipants(OR, 1.07 per SD; 95% CI, 1.01 to 1.13; P=0.01). Additional exploratory MR analyses identified angiotensin-converting enzyme (ACE) as a regulator of HER2 levels (b=0.13 per SD; 95% CI, 2 0.08 to 0.16; P=2.5310 7). This finding was corroborated by an inverse relationship between ACE inhibitor use and HER2 levels. Thus, UMOD and HER2 are independent causal mediators of CKD in humans, and serum HER2 levels are regulated in part by ACE. These biomarkers are potential therapeutic targets for CKD prevention. J Am Soc Nephrol 29: 1326–1335, 2018. doi: https://doi.org/10.1681/ASN.2017070812 CKD is a growing public health problem that in- epidemiologic approaches may be confounded creases the risk of cardiovascular disease, kidney with, or caused by, other unmeasured biomarkers failure, and other complications.1 Whereas glucose or mechanisms. Under a strict set of assumptions, lowering, BP lowering, and therapies that target the renin-angiotensin-aldosterone system (RAAS)2 can slow progression of CKD, the mechanism(s) Received July 28, 2017. Accepted January 18, 2018. Published online ahead of print. Publication date available at by which they work are not fully understood. www.jasn.org. Elucidation of these and other CKD-related mech- Correspondence: Dr. Guillaume Paré, McMaster University, anisms may identify novel therapies, and the iden- Population Health Research Institute, David Braley Cardiac, tification of causal biomarkers for CKD represents Vascular and Stroke Institute, 237 Barton Street East – C3 103, one promising approach. Unfortunately, candi- Hamilton, ON L8L 2X2, Canada. Email: [email protected] date biomarkers identified using traditional Copyright © 2018 by the American Society of Nephrology 1326 ISSN : 1046-6673/2904-1326 JAmSocNephrol29: 1326–1335, 2018 www.jasn.org CLINICAL RESEARCH Mendelian randomization (MR) can overcome these Significance Statement problems.3 MR is a powerful genetic methodology that is on the basis of Inhibition of the renin-angiotensin-aldosterone system by angio- the principle that genetic variants are inherited randomly and tensin-converting enzyme (ACE) inhibitors is one of the best es- independently of other risk factors for disease. If the levels of a tablished strategies to reduce the decline of kidney function in CKD. This study, which uses a novel Mendelian randomization–based particular biomarker are affected by the presence of a genetic approach, identifies human EGF receptor 2 (HER2) and uromodulin variant, and if that variant also affects the incidence of a disease, (UMOD) as potential causal mediators of CKD, and ACE as a po- the variant may be causing the disease by modulating the levels tential regulator of HER2 levels. These findings implicate HER2 as a of the risk factor. The random distribution of the genetic var- mediator of ACE inhibitors’ protective effect on CKD and as a fi iant at birth minimizes the possibility of confounding or marker which may help reveal patients likely to bene t from ACE inhibition. Both UMOD and HER2 inhibition represent potential reverse causation as explanations for the link between the bio- novel targets for interventions to slow progression of CKD. marker and disease, in the same way that the random allocation of a therapy in a randomized, controlled trial minimizes this 25 possibility.4 These principles have been successful in identifying HER2 (OR, 1.30 per SD; 95% CI, 1.14 to 1.48; P=8.0310 , risk factors that are causal for CVD, and biomarkers identified number of SNPs=5) on CKD. All SNPs used in the MR models using MR have been subsequently validated in randomized trials had P,0.01 and FDR,0.05 for the SNP-biomarker associations of therapeutic agents.5 Specifically, MR techniques have con- (Supplemental Tables 1 and 2). Regional plots of SNP associations firmed LDL cholesterol, IL-6 receptor, and lipoprotein(a) as with serum UMOD and HER2 at the UMOD and ERBB2 loci, causal biomarkers of coronary artery disease.6–8 Whereas there respectively, are depicted in Supplemental