Vitamin D deficiency, change in kidney function, and genetic effect modifications in population-based studies 公开

Abstract

Molecular evidence suggest that sufficient 25[OH]D levels could protect against renal function loss, but population-based studies on the association of 25[OH]D with change in estimated glomerular filtration rate (eGFR) and incident chronic kidney disease (CKD) are limited and results discordant. No study explored the potential effect modification of VDR genetic variants on the relationship between 25[OH]D and change in kidney function. We used cross-sectional data from the 2010-2011 Swiss Study on Salt intake to compare the 25[OH]D levels, deficiency status and 25[OH]D level determinants in populations without CKD and with CKD. We tested the interaction of CKD status with six a priori defined attributes on vitamin D. We used baseline (2003-2006) and 5-year follow-up data (CoLaus study) of adults from the general population to evaluate the association of serum 25[OH]D with change in kidney function, rapid decline in kidney function, and incidence of CKD. Ten genetic polymorphisms, of which five were within the VDR gene, were considered a priori. We found that vitamin D insufficiency or deficiency (25(OH)D<30 ng/ml) was frequent among participants with CKD (74.8%, 95%CI 58.4-92.8) but neither the prevalence of vitamin D insufficiency/deficiency nor the mean 25(OH)D levels were different in patients with and without CKD. CKD status did not interact with major determinants of vitamin D for its effect on vitamin D status or levels. We found that annual eGFR change was associated with baseline vitamin D levels and that higher baseline vitamin D level was associated with decreased risk of rapid decline in eGFR. We found a significant Cdx2 VDR genotype-25(OH)D interaction on the risk of rapid eGFR decline or incident CKD (P-value for interaction=0.022). Among participants with the Cdx2 VDR risk allele (CT/TT genotype), the adjusted ROR was 1.17 (95%CI: 1.03-1.34), no association was found among participants without the Cdx 2 VDR risk allele genotype (CC genotype). Our results suggest that serum vitamin D may play an important role in the early stages of eGFR decline in adults from the general population. This association may vary with common genetic differences in the VDR gene.

