Vitamin D and Isoforms of its Binding Protein, Tissue Biomarkers of Inflammation, and Colorectal Cancer Risk and Survival Public

Abstract

Colorectal cancer (CRC) is a leading cause of cancer mortality in the United States.  Vitamin D may influence CRC development and progression in part via reducing inflammation, but the effect of supplemental vitamin D on inflammation in humans and whether certain individuals may particularly benefit from higher vitamin D for CRC prevention and prognosis is unclear. 

In the first study, we tested the effects of supplemental vitamin D (1000 I.U./day) and/or calcium (1,200 mg/day) on two inflammation-related biomarkers of risk for CRC (COX-2 and 15-HPGD) in the rectal mucosa of 62 colorectal adenoma patients in a placebo-controlled chemoprevention trial.  We found that after one year of treatment the pro-inflammatory ratio of COX-2 /15-HPGD expression in full-length crypts statistically significantly decreased 47%more in the vitamin D group than in the placebo group (95% confidence interval [CI]: 36–76%) .

In the second study, we investigated whether the association of circulating vitamin D (25[OH]D) with CRC risk differed by the missense GC-rs4588*A variant (Thr436Lys), encoding the vitamin D-binding protein-2 (DBP2) isoform, among 1,710 incident CRC cases and 1,649 matched controls nested within three prospective cohorts.  Multivariable-adjusted relative risks for CRC associated with 25(OH)D concentrations considered sufficient (≥50 nmol/L), relative to deficient (<30 nmol/L), were 0.47 (95% CI: 0.33–0.67) among individuals with DBP2, and 0.88 (95% CI: 0.61–1.27) among individuals without DBP2 (Pheterogeneity = 0.01).  

In the third study, we investigated whether the association of pre-diagnostic 25(OH)D with mortality among CRC patients differed by the DBP2 isoform among 1,281 CRC cases (635 deaths, 483 from CRC) in two large prospective cohorts.  In the pooled analysis, multivariable-adjusted hazard ratios for CRC-specific mortality associated with deficient relative to sufficient 25(OH)D concentrations were 2.24 (95% CI: 1.44–3.49) among those with DBP2, and 0.94 (95% CI: 0.68–1.22) among those without DBP2 (Pinteraction = 0.0002). 

The results of these studies indicate that vitamin D supplementation reduces CRC-promoting inflammation in the gut and that individuals with the inherited DBP2-encoding GC-rs4588*A missense variant—linked to vitamin D insufficiency—may particularly benefit from higher vitamin D exposure for CRC prevention and prognosis. 

Table of Contents

CHAPTER I:  Introduction and Background …………………………………………………... 6

Introduction ………………………………………………………………….................…………… 7

Background …….……………………………………………………….................………………....8

Colorectal Cancer ……………………………………………….........................………………....8

Vitamin D Metabolism …………………………………………………………..........................15

Vitamin D, Calcium, and Biomarkers of Risk for Colorectal Neoplasms……............… 22

Epidemiologic Studies of Vitamin D and Colorectal Neoplasms ………….............…… 24

Vitamin D-Binding Protein ………………………………………………….......................….. 28 

Interaction Between Vitamin D and Vitamin D-Binding Protein Isoforms in 

Epidemiologic Studies …………………………………………........................…………….…. 38

Summary and Rationale for the Proposed Research ……………………………......……… 42

CHAPTER II:  Research Aims and Approach ……………………………….………………... 43

Specific Aims ……………………………………………………………………..................……... 44

Research Approach..………………………………………………................……………………. 45

Innovation and Significance …………………..………………….............…………………….. 49

CHAPTER III:  Modulation of inflammation by vitamin D and calcium in the

morphologically normal colorectal mucosa of colorectal adenoma patients in a

randomized chemoprevention trial…………………………………………………………..…… 50

Manuscript Information…………………………………………………………...............…….... 51

Abstract……………………………………………………………………….....................…………. 52

Introduction ………………………………………………………...................…………………….. 53

Methods ……………………………………………………….....................………………………… 54

Results…………………………………………………….....................……………………………... 61

Discussion …………………………………………….....................………………………………… 64

Main Tables and Figures…………………………….................…………………………………...70

Supplementary Tables and Figures……………….............……………………………………... 78

CHAPTER IV:  Association of circulating vitamin D with colorectal cancer depends

on vitamin D-binding protein isoforms:  A pooled nested case-control study…….…... 86

Manuscript Information …………………………………………………………................……... 87

Abstract ……………………………………………………………………………......................…… 90

Introduction …………………………………………………………....................………………….. 91

Methods ……………………………………………………………......................…………………… 92

Results ……………………………………………………......................…………………………….. 98

Discussion  …………………………………………….....................………………………………. 100

Main Tables and Figures ………………………….................…………………………………… 105

Supplementary Tables and Figures…………………..............………………………………….110

CHAPTER V:  Association of pre-diagnostic vitamin D status with colorectal

cancer mortality differs by common, inherited vitamin D-binding protein

isoforms ………………………………………………………………………………………….……...115

Manuscript Information …………………………………………..............……………..……….116

Abstract ...…………………………………………………………...................………….………...119

Introduction ………………………………………………………..................………….…………120

Methods ……………………………………………………………...................………….………..121

Results ………………………………………………………………………….....................………125

Discussion ………………………………………………………………...................……….……..128

Main Tables and Figures …………………………………………................……………………132

Supplementary Tables and Figures ………………………............…………………………… 137

CHAPTER VI:  Conclusions, Public Health Implications, and Future Research……. 144

REFERENCES ………………………………………………………………………...........………. 148

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School	Laney Graduate School
Department	Epidemiology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Oncology Health Sciences, Epidemiology
Mot-clé	Single nucleotide polymorphism Inflammation Case-control study Vitamin D-binding protein Genetic variant Colorectal cancer Survival analysis Cohort study Randomized controlled study Vitamin D Biomarkers
Committee Chair / Thesis Advisor	Roberd M. Bostick, Emory University Veronika Fedirko, Emory University
Committee Members	W. Dana Flanders, Emory University Marjorie L. McCullough, Emory University

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