Close
About
FAQ
Home
Collections
Login
USC Login
Register
0
Selected
Invert selection
Deselect all
Deselect all
Click here to refresh results
Click here to refresh results
USC
/
Digital Library
/
University of Southern California Dissertations and Theses
/
Association of vitamin D receptor gene polymorphisms with colorectal adenoma
(USC Thesis Other)
Association of vitamin D receptor gene polymorphisms with colorectal adenoma
PDF
Download
Share
Open document
Flip pages
Contact Us
Contact Us
Copy asset link
Request this asset
Transcript (if available)
Content
INFORMATION TO USERS
This manuscript has been reproduced from the microfilm master. UMI films
the text directly from the original or copy submitted. Thus, som e thesis and
dissertation copies are in typewriter face, while others may be from any type of
computer printer.
The quality cf this reproduction is dependent upon the quality of the
copy submitted. Broken or indistinct print, colored or poor quality illustrations
and photographs, print bleedthrough, substandard margins, and improper
alignment can adversely affect reproduction.
In the unlikely event that the author did not send UMI a complete manuscript
and there are missing pages, these w ill be noted. Also, if unauthorized
copyright material had to be removed, a note will indicate the deletion.
Oversize materials (e.g., maps, drawings, charts) are reproduced by
sectioning the original, beginning at the upper left-hand comer and continuing
from left to right in equal sections with small overlaps.
Photographs included in the original manuscript have been reproduced
xerographically in this copy. Higher quality 6” x 9” black and white
photographic prints are available for any photographs or illustrations appearing
in this copy for an additional charge. Contact UMI directly to order.
ProQuest Information and Learning
300 North Zeeb Road, Ann Arbor, M l 48106-1346 USA
800-521-0600
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ASSOCIATION OF VITAMIN D RECEPTOR GENE
POLYMORPHISMS WITH COLORECTAL ADENOMA
by
JUN WANG
A T h esis P resen ted to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CARLIFORNIA
In Partial Fulfillm ent o f the
R equirem ents for the Degree
MASTER OF SCIENCE
(MOLECULAR EPIDEMIOLOGY)
A u gu st 2000
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
UMI N um ber: 1405256
___ ®
UMI
UMI Microform 1405256
Copyright 2001 by Bell & Howell Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
Bell & Howell information and Learning Company
300 North Zeeb Road
P.O. Box 1346
Ann Arbor, Ml 48106-1346
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
U N IV E R SIT Y O F S O U T H E R N C A L IF O R N IA
T H E G R A D U A T E S C H O O L
U N IV E R S IT Y P A R K
L O S A N G E L E S . C A L I F O R N IA S O O O T
This thesis, written by
____________________________
under the direction of A -g.tT. Thesis Committee,
and approved by all its members, has been pre
sented to and accepted by the Dean of The
Graduate School, in partial fulfillm ent of the
requirements fo r the degree of
Master °-t
Dtmm
71/ztr A u g u st 7 , 2000
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ACKNOWLEDEMENTS
This work was done under the direction o f Dr. Sue Ingles. I am grateful to Dr. Sue Ingles
for providing me with inspiration and the professional guidance that enable me to gain
valuable experience in the field o f molecular epidemiology. I appreciate her kind help in
the writing o f this dissertation.
I wish to thank my committee members, Dr. Robert Haile and Dr. Gerhard Coetzee for
their generous review of this dissertation.
Thanks to my friends and lab-mates, Wendy, Katherine, Hui-lee, Rowena, Katie and
Betsy for their help in my work.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
CONTENTS
ACKNOWLEDGEMENTS...........................................................................ii
LIST OF TA BLES....................................................................................... iv
A BSTRACT................................................................................................. v
INTRODUCTION ................ ...................................................................... 1
MATERIALS AND M ETHODS............................................................... 4
RESU LTS......................................................................................................7
DISCUSSION...............................................................................................15
REFERENCES ........................................................................................... 21
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
LIST OF TABLES
Table 1 Characteristics of study population................................................................. 4
Table 2 Genotype frequency o f controls in each ethnic group
and with all ethnic groups combined................................................................. 8
Table 3 VDR FokI genotype and ORs for risk of colorectal
adenoma by size and location of adenoma....................................................... 9
Table 4 VDR FokI genotype and ORs for risk o f large colorectal
adenoma (> 1 cm in diameter) associated with skin color,
intake o f vitamin d and calcium ........................................................................11
Table 5 VDR BsmI genotype and ORs for risk o f colorectal
adenoma by size and location of adenoma (all ethnic
groups combined).................................................................................................13
Table 6 VDR BsmI genotype and ORs for risk o f colorectal
adenoma by size and location of adenoma (excluding
African-American)............................................................................................... 14
iv
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
ABSTRACT
The vitamin D receptor (VDR) has been demonstrated to play a role in the
development o f a variety o f cancers. Polymorphisms in the VDR gene have been
associated with bone mineral density and with risk o f prostate cancer and breast cancer.
