Calcium, Colorectal Cancer, and Other Health Outcomes Open Access

Yang, Baiyu (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/sq87bv016?locale=en
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Abstract

Calcium is an essential nutrient for the human body. There is strong evidence that calcium may be protective against colorectal neoplasms. However, the mechanisms for calcium's chemopreventive properties are not fully understood. In addition, despite compelling evidence for an inverse association of calcium intake with colorectal cancer incidence, there are limited data regarding the impact of calcium on colorectal cancer survival. Furthermore, the association of calcium intake with other major causes of death, such as cardiovascular disease (CVD), needs to be investigated in order to comprehensively evaluate the benefits and harms of calcium intakes and better inform dietary recommendations.

In the first study, we tested the effect of calcium supplementation on plasma biomarkers of inflammation, oxidative stress, and gut permeability over a 4-month treatment period, among colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193); we observed no appreciable effects either overall or within strata of several major risk factors for colorectal carcinogenesis. In the second study, among 2,284 persons diagnosed with invasive, non-metastatic colorectal cancer, we observed lower all-cause mortality among those with higher post-diagnosis total calcium or milk intakes, and marginally lower colorectal cancer-specific mortality among those with higher post-diagnosis total calcium intakes. In the third study, among 132,823 participants in a large cohort initially free from cancer or CVD at baseline, we found that calcium intake in general was not associated with risk of mortality in this cohort, but high intake of supplemental calcium (1,000 mg/d or more) in men may be associated with increased all-cause and CVD-specific mortality.

Overall, this dissertation contributes to a better understanding of the role of calcium in colorectal cancer development and progression, and adds to the limited evidence base regarding whether or not increasing calcium consumption would, on balance, be of public health benefit.

Table of Contents

Table of Contents

CHAPTER 1. INTRODUCTION AND BACKGROUND ......................................................................................................1
Introduction .......................................................................................................................................................1
Background .......................................................................................................................................................3
Epidemiology of Colorectal Cancer ..................................................................................................... ...................3
Colon Carcinogenesis ...........................................................................................................................................4
Molecular Subtypes of Colorectal Cancer .................................................................................................................6
Inflammation, Oxidative Stress, and Colorectal Cancer ..............................................................................................7
Gut Permeability and Colorectal Cancer ..................................................................................................................11
Factors Associated with Colorectal Cancer Incidence .................................................................................................16
Factors Associated with Colorectal Cancer Survival ...................................................................................................22
Calcium and Other Health Outcomes .......................................................................................................................31
Hypotheses ........................................................................................................................................................34
Objectives .........................................................................................................................................................34
Specific Aims .....................................................................................................................................................34
Methods and Power Calculations ............................................................................................................................36
CHAPTER 2. CIRCULATING BIOMARKERS OF GUT BARRIER FUNCTION: CORRELATES AND RESPONSES TO CALCIUM SUPPLEMENTATION

AMONG SPORADIC COLORECTAL ADENOMA PATIENTS IN A DOSE-RESPONSE RANDOMIZED CONTROLLED TRIAL ..................38
Abstract ............................................................................................................................................................39
Introduction .......................................................................................................................................................40
Patients and Methods ...........................................................................................................................................41
Results .............................................................................................................................................................45
Discussion .........................................................................................................................................................47
Tables and Figures ..............................................................................................................................................52
CHAPTER 3. EFFECTS OF CALCIUM SUPPLEMENTATION ON CIRCULATING BIOMARKERS OF INFLAMMATION AND OXIDATIVE STRESS

IN COLORECTAL ADENOMA PATIENTS: A RANDOMIZED CONTROLLED TRIAL ...................................................................60
Abstract ...........................................................................................................................................................61
Introduction ......................................................................................................................................................62
Patients and Methods ..........................................................................................................................................63
Results .............................................................................................................................................................68
Discussion ........................................................................................................................................................69
Tables and Figures .............................................................................................................................................73
CHAPTER 4. CALCIUM, VITAMIN D, DAIRY PRODUCTS, AND MORTALITY AMONG COLORECTAL CANCER SURVIVORS:

THE CANCER PREVENTION STUDY-II NUTRITION COHORT .........................................................................................79
Abstract ...........................................................................................................................................................80
Introduction ......................................................................................................................................................81
Patients and Methods .........................................................................................................................................82
Results ............................................................................................................................................................85
Discussion ........................................................................................................................................................87
Tables and Figures .............................................................................................................................................91
CHAPTER 5. CALCIUM INTAKE AND MORTALITY FROM ALL CAUSES, CANCER, AND CARDIOVASCULAR DISEASE:

THE CANCER PREVENTION STUDY II NUTRITION COHORT .........................................................................................113
Abstract ...........................................................................................................................................................114
Introduction ......................................................................................................................................................114
Methods ...........................................................................................................................................................116
Results ............................................................................................................................................................119
Discussion ........................................................................................................................................................121
Tables and Figures .............................................................................................................................................126
CONCLUSIONS AND PUBLIC HEALTH RELEVANCE .....................................................................................................147
FUTURE DIRECTIONS ..........................................................................................................................................148
REFERENCES .....................................................................................................................................................151

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