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Publication Information
Affiliation
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;; Center for Research on Health Care, and.; Section of Nephrology, University of Chicago, Chicago, Illinois;; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;; Kidney Institute, Kansas University Medical Center, Kansas City, Kansas;; Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania;; Division of Nephrology, University of Colorado Health Sciences Center, Denver, Colorado;; Division of Nephrology, Tufts Medical Center, Boston, Massachusetts;; Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio;; Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, Massachusetts;; Division of Nephrology, University of Alabama, Birmingham, Alabama;; Kidney Institute, Kansas University Medical Center, Kansas City, Kansas;; Division of Nephrology, University of Colorado Health Sciences Center, Denver, Colorado;; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota;; Legacy Transplant Services, Legacy Good Samaritan Hospital, Portland, Oregon;; National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland; and.; Dickson Advanced Analytics, Carolinas HealthCare System, Charlotte, North Carolina.; Center for Research on Health Care, and.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; harris.peter@mayo.edu.
Authors
Heyer Christina M, Sundsbak Jamie L, Abebe Kaleab Z, Chapman Arlene B, Torres Vicente E, Grantham Jared J, Bae Kyongtae T, Schrier Robert W, Perrone Ronald D, Braun William E, Steinman Theodore I, Mrug Michal, Yu Alan S L, Brosnahan Godela, Hopp Katharina, Irazabal Maria V, Bennett William M, Flessner Michael F, Moore Charity G, Landsittel Douglas, Harris Peter C
Studies
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) often results in ESRD but with a highly variable course. Mutations to PKD1 or PKD2 cause ADPKD; both loci have high levels of allelic heterogeneity. We evaluated genotype-phenotype correlations in 1119 patients (945 families) from the HALT Progression of PKD Study and the Consortium of Radiologic Imaging Study of PKD Study. The population was defined as: 77.7% PKD1, 14.7% PKD2, and 7.6% with no mutation detected (NMD). Phenotypic end points were sex, eGFR, height-adjusted total kidney volume (htTKV), and liver cyst volume. Analysis of the eGFR and htTKV measures showed that the PKD1 group had more severe disease than the PKD2 group, whereas the NMD group had a PKD2-like phenotype. In both the PKD1 and PKD2 populations, men had more severe renal disease, but women had larger liver cyst volumes. Compared with nontruncating PKD1 mutations, truncating PKD1 mutations associated with lower eGFR, but the mutation groups were not differentiated by htTKV. PKD1 nontruncating mutations were evaluated for conservation and chemical change and subdivided into strong (mutation strength group 2 [MSG2]) and weak (MSG3) mutation groups. Analysis of eGFR and htTKV measures showed that patients with MSG3 but not MSG2 mutations had significantly milder disease than patients with truncating cases (MSG1), an association especially evident in extreme decile populations. Overall, we have quantified the contribution of genic and PKD1 allelic effects and sex to the ADPKD phenotype. Intrafamilial correlation analysis showed that other factors shared by families influence htTKV, with these additional genetic/environmental factors significantly affecting the ADPKD phenotype.