To investigate whether VDR gene polymorphisms are related to the risk of colorectal
adenoma, we genotyped VDR 5’ FokI and 3’BsmI polymorphisms for 373 colorectal
adenoma cases and 394 controls from a multiethnic population. Overall, no significant
association between FokI polymorphism and adenoma risk was found. However, after
stratification by adenoma size, a significant trend o f decreasing risk of large polyps (> 1
cm) was observed wdth increasing copies of the f allele (p=0.04). Compared to the FF
genotype, adjusted ORs for the F f and ff genotypes were 0.79 (95% Cl: 0.44-1.41) and
0.32 (95% Cl: 0.11-0.91), respectively. Further analysis suggested an interaction between
the VDR FokI genotypes and calcium and vitamin D status, with genotype being more
strongly related to large polyps risk among people with low dietary calcium intake (OR
forFfw as 0.48, 95% Cl: 0.17-1.34. OR for ffwas 0.21, 95% Cl: 0.04-1.28), low dietary
vitamin D intake (OR for F f was 0.25, 95% Cl: 0.09-0.69; OR for ff was 0.22, 95% Cl:
0.04-1.24), or dark skin color (OR for F f was 0.66, 95% Cl: 0.27-1.59; OR for ff was
0.10,95% Cl: 0.01-1.00). No association between the BsmI polymorphism and colorectal
adenoma risk was observed in this study. Our results indicate that the VDR FokI
polymorphism may influence colorectal adenoma risk, and that the effect is modified by
calcium and vitamin D status. Further investigation on the relationship between VDR
variants and colorectal cancer is warranted.
v
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
INTRODUCTION
Colorectal cancer is a major public health problem in western industrialized
countries. The etiology o f colorectal cancer is unknown, but it has been widely accepted
that colorectal carcinogenesis is the result o f a multistep process. Most o f colorectal
adenocarcinomas, whether familial or sporadic, are believed to arise from adenomas
through what is known as the adenoma-to-adenocarcinoma sequence. The importance of
dietary factors in colon cancer development has been suggested by numerous
epidemiological studies (reviewed by Potter et al., 1993), but the research to identify
biochemical or genetic markers that correlate w ith colorectal cancer is still lacking.
Epidemiologic studies that link environmental data with the molecular biology of
colorectal cancer will be helpful for better understanding o f the etiology o f the disease.
The active hormonal form of vitamin D, 1,25-dihydroxyvitamin D3 [1,25-
(OH)2D3 ], has a central role in calcium and phosphate homeostasis and the maintenance
o f bone. Apart from controlling calcium balance, l,25-(OH)2D3 regulates cell growth and
differentiation in many target tissues. Its potent anti-mitogenic and prodifferentiating
properties have been demonstrated in normal as well as tumor cells (reviewed by
Studzinski et al., 1993). Epidemiological studies have indicated an inverse relationship
between colorectal cancer risk and dietary vitamin D and calcium (reviewed by Martinez
et al., 1998). Serum 25-hydroxyvitamin D level was also reported to be inversely related
to the risk o f rectal cancer in a dose-related manner (Garland et al., 1989).
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Most o f the currently known effects of vitamin D are mediated through a genomic
pathway via the vitamin D receptor (VDR), a member o f the steroid hormone receptor
superfamily (Studzinski et al., 1993). VDR binds to specific target sequences of DNA
and functions as a ligand-inducible transcription factor to regulate target gene expression.
VDR is expressed in many normal tissues and solid epithelial tumors, including breast,
colon, and prostate (Lointier et al., 1991; Buras et al., 1994; Peehl et al., 1994). In vitro
studies with several colorectal carcinoma cell lines demonstrated that VDR level is
related to the degree o f cell differentiation, with well-differentiated cell lines having high
VDR expression (Shabahang et al., 1993). Cross et al (1996) found that in colon
carcinoma cells, VDR expression was up-regulated except for advanced stage of tumor.
There is also clinical evidence that a high level o f VDR expression is associated with a
favorable prognosis o f colorectal cancer (Evans et al., 1998).
