Genetic Risk of Membranous Nephropathy

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Lili Liu, PHD, Junying Zhang, Krzysztof Kiryluk, MD, MS

This calculator is designed to assess the risk of membranous nephropathy in an individual presenting with nephrotic syndrome. The risk calculation is based on a genetic risk profile combined with a serologic test for anti-PLA2R antibody. The genetic risk score equations are derived from GWAS analysis of 12,820 individuals (3,782 primary MN and 9,038 controls), including 4,841 individuals of East Asian ancestry (1,632 cases and 3,209 controls) and 7,979 individuals of European ancestry (2,150 cases and 5,829 controls). The risk score is calculated separately for Europeans and East Asians and standard-normalized using genotypes of healthy ancestry-matched controls. The serologic test results refer to antibody levels as determined by the anti-PLA2R IgG ELISA (EUROIMMUN Medizinische Labordiagnostika AG). The cut-offs that define a positive test (i.e. high risk patient) have 99% specificity and are described in the reference below.

To calculate the disease risk, select the genotypes from the following drop-down menus:

Enter Ancestry:

Asian
European

Is anti-PLA2RAb ELISA available?:

Yes, please enter level value(u/mL):
No

SNP [Risk Allele]	Genotype
rs9269027 [A]
rs1974461 [T]
rs6707458 [G]
rs230540 [C]
rs9405192 [G]

SNP [Risk Allele]	Genotype
rs9271541 [C]
rs9265949 [T]
rs2858309 [C]
rs6707458 [G]
rs230540 [C]
rs9405192 [G]

Please enter a value for all SNPs for the group listed above.

Genetic Risk Score

Select SNP genotypes to calculate risk.

East Asian Risk Score Equations:

Standardized Genetic Risk Score (GRS) =
[0.69173 × N(rs9269027:A) + 1.23685 × N(rs1974461:T) + 0.36687 × N(rs6707458:G) + 0.25098 × N(rs230540:C) + 0.39127 × N(rs9405192:G) + 0.48798 × N(rs9269027:A) × N(rs6707458:G)–GRS_Asian_control_mean)] / (GRS_Asian_control_SD);

N = number of reference alleles for each SNP (0, 1, or 2 per individual genotype).
GRS_Asian_control_mean = 1.680372, GRS_Asian_control_SD = 1.003153

Combined Risk Score (CRS) =
[Standardized Genetic Risk Score + 1.771211 × log(antiPLA2R titer+0.001)– CRS_Asian_control_mean] / (CRS_Asian_control_SD);

CRS_Asian_control_mean = 0.3723719, CRS_Asian_control_SD = 2.750298;

European Risk Score Equations:

Standardized Genetic Risk Score (GRS) =
[ 0.34945 × N(rs9271541:C) + 0.67919 × N(rs9265949:T) + 0.30707 × N(rs2858309:C) + 0.34601 × N(rs6707458:G) + 0.1745 × N(rs230540:C) + 0.18343 × N(rs9405192:G) + 0.33782 × N(rs9271541:C) × N(6707458:G) – GRS_European_control_mean ] / (GRS_European_control_SD);

N = number of reference alleles for each SNP (0, 1, or 2 per individual genotype).
GRS_European_control_mean = 1.508911, GRS_European_control_SD = 0.8201664

Combined Risk Score (CRS) =
[Standardized Genetic Risk Score + 0.4828663 × log(antiPLA2R titer+0.001) – CRS_European_control_mean ] / (CRS_European_control_SD;

CRS_European_control_mean = -1.49821, CRS_European_control_SD = 1.435376;

References:

Xie J, Liu L, Mladkova N, Li Y, Ren H, Wang W, Cui Z, Lin L, Hu X, Yu X, Xu J, Liu G, Caliskan Y, Sidore C, Balderes O, Rosen RJ, Bodria M, Zanoni F, Zhang JY, Krithivasan P, Mehl K, Marasa M, Khan A, Ozay F, Canetta PA, Bomback AS, Appel GB, Sanna-Cherchi S, Sampson MG, Mucha K,, Moszczuk B, Foroncewicz B, Pączek L, Habura I, Ars E, Ballarin J, Mani L-Y, Vogt B, Ozturk S, Yildiz A, Seyahi N, Arikan H, Koc M, Basturk T, Karahan G, Akgul SU, Sever MS, Zhang D, Santoro D, Bonomini M, Londrino F, Gesualdo L, Reiterova J, Tesar V, Izzi C, Savoldi S, Spotti D, Marcantoni C, Messa P, Galliani M, Roccatello D, Granata S, Zaza G, Lugani F, Ghiggeri GM, Allegri L, Sprangers B, Park J-H, Cho B, Kim YS, Kim DK, Suzuki H, Amoroso A, Cattran DC, Fervenza FC, Pani A, Hamilton P, Harris S, Gupta S, Cheshire C, Dufek S, Issler N, Pepper RJ, Connolly J, Powis S, Bockenhauer D, Stanescu HC, Ashman N, Loos JJF, Kenny EE, Wuttke M, Eckardt K-U, Köttgen A, Zoledziewska M, Cucca F, Ionita-Laza I, Lee H, Hoxha E , Stahl RAK, Brenchley P, Scolari F, Zhao M-H, Gharavi AG, Kleta R, Chen N, and Kiryluk K. Genetic Architecture of Membranous Nephropathy and Its Potential to Improve Non-invasive Diagnosis. Nature Communications 11, 1600 (2020).

Disclaimer:

This tool is designed for individual risk prediction, however, it does not imply medical advice and it should not be used to guide clinical management until additional studies confirm its clinical utility. This risk assessment may not be applicable to all populations. Please refer to the original publication for detailed characteristics of the populations used for risk score discovery.

Last updated 02/2020