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Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease.
Tuesday,2023-01-31 14:15 America/Los_Angeles — ecterry
| Title | Whole-Exome Sequencing Study Identifies Four Novel Gene Loci Associated with Diabetic Kidney Disease. |
| Publication Type | Journal Article |
| Year of Publication | 2022 |
| Authors | Pan, Y, Sun, X, Mi, X, Huang, Z, Hsu, Y, Hixson, JE, Munzy, D, Metcalf, G, Franceschini, N, Tin, A, Köttgen, A, Francis, M, Brody, JA, Kestenbaum, B, Sitlani, CM, Mychaleckyj, JC, Kramer, H, Lange, LA, Guo, X, Hwang, S-J, Irvin, MR, Smith, JA, Yanek, LR, Vaidya, D, Chen, Y-DI, Fornage, M, Lloyd-Jones, DM, Hou, L, Mathias, RA, Mitchell, BD, Peyser, PA, Kardia, SLR, Arnett, DK, Correa, A, Raffield, LM, Vasan, RS, L Cupple, A, Levy, D, Kaplan, RC, North, KE, Rotter, JI, Kooperberg, C, Reiner, AP, Psaty, BM, Tracy, RP, Gibbs, RA, Morrison, AC, Feldman, H, Boerwinkle, E, He, J, Kelly, TN |
| Corporate/Institutional Authors | NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Kidney Function Working Group, CRIC Study Investigators |
| Journal | Hum Mol Genet |
| Date Published | 2022 Nov 29 |
| ISSN | 1460-2083 |
| Abstract | <p>Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease (CKD) and diabetes. Our two-stage whole-exome sequencing study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort (CRIC) and Atherosclerosis Risk in Communities (ARIC) studies (stage-1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine (TOPMed) participants (stage-2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex, and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test (SKAT-O) implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds (95% confidence interval: 33.6, 1105) of DKD compared with non-carriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% confidence interval: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD.</p> |
| DOI | 10.1093/hmg/ddac290 |
| Alternate Journal | Hum Mol Genet |
| PubMed ID | 36444934 |
| Grant List | R01 DK117445 / DK / NIDDK NIH HHS / United States R01 MD012765 / MD / NIMHD NIH HHS / United States |
ePub date:
22/11