Polymorphisms in the VDR gene may potentially influence the expression or
function o f VDR, or may serve as a marker of VDR function. A great deal o f research has
addressed the VDR 3’ UTR and 5’ start codon polymorphisms as predictive markers of
bone mineral density (BMD) and osteoporosis (Cooper et al., 1996). VDR gene
polymorphisms were also reported to be associated with several different cancer types,
such as breast cancer and prostate cancer (Curran et al., 1999; Taylor et al., 1996; Ingles
et a., 1997a, 2000). No association between VDR gene polymorphisms and colorectal
cancer has yet been reported.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Given the experimental and epidemiological evidence for a role o f vitamin D in
colorectal cancer, we set out to examine whether VDR genotype, as determined by 5’ and
3’ polymorphisms, is associated with risk o f colorectal adenoma, a precursor lesion for
colorectal carcinoma, in a multiethnic population.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
MATERIAL A N D METHODS
Study population
Subjects were from either o f two southern California Kaiser Permanente Medical
Centers (Bellflower or Sunset) and had a sigmoidoscopy during the period from January
1,1991, through August 25,1993. Eligible mem and women were 50-74 years old, fluent
in English, and residents o f Los Angeles country. Each had no history o f invasive cancer,
inflammatory bowel disease, familial polyposis, previous bowel surgery, severe
gastrointestinal symptoms, or physical or m ental disability that would preclude an
interview. Cases had a first time diagnosis o f one or more colorectal adenomas,
confirmed by histology. Controls were selected from subjects who had no current or past
polyp and were matched to cases by gender, ag;e, date of sigmoidoscopy, and Kaiser
center. More detailed information of this study population has been described previously
(Lin et al., 1995). VDR FokI and BsmI genotyping was performed on 373 cases and 394
controls blood samples. General characteristics of these cases and controls are presented
in Table 1.
Table 1. C haracteristics of study p o p u lstio n
Case Control
Number
373 394
Age (mean)
62.3 62.2
Gender
Female
119 (3 2 Vo) 132 (34%)
Male
254 (68%) 262 (66%)
Ethnicity
Non-Hispanic White
218(58% ) 225 (57%)
African-American
55 (15%) 60(15%)
Hispanic
58 (16%) 72 (18%)
Asian-American
42(11% ) 37 (9%)
4
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Genotyping
Genomic DNA was obtained from frozen buffy coat specimens. FokI and BsmI
polymorphisms were detected by polymerase chain reaction (PCR) assay. Primers for the
FokI start codon polymorphism were used as previously reported (Gross et al., 1996),
with 5’-AGCTGGCCCTGGCACTGACTCTGCTCT-3’ and 5’-ATGGAAACACCTTGC
TTCTTCTCCCTC-3’. PCR was carried out in a 20 pi system, containing 15 ng genomic
DNA, 0.25 pM o f each primer, 200 pM deoxynucleosides triphosphate (dNTP), 1.5 mM
M gCt, and 0.6 U o f the Taq polymerase (Promega). The PCR conditions were 94°C, 3
minutes, then 94°C 20 seconds, 62°C, 30 seconds, 72°C, 45 seconds, for 30 cycles. A
final elongation period o f 5 minutes at 72°C was added after the last cycle. PCR products
were digested w ith FokI (New England Biolabs) for 2 hours at 37°C, and then separated
electrophoretically on 2% agarose gels. FokI genotypes were defined as FF, Ff, or ff, with
capital letters denoting the absence, and small letters the presence, o f the restriction site.
VDR 3 ’ UTR containing BsmI polymorphism was amplified with primers 5’-
CAACCACGCCTACAAGTCCCGCGTCAG-3 ’ and 5 AACCAGCGGGAAGAGGTC
AAGGG-3’, as previously described (Morrison et al., 1994). PCR was carried out in a 20
pi system, containing 15 ng genomic DNA, 0.25 pM of each primer, 200 pM
deoxynucleosides triphosphate (dNTP), 1.5 mM MgCl2, and 0.6 U o f the Taq
polymerase. The PCR conditions were 94°C, 3 minutes, then 94°C 20 seconds, 62°C, 30
seconds, 72°C, 1.5 minutes, for 30 cycles. A final elongation period o f 5 minutes at 72°C
was added after the last cycle. PCR products were digested with BsmI (New England
Biolabs) for 2 hours at 65 °C, and then separated electrophoretically on 1.5% agarose gels.
5
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
BsmI genotypes were defined as BB, Bb, or bb, with capital letters denoting the absence,
and small letters the presence, o f the restriction site.
Statistical analysis
Genotype distributions were examined separately in different ethnic groups. A
standard Chi-square test was used to compare observed genotype frequencies with those
expected under Hardy-Weinberg equilibrium. Unconditional logistic regression models
were used to estimate odds ratios adjusted for matching factors (age, gender, ethnicity,
date of sigmiodoscopy, Kaiser center attended), and odds ratios further adjusted for
potential confounders, including BMI (< 26 vs. > 26), total calorie intake (< 1850 vs. >
1850 kcal/day), total fat intake (< 50 vs. > 50 g/day), total fiber intake (< 18 vs. > 18
g/day), serum triglyceride level (quartiles), calcium intake (quartiles), vitamin D intake
(quintiles), non-steroidal anti-inflammatory drug usage (yes/no), physical activity (< 3 vs.
>3 hours/week) and smoking (current vs. non-smoker). Subjects were stratified on
adenoma size (> 1 vs. < 1 cm in diameter) and site (rectal vs. left-sided colon), and
heterogeneity tests were performed by testing the equality of the trend across strata. To
determine whether the effect o f genotype is modified by factors affecting vitamin D
status, the population was further stratified into high/low dietary calcium groups,
high/low dietary vitamin D groups based on median values. According to a scale for skin
color, which used 1 - 7 to represent milk-white skin to dark-black skin, subjects were
also stratified into light (< 3)/dark (> 3) skin color groups. Relative risks of colorectal
polyps were analyzed in each stratum. The Mantel extension test was used to evaluate
linear trends across categories o f genotypes.
