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Genetic variation of DKK3 may modify renal disease severity in ADPKD.

ABSTRACT: Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) genotyping association study of 173 biological candidate genes in 794 white patients from 227 families with PKD1. We analyzed two primary outcomes: (1) eGFR and (2) time to ESRD (renal survival). For both outcomes, we used multidimensional scaling to correct for population structure and generalized estimating equations to account for the relatedness among individuals within the same family. We found suggestive associations between each of 12 SNPs and at least one of the renal outcomes. We genotyped these SNPs in a second set of 472 white patients from 229 families with PKD1 and performed a joint analysis on both cohorts. Three SNPs continued to show suggestive/significant association with eGFR at the Dickkopf 3 (DKK3) gene locus; no SNPs significantly associated with renal survival. DKK3 antagonizes Wnt/beta-catenin signaling, which may modulate renal cyst growth. Pending replication, our study suggests that genetic variation of DKK3 may modify severity of ADPKD resulting from PKD1 mutations.

SUBMITTER: Liu M

PROVIDER: S-EPMC3013521 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Genetic variation of DKK3 may modify renal disease severity in ADPKD.

Liu Michelle M Shi Sally S Senthilnathan Sean S Yu Julie J Wu Elliot E Bergmann Carsten C Zerres Klaus K Bogdanova Nadja N Coto Eliecer E Deltas Constantinos C Pierides Alkis A Demetriou Kyproula K Devuyst Olivier O Gitomer Berenice B Laakso Marku M Lumiaho Anne A Lamnissou Klea K Magistroni Riccardo R Parfrey Patrick P Breuning Martijn M Peters Dorien J M DJ Torra Roser R Winearls Christopher G CG Torres Vicente E VE Harris Peter C PC Paterson Andrew D AD Pei York Y

Journal of the American Society of Nephrology : JASN 20100708 9

Significant variation in the course of autosomal dominant polycystic kidney disease ( ADPKD) within families suggests the presence of effect modifiers. Recent studies of the variation within families harboring PKD1 mutations indicate that genetic background may account for 32 to 42% of the variance in estimated GFR (eGFR) before ESRD and 43 to 78% of the variance in age at ESRD onset, but the genetic modifiers are unknown. Here, we conducted a high-throughput single-nucleotide polymorphism (SNP) ...[more]

PMID: 20616171

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Project description:ObjectivesWe examined the association between delirium severity and outcomes of delirium among persons with and without Alzheimer's disease and related dementias (ADRD).DesignProspective cohort study.SettingAcademic tertiary medical center.ParticipantsA total of 352 medical and surgical patients.MeasurementsDelirium incidence and severity were rated daily using the Confusion Assessment Method (CAM) and CAM-Severity (CAM-S) score during hospitalization. Severe delirium was defined as a CAM-S Short Form score in the highest tertile (3-7 points out of 7). ADRD status was determined by a clinical consensus process. Clinical outcomes included prolonged length of stay (>6 d), discharge to post-acute nursing facility, any decline in activities of daily living (ADLs) at 1 month from prehospital baseline, ongoing nursing facility stay, and mortality.ResultsPatients with ADRD (n = 85 [24%]) had a significantly higher relative risk (RR) for incident delirium (RR = 2.31; 95% confidence interval [CI] = 1.64-3.28) and higher peak CAM-S scores (mean difference = 1.24 points; CI = .83-1.65; P < .001). Among patients with ADRD, severe delirium significantly increased the RR for nursing facility stay (RR = 2.22; CI = 1.05-4.69; P = .04) and increased the RR for mortality (RR = 2.10; CI = .89-4.98; P = .09). Among patients without ADRD, severe delirium was associated with a significantly increased risk for all poor outcomes except mortality including prolonged length of stay in the hospital (RR = 1.47; CI = 1.18-1.82) and discharge to a post-acute nursing facility (RR = 2.17; CI = 1.58-2.98) plus decline in ADLs (RR = 1.30; CI = 1.05-1.60) and nursing facility stay at 1 month (RR = 1.93; CI = 1.31-2.83).ConclusionSevere delirium is associated with increased risk for poor clinical outcomes in patients with and without ADRD. In both groups, severe delirium increased risk of nursing home placement. In patients with ADRD, delirium was more severe and associated with a trend toward increased mortality at 1 month. Although the increased risk remains substantial by RR, the study had limited power to examine the rarer outcome of death. J Am Geriatr Soc 68:1722-1730, 2020.

Dataset Information

Genetic variation of DKK3 may modify renal disease severity in ADPKD.

Publications

Genetic variation of DKK3 may modify renal disease severity in ADPKD.

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