Figure 1. To assess for are fewer examples of MR in the field of nephrology, this ap- the presence of unmeasured horizontal pleiotropy, we utilized the proach has recently identified a causal effect of lower iron and MR–Egger12 method where the y intercept is allowed to float, ferritin levels on decreased kidney function and has ruled out a rather than be fixed at zero. We found no evidence of pleiotropy causal relationship between fetuin-A and mortality in patients as determined by the significance of the y intercept (P.0.05). As a on dialysis.9,10 sensitivity analysis, we use a leave-one-out strategy in which MR MR methodology has traditionally been used to determine analyses were repeated, excluding one variant at a time, and con- whether a candidate biomarker is causally related to a clinical sistent estimates were obtained for each SNP excluded (see Sup- outcome (clinicaltrials.gov; NCT 00069784). However, when plemental Tables 3 and 4 for full results). combined with a large panel of biomarkers measured in a pro- spective study which accrued many clinical outcomes, it can Association of UMOD and HER2 Concentration with also be used to identify new, unsuspected biomarkers that are CKD in ORIGIN likely to be causally related to the clinical outcome. We there- The MR-generated hypothesisthat these biomarkers promoted fore sought to identify such CKD biomarkers by applying MR CKD was then tested using the ORIGIN data. We therefore techniques to a comprehensive panel of 237 biomarkers cov- assessed the epidemiologic relationship of baseline UMOD and ering cardiovascular, metabolic, and inflammatory processes HER2 with incident CKD. We found that increased levels of within the recently completed Outcome Reduction with an blood UMOD were significantly associated with decreased risk Initial Glargine Intervention (ORIGIN) trial that was per- of CKD, whereas increased levels of blood HER2 were associ- formed in people with type 2 diabetes or prediabetes.11 ated with an increasedriskof incident CKDin models adjusting for age, sex, and ethnicity (UMOD: OR, 0.83 per SD; 95% CI, 0.78 to 0.88; P,0.001 and HER2: OR, 1.07 per SD; 95% CI, RESULTS 1.01 to 1.13; P=0.01). Consistent results were also observed in models fully adjusted for CKD risk factors and are provided in Identification of CKD Biomarkers Using MR the Supplemental Material. We performed subgroup analyses Two hundred twenty-seven serum biomarkers were tested for an to assess the consistency of the association of UMOD and association with CKD using an MR approach. After removing HER2 concentration with CKD. No significant interaction biomarkers without any significant cis single nucleotide polymor- across subgroups was observed after adjustment for multiple phism (SNP) associations and with minor allele frequency,0.05 hypothesis testing (Figure 2). (according to CKD genetics consortium [CKDGen]), 197 bio- markers were retained for downstream analysis. After MR analy- Association of UMOD with Kidney Mass in Healthy sis, two biomarkers were found to be significantly associated with Patients Undergoing Nephrectomy CKD after Bonferroni correction for multiple hypothesis testing We assessed for the possibility that reverse causation could (P,0.05/197), namely uromodulin (UMOD, also known as playa role in the apparentdiscrepant epidemiologic association Tamm–Horsfall glycoprotein) and human EGF receptor 2 (HER2). of UMOD with CKD (OR, 0.83; 95% CI, 0.78 to 0.88) and the As noted in Figure 1, the MR analysis suggested a deleterious effect evidence for UMOD as a CKD risk factor found in the MR (OR, of UMOD (odds ratio [OR], 1.30 per SD; 95% confidence interval 1.30; 95% CI, 1.25 to 1.35). Because UMOD is exclusively 2 [95% CI], 1.25 to 1.35; P,5310 20, number of SNPs=17) and synthesized in the kidney, we hypothesized that UMOD is J Am Soc Nephrol 29: 1326–1335, 2018 UMOD and HER2 as New Causal Mediators of CKD Using MR 1327 CLINICAL RESEARCH www.jasn.org Figure 1.
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