6
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
RESULTS
VDR gene start codon polymorphisms and colorectal polyps
The prevalence of VDR start codon polymorphism (FokI) in this study population
is shown in Table2. Allele frequencies among controls for each ethnic group are: 59% F /
41% f for Caucasian, 74% F / 26% f for African-American, 56% F / 44% f for Hispanic-
American, and 54% F / 46% f for Asian-American. The frequency of the F allele is
significantly higher in African-Americans than other ethnic groups. All these genotype
distributions are similar to previous reports (Lucotte et al., 1999; Ame et al., 1999,
Gennari et al., 1999; Zmuda et al., 1999) and are in Hardy-Weinberg equilibrium.
Because the FokI polymorphism provides a structural change that could alter the
function o f the VDR protein, we analyzed the relationship o f the FokI polymorphism and
risk o f colorectal adenoma with all ethnic groups combined. Results are shown in Table
3. After adjustment for matching variables (age, sex, ethnicity, Kaiser location and exam
date) and potential confounders (BMI, total calorie intake, total fat intake, total fiber
intake, calcium and vitamin D intake, serum triglyceride level, non-steroidal anti
inflammatory drug usage, physical activity and smoking), no statistically significant
relationship was found between the FokI polymorphism and overall colorectal polyps
risk. We then analyzed the FokI polymorphisms by adenoma size (< 1 vs. >1 cm in
diameter) and site (rectal vs. left-sided colon). A statistically significant decrease in risk
of large polyps was found with increasing number o f f alleles (p=0.04 (Table 3).
Compared to FF genotype, ORs for F f and ff genotype are 0.79 (95% Cl: 0.44-1.41) and
0.32 (95% Cl: 0.11-0.91), respectively. Such a trend was not found in the small polyps
7
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 2. Genotype frequency of controls in each ethnic group and with all ethnic groups
combined
Ethnic groups FokI BsmI genotypes
genotypes BB Bb bb Total
Total FF 27 64 54 145 (36.8%)
Ff 27 74 82 183 (46.5%)
ff 12 19 35 66 (16.8%)
Total 66(16.8%) 157 (39.9%) 171 (43.4%) 394
Caucasian FF 16 38 22 76 (33.8%)
Ff 21 45 4 6 1 1 2 (4 9 .8 % )
ff 10 13 14 37 (16.4%)
Total 47 (20.9%) 96 (42.7%) 82 (36.4%) 225
African- FF 6 12 14 32 (53.3%)
American Ff 2 13 9 24 (40.4%)
ff 1 1 2 4 (6.67%)
Total 9(15.0%) 26 (43.3%) 25 (41.7%) 60
Hispanic- FF 5 12 8 25 (34.7%)
American Ff 2 14 15 31 (43.1%)
ff 0 4 12 16 (22.2%)
Total 7 (9.7%) 30(41.7%) 35 (48.6%) 72
Asian- FF 0 2 10 12(32.4%)
American Ff 2 2 12 16(43.2%)
ff 1 1 7 9 (24.3%)
Total 3(8.1%) 5(13.5%) 29 (78.4%) 37
00
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 3. VDR FokI genotype and ORs for risk of colorectal adenoma by size and location of
adenoma
Case (% ) Control
(%)
Adjusted OR*
(95% Cl)
Further Adjusted
OR** (95% Cl)
Trend
Test
Heterogeneity
Test on Trend
Total FF 142 (38) 145 (37) 1.0 1.0
Ff 173 (46) 183 (46) 0.96 (0.70-1.32) 1.00 (0.72-1.39)
ff 58(16) 66 (17) 0.89 (0.58-1.37) 0.94 (0.60-1.47) p=0.81
Large FF 33 (47) 145 (37) 1.0 1.0
adenom a F f 32 (46) 183 (46) 0.76 (0.44-1.31) 0.79 (0.44-1.41)
(> 1 cm) ff 5(7) 66(17) 0.35 (0.13-0.94) 0.32 (0.11-0.91) p=0.04
Large vs.
Small FF 109 (36) 145 (37) 1.0 1.0 small adenoma
adenom a F f 141 (47) 183(46) 1.03 (0.73-1.44) 1.08 (0.76-1.54) p= 0,02
(< 1 cm) ff 53(17) 66(17) 1.06(0.68-1.66) 1.13 (0.71-1.81) p=0.58
Rectal FF 44 (38) 145 (37) 1.0 1.0
adenom a Ff 46 (40) 183(46) 0.79 (0.49-1.28) 0.85 (0.51-1.41)
ff 25 (22) 66(17) 1.18(0.65-2.13) 1.35 (0.72-2.53) p=0.50
Rectal vs. left
Left colon FF 98 (38) 145 (37) 1.0 1.0 colon adenoma
adenom a Ff 127 (49) 183(46) 1.03 (0.72-1.45) 1.07 (0.74-1.54) p=0.22
ff 33(13) 66(17) 0.76 (0.46-1.26) 0.75 (0.44-1.27) p=0.45
* Adjusted for matching factors (age, gender, ethnicity, date o f sigm iodoscopy, Kaiser center attended).