Table of Contents

TABLE OF CONTENTS CHAPTER 1 General introduction 1.A Vitamin D 1.A.1 Sources of vitamin D and first steps in vitamin D synthesis 1.A.2 Genomic and non genomic vitamin D functions 1.A.3 VitaminD receptor (VDR) 1.A.4 Calcium-related actions of vitamin D 1.A.5 Non calcium-related actions of vitamin D 1.A.6 Vitamin D status 1.A.7 Vitamin D deficiency 1.A.8 Major factor influencing vitamin D levels 1.B Chronic kidney disease 1.B.1 Definition of chronic kidney disease 1.B.2 Etiologies of chronic kidney disease 1.B.3 Health consequences of chronic kidney disease 1.B.4 Prevalence, time trends, and risk of chronic kidney disease References for chapter 1 CHAPTER 2 Project-specific study aims and literature review 2.A Literature review related to project 1 2.A.1 Prevalence of vitamin D deficiency 2.A.2 Prevalence of vitamin D deficiency in Switzerland 2.A.3 Prevalence and determinants of vitamin D deficiency in the chronic kidney disease population 2.B Literature review related to project 2 2.B.1 Vitamin D and kidney function 2.B.2 Vitamin D and blood pressure (epidemiological studies) 2.C Literature review related to project 3 2.C.1 VDR variants and end-stage renal disease or chronic kidney disease 2.C.2 VDR variants and albuminuria 2.C.3 VDR variants, vitamin supplementation, and kidney function 2.C.4 VDR and chronic kidney disease major risk factors 45 2.C.5 VDR-vitamin D interaction 47 References for chapter 2 CHAPTER 3 PROJECT 1 Abstract Introduction Methods Results Discussion Conclusions References for chapter 3 CHAPTER 4 PROJECT 2 Abstract Introduction Methods Results Discussion Conclusions References for chapter 4 Supplementary material CHAPTER 5 PROJECT 3 Abstract Introduction Methods Results Discussion Conclusions References for chapter 5 Supplementary material CHAPTER 6 General discussion References for chapter 6 APPENDIX Collinearity and backward change in estimate elimination approach LIST OF TABLES AND FIGURES CHAPTER 1 Figure 1 Sources of vitamin D and first steps in vitamin D synthesis Figure 2 Genomic structure of the VDR locus on chromosome 12q13 and position of some polymorphisms in the vitamin D receptor gene Figure 3 Possible mechanisms of associations between vitamin D and chronic kidney disease Table 1 Examples of vitamin D status definitions Table 2 Chronic kidney disease, definition Table 3 Chronic kidney disease, stages Table 4 Chronic kidney disease, risk factors CHAPTER 2 Figure 1 Adjusted means of 25(OH)D by periods of the year (Panel A), speaking region (Panel B), and body mass index category (Panel C) Figure 2 Distributions of 25(OH)D by speaking region and body mass index category Figure 3 Outline of renoprotective and blood pressure regulation mechanisms of vitamin D Table 1 Some associations between VDR polymorphisms and disease or traits related to kidney function CHAPTER 3 PROJECT 1 Table 1 Characteristics of the SSS participants, by chronic kidney disease (CKD) status (N=1145) Figure 1 Vitamin D levels and chronic kidney disease (CKD), unadjusted (Panel A), fully adjusted* (Panel B), and restricted to participants without vitamin D supplements or therapy (Panel C) Table 2 Raw numbers and weighted prevalences of sufficient (>=30 ng/ml), insufficient (20-29.9 ng/ml), and deficient (<20 ng/ml) vitamin D status, by chronic kidney disease (CKD) status (N=1145) Table 3 Adjusted a priori interaction tests of characteristics with transformed 25(OH)D levels using linear regression, chunck test, and backward elimination procedures (step 1 to 6), N=1145 Table 4 P values for interaction of selected attributes with CKD status and stages on vitamin D levels and month-specific tertiles (models 3 to 6) CHAPTER 4 PROJECT 2 Table 1 Baseline Characteristics of the CoLaus participants, by vitamin D status (N=4474) Table 2 Kidney phenotypes and outcomes, by vitamin D status (N=4474) Table 3 Associations of baseline 25(OH)D level with annual change in eGFR, rapid loss in eGFR, and incident CKD Table S1 Multivariate association of vitamin D status at baseline with annual change in estimated GFR (N=4474), Full and reduced Models Table S2 Multivariate association (Correlated binary logistic regression) of vitamin D level at baseline with CKD status at baseline and at follow-up (N=4474), Full and reduced Models Table S3 Difference in Annual Change in estimated GFR (ml/min/1.73m2) (95%CI), by vitamin D month-specific quintiles Table S4 Risk of rapid decline in eGFR, Risk Odds Ratio (95%CI), by vitamin D month-specific quintiles 120 Table S5 Risk of CKD, Risk Odds Ratio (95%CI), by vitamin D month-specific quintiles CHAPTER 5 Table 1 Baseline Characteristics of the CoLaus participants, by vitamin D status (N=3954) Table 2 Adjusted association of 25(OH)D month-specific quintiles with annual change in estimated GFR, by Cdx2 VDR genotype Table 3 Adjusted association of 25(OH)D month-specific quintiles with the risk of rapid decline in estimated GFR, the risk of chronic kidney disease (CKD), and the risk of rapid decline in estimated GFR or CKD, by Cdx2 VDR genotypes (rs11568820) Table 4 Adjusted association of 25(OH)D month-specific quintiles with the risk of chronic kidney disease (CKD), and the risk of rapid decline in estimated GFR or CKD, by Cdx2 VDR genotypes rs11568820) Table S1 Candidate polymorphisms pair-wise correlations, R2 Table S2 Association between candidate variants considered separately and mean annual change in eGFR Table S3 Association between candidate variants and vitamin D phenotypes

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School	Laney Graduate School
Department	Epidemiology
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Epidemiology
关键词	Population Genes Kidney function Vitamin D
Committee Chair / Thesis Advisor	McClellan, William, Emory University
Committee Members	Vaccarino, Viola, Emory University Bochud, Murielle, Lausanne University Hospital Kleinbaum, David, Emory University Fred, Paccaud, Lausanne University Hospital

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