** Further adjusted for potential confounders, including BM I (< 26 vs. > 26), total calorie intake (< 1850 vs. > 1850 kcal/day), total fat
intake (< 50 vs. > 50 g/day), total fiber intake (< 18 vs. > 18 g/day), serum triglyceride level (quartiles), calcium intake (quartiles),
vitam in D intake (quintiles), non-steroidal anti-inflammatory drug usage (yes/n o), physical activity (< 3 vs. >3 hours /w eek) and
sm oking (current vs. non-smoker).
VO
group. The association between the FokI genotype and risk o f polyps are significantly
different between large and small polyps groups (Heterogeneity test on trend: p=0.02).
After stratification by adenoma site, no significant association was found between FokI
genotype and adenoma risk in either rectum or left-sided colon (Table 3).
We further analyzed the association between VDR FokI genotype and risk for large
polyps according to dietary calcium intake, dietary vitamin D intake and skin color.
Among subjects with lower dietary calcium (< 750mg/day), there is a statistically
significant trend for lower risk o f large polyps with the increasing numbers o f f alleles
(p=0.05) (Table 4). The ORs for F f and ff, compared to FF genotype, are 0.48 (95% Cl:
0.17-1.34) and 0.21 (95% Cl: 0.04-1.28), respectively. A similar trend was also found in
the higher dietary calcium group, but not to a significant level (p=0.22). When stratifying
by dietary vitamin D intake, a trend o f decreasing risk with increasing numbers of f
alleles was found in the lower dietary vitamin D group (< 270 mg/day) (p=0.01). The
ORs for F f and ff, compared to FF, are 0.25 (95% Cl: 0.09-0.69) and 0.22 (95% Cl: 0.04-
1.24), respectively. No significant association was found between the FokI polymorphism
and large polyps risk in the high dietary vitamin D group. Since skin color is highly
associated with vitamin D status, the FokI polymorphism was also analyzed according to
skin color. We found that among those with darker skin color (> 3), there was a
statistically significant trend of decreasing risk of large polyps with increasing numbers
of f alleles (p=0.04). Compared to FF genotype, the ORs for F f and ff genotype are 0.66
(95% Cl: 0.27-1.59) and 0.10 (95% Cl: 0.01-1.00), respectively. No significant trend was
found in fighter skin color group (p=0.60).
10
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 4. VDR FokI genotype and ORs for risk of large colorectal adenoma (> 1 cm in diameter)
associated with skin color, intake o f vitam in D and calcium
Case (% ) Control (%) Adjusted OR*
(95% Cl)
Further Adjusted
OR** (95% Cl)
Trend Test
Dietary <750mg/d FF 17(53) 70 (36) 1.0 1.0
calcium Ff 13(41) 89(46) 0.54 (0.23-1.28) 0.48 (0.17-1.34)
ff 2(6) 34(18) 0.23 (0.05-1.14) 0.21 (0.04-1.28) p=0.05
> 750mg/d FF 16(42) 75 (37) 1.0 1.0
F f 19(50) 94 (47) 0.84 (0.38-1.85) 0.95 (0.39-2.29)
ff 3(8) 32(16) 0.47 (0.12-1.82) 0.34 (0.08-1.47) p=0.22
Dietary < 270mg/d FF 18(58) 74 (35) 1.0 1.0
vitamin D Ff 11(35) 99 (47) 0.44 (0.19-1.04) 0.25 (0.09-0.69)
ff 2(6) 36(17) 0.22 (0.05-1.05) 0.22 (0.04-1.24) p=0.01
> 270mg/d FF 15(38) 71 (38) 1.0 1.0
Ff 21 (54) 84 (45) 1.18 (0.54-2.56) 1.54 (0.66-3.60)
ff 3(8) 30(16) 0.57(0.14-2.25) 0.44 (0.10-1.94) p=0.69
S k in < 3 FF 14 (42) 73 (38) 1.0 1.0
color Ff 15(45) 89 (46) 0.85 (0.38-1.92) 0.98 (0.39-2.47)
ff 4(12) 32(16) 0.60 (0.18-2.07) 0.66 (0.18-2.49) p=0.60
>3 FF 19(51) 72 (36) 1.0 1.0
Ff 17(46) 94 (47) 0.65 (0.29-1.42) 0.66 (0.27-1.59)
ff
1 0 ,
34(17) 0.14(0.02-1.11) 0.10(0.01-1.00) p=0.04
* Adjusted for m atching factors (age, gender, ethnicity, date o f sigm iodoscopy, Kaiser center attended).
** Further adjusted for potential confounders, including BM1 (< 26 vs. > 26), total calorie intake (< 1850 vs. > 1850 kcal/day), total fat
intake (< 50 vs. > 50 g/day), total fiber intake (< 18 vs. > 18 g/day), scrum triglyceride level (quartiles), calcium intake (quartiles),
vitamin D intake (quintiles), non-steroidal anti-inflammatory drug usage (yes/no), physical activity (< 3 vs. >3 hours /w eek) and
sm oking (current vs. non-smoker).
VDR gene 3’ UTR polymorphisms and colorectal polyps
The distribution o f the 3’UTR BsmI polymorphism of the VDR in this study
population is shown in Table 2. Allele frequencies in different ethnic groups are 42% B /
58% b for Caucasian, 37% B / 63% b for African-American, 31% B / 69% b for
Hispanic-American, and 15% B / 85% b for Asian-American. Asian-Americans have
extraordinarily low frequency of the B allele as previously reported (Niimi et al., 1999).
BsmI genotype distribution o f Hispanic- and Asian-Americans deviated slightly from
Hardy-Weinberg equilibrium, probably due to the small sample size. We checked the
linkage between FokI and BsmI loci in the Caucasian group and found no linkage
disequilibrium between these two polymorphisms. The same analysis could not be
conducted in other ethnic groups due to small sample size.
When analyzing all 373 cases and 394 controls together, we observed no
association between the BsmI polymorphism and risk of polyps. After stratification by
polyp size and site, a nonsignificant trend toward increasing risk of polyps with
increasing number o f B alleles was observed in the large polyps group (p=0.27) (Table
5). There is no significant difference of the trend between large and small polyps groups
(Heterogeneity test on trend: p=0.38). Since the BsmI polymorphism is not in linkage
disequilibrium with other VDR 3’UTR polymorphisms in African-American (Ingles et
al., 1998), we further did the analysis in this multiethnic population with African-
Americans excluded. After excluding African-Americans from the data set, the
association between the B allele and large polyps risk was even weaker (p=0.64) (Table
6).
12
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 5. VDR BsmI genotype and ORs for risk of colorectal adenoma by size and location of
adenoma (all ethnic groups combined)
Case (%) Control
(%)
Adjusted OR*
(95% Cl)
Further Adjusted
OR** (95% Cl)
Trend
Test
Heterogeneity
Test on Trend
Total bb 155 (42) 171 (43) 1.0 1.0
Bb 156(42) 157(40) 1.12(0.81-1.55) 1.11 (0.79-1.56)
BB 62(17) 66(17) 1.06 (0.69-1.62) 1.14(0.73-1.77) p=0.51
Large bb 28 (40) 171(43) 1.0 1.0
adenoma Bb 27 (39) 157(40) 1.04 (0.57-1.88) 1.11 (0.58-2.12)
(> 1 cm) BB 15(21) 66(17) 1.35 (0.66-2.78) 1.60 (0.74-3.47) p=0.27
Large vs.
Small bb 127(42) 171 (43) 1.0 1.0 small adenoma
adenoma Bb 129(43) 157(40) 1.15 (0.82-1.63) 1.16(0.80-1.66) p= 0.38
(< 1 cm) BB 47 (16) 66(17) 1.00 (0.64-1.58) 1.07 (0.67-1.71) p=0.65
Rectal bb 46 (40) 171 (43) 1.0 1.0
adenoma Bb 49 (43) 157(40) 1.23 (0.76-2.01) 1.16(0.69-1.94)
BB 20(17) 66(17) 1.20(0.64-2.24) 1.34 (0.69-2.58) p=0.37
Rectal vs. left
Left colon bb 109 (42) 171 (43) 1.0 1.0 colon adenoma
adenoma Bb 107(41) 157(40) 1.08 (0.75-1.55) 1.09 (0.75-1.60) p=0.80
BB 42 (16) 66(17) 1.03 (0.65-1.66) 1.06 (0.65-1.74) p=0.73
* Adjusted for matching factors (age, gender, ethnicity, date o f sigm iodoscopy, Kaiser center attended),
** Further adjusted for potential confounders, including BM I (< 2 6 vs. > 2 6 ), total calorie intake (< 1850 vs, > 1850 kcal/day), total fat
intake (< 50 vs. > 50 g/day), total fiber intake (< 18 vs. > 1 8 g/day), serum triglyceride level (quartiles), calcium intake (quartiles),
vitamin D intake (quintiles), non-steroidal anti-inflammatory dnig usage (yes/no), physical activity (< 3 vs. >3 hours /w eek) and
sm oking (current vs. non-smoker).
u >
Reproduced w ith permission o f th e copyright owner. Further reproduction prohibited without permission.
Table 6. VDR BsmI genotype and ORs for risk of colorectal adenoma by size and location of
adenoma (excluding African-American)
Case (%) Control (%) Adjusted OR*
(95% Cl)
Further Adjusted
OR** (95% Cl)
Trend
Test
Heterogeneity
Test on Trend
Total bb 137(43) 146 (44) 1.0 1.0
Bb 126(40) 131 (39) 1.04 (0.73-1.48) 1.04 (0.71-1.51)
BB 55 (17) 57(17) 1.05 (0,66-1.65) 1.14(0.71-1.84) p=0.60
Large bb 24(43) 146(44) 1.0 1.0
adenoma Bb 20 (36) 131(39) 0.91 (0.47-1.77) 0.87 (0.42-1.78)
(> 1 cm) BB 12(21) 57(17) 1.22 (0.55-2.71) 1.35 (0.57-3.21) p=0.64
Large vs.
Small bb 113(43) 146 (44) 1.0 1.0 small adenoma
adenoma Bb 106(40) 131 (39) 1.08 (0.74-1.58) 1.09 (0.73-1.62) p= 0.57
(< 1 cm) BB 43 (16) 57(17) 1.02 (0.63-1.66) 1.10(0.66-1.82) p=0.70
Rectal bb 42 (41) 146(44) 1.0 1.0
adenoma Bb 41 (40) 131 (39) 1.15 (0.68-1.94) 1.08 (0.62-1.88)
BB 19(19) 57(17) 1.27 (0.66-2.45) 1.48 (0.73-2.96) p=0.31
Rectal vs. left
Left colon bb 95 (44) 146 (44) 1.0 1.0 colon adenoma
adenoma Bb 85 (39) 131 (39) 1.00 (0.67-1.49) 1.01 (0.66-1.54) p=0.67
BB 36(17) 57(17) 1.00 (0.60-1.66) 1.03 (0.60-1.76) p=0.92
* Adjusted for m atching factors (age, gender, ethnicity, date o f sigm iodoscopy, Kaiser center attended).
** Further adjusted for potential confounders, including BM I (< 26 vs. > 26), total calorie intake (< 1850 vs, > 1850 kcal/day), total fat
intake (< 50 vs. > 50 g/day), total fiber intake (<18 vs. >18 g/day), serum triglyceride level (quartiles), calcium intake (quartiles),
vitamin D intake (quintiles), non-steroidal anti-inflammatory drug usage (yes/no), physical activity (< 3 vs, >3 hours /w eek) and
sm oking (current vs, non-smoker),
DISCUSSION
In this study, we identified a significant association between the FokI
polymorphism o f the VDR and colorectal polyps. These are the first data demonstrating a
relationship between VDR genotype and risk o f colorectal polyps.
The FokI polymorphism, a C to T transition at the VDR translation initiation site,
creates an upstream initiation codon, resulting in VDR molecules elongated by three
amino acids (f allele) compared with those initiating translation from the downstream site
(F allele) (Gross et al., 1996). The initiation codon polymorphism is currently the only
common VDR variant that results in an alteration in the amino acid sequence and could
potentially alter the function of VDR protein. A previous study by Arai et al. (1997)
suggested that the longer form of VDR (f) showed weaker transactivation activity than
the shorter form (F), while other studies failed to detect functional difference between
these two VDR forms (Sturzenbecker et al., 1994; Gross et al., 1998).
In contrast to the controversial results from in vitro functional studies,
epidemiologic studies showed relatively consistent evidence suggesting that the f allele is
associated with decreased bone mineral density (Harris et al., 1997; Gross et al., 1996;
Ames et al., 1999). Studies relating the VDR Fold polymorphism to occurrence of cancer
are quite new. Two studies reported that the FokI polymorphism was not related to risk o f
breast cancer (Curran et al., 1999; Ingles et al., 2000). In our present study, however, an
effect o f the FokI polymorphism on the risk o f colorectal adenoma was observed.
15
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Stratification by size o f adenomas suggested an association between the FokI
polymorphism F allele and increased risk o f large adenoma.
It has been estimated that fewer than 10% o f adenomas progress to
adenocarcinoma (Williams et al., 1990). The malignant potential o f colonic adenomas
depends on size, histologic type, and degree o f epithelial atypsia (Kim et al., 1997). With
adenoma size being one o f the most significant risk factors for progression, it is reported
that the relative risk of carcinoma was only 1 . 2 in subjects with polyps less than 1 cm but
rose to 2.7 to 3.6 in subjects whose adenomas were greater than 1 cm (Atkin et al., 1992).
Our finding that, the VDR FokI polymorphism is associated with the large polyps but not
small polyps, suggests an effect o f VDR in large polyps development and colorectal
carcinogenesis.
When we further analyzed the association between VDR FokI polymorphism and
occurrence o f large polyps, a possible interaction between FokI genotype with calcium
and vitamin D metabolism was observed. The association between FokI polymorphism
and large polyps risk was much stronger in subjects with low calcium intake, low vitamin
D intake or dark skin color than in subjects with high calcium intake, high vitamin D
intake and light skin color. Vitamin D, calcium and sunlight have been reported to be
protective factors for colorectal cancer in many studies (Garland et al., 1985; Emerson et
al., 1992). A biological mechanism for the protective effect of calcium is thought to
involve the formation o f insoluble calcium soaps in the colorectal lumen from ionized
fatty and secondary bile acids, such that the harmful effects o f fatty acids and secondary
bile acids on the colorectal epithelium is reduced (Wargovich et al., 1994). A more direct
16
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
effect of calcium-induced terminal differentiation has also been proposed (Buset et al.,
1986). Since it was suggested that calcium absorption is less dependent upon vitamin D
at high dietary calcium intake (Gallagher et al., 1979), our finding of an association
between VDR FokI genotypes and large polyps risk mainly in subjects with low dietary
calcium suggests that the functional difference between the VDR variants is apparent
when calcium is deficient, but may have been masked by high dietary calcium intake.
Besides the role in maintaining calcium homeostasis, vitamin D has also been
shown to have anti-proliferative and pro-differentiating effects in a variety o f human
cancer cells. 25-(OH)aD3 has been found to be a potent inhibitor of malignant growth of
human colon adenocarcinoma-derived cell lines (Giuliano et al., 1991; Cross et al., 1992;
Bischof et al., 1995). The incidence o f colon cancer is associated with low intake of
vitamin D and consequently, low serum concentrations o f 25-hydroxyvitamin D (Garland
et al., 1985; Garland et al., 1989). We found that in subjects with low dietary vitamin D,
the FokI genotypes were associated with risk of large colorectal adenomas. This
interaction between VDR genotype and vitamin D intake reflects the importance o f both
environmental factors and genetic components in the regulatory function o f the vitamin D
pathway. Evidence from in vitro functional studies on these two variants is inconclusive,
probably due to the subtlety o f the difference (Sturzenbecker et al., 1994; Arai et al.,
1996; Gross et al., 1998). However, since even small differences in VDR expression,
which amplify the vitamin D signal through a network o f genes, could mediate significant
variation in the products o f target genes, our results suggest that vitamin D status might
17
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
accentuate small differences in VDR function and thus lead to measurable differences in
colorectal adenoma risk across FokI genotype.
Sunlight-mediated vitamin D synthesis is well known as an important
endogenous source o f circulating vitamin D. Melanin in the skin, which albsorbs UV
photons in competition with 7-dehydrocholesterol, is an important factor determining the
amount of vitamin D 3 that will be converted from 7-dehydrocholesterol b y an exposure of
skin to sunlight (Hoiick et al., 1980). Several publications have reported lower circulating
concentrations of 25-hydroxyvitamin D3 in dark-skinned people (Clemems et al., 1982;
Matsuoka et al., 1991; Harris et al., 1998). Our finding that the VDR FokI polymorphism
is associated with large polyps risk in dark-skinned people is consistent w ith our finding
upon stratification by dietary vitamin D level, and further suggests a functional difference
between VDR variants, as a genetic component, in large polyps development and
colorectal carcinogenesis.
In contrast to the association we found between FokI polymorphism and
colorectal adenoma risk, we failed to find a significant relationship between the 3’UTR
BsmI polymorphism and risk of colorectal adenoma. When all ethnic groups were
combined, we observed a nonsignificant trend of increasing large polyps risk with
increasing number of B alleles. It has been demonstrated that in all ethnic populations
except African-Americans, the 3’-region polymorphisms, defined by Bsm i, Apal, TaqI
and a poly-A microsatellite, are in linkage disequilibrium, where BAtS an.-d baTL (b, a, t
are cut by Bsmi, Apal and TaqI, respectively, while B, A, T are not cut; S is poly-A
18
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
microsatellite shorter than 18, while L is longer than 18) are the two most common alleles
(Ingles et al., 1997b). Therefore, the Bsmi polymorphism can be used to represent the
3’UTR polymorphisms in all populations except African-American. In this study, after
excluding African-American samples from the analysis, the apparent trend of increasing
large polyps risk w ith increasing number o f B alleles almost disappeared.
3’UTR polymorphisms of the VDR gene have been the most extensively studied
genetic markers in relation to bone mineral density (Cooper et al., 1996). More recently,
they have also been studied with respect to different types o f cancer. Taylor et al (1996)
reported a 3-fold increased risk of prostate cancer associated with the TaqI TT genotype.
Ingles et al (1997a) demonstrated a 4-5 fold increase in prostate cancer risk for LL
genotype. The bb genotype was found associated with a 2-fold increase in prostate cancer
risk among men w ith low plasma 25-hydroxyvitamin D in the Physician’s Health Study
(Ma et al., 1998). W hile findings in prostate cancer were relatively consistent, the
evidence for breast cancer is controversial. Curran et al (1999) found a significant
association betw een Apal a allele and increased risk of breast cancer. Ingles et al (2000)
reported the increasing risk with increasing number of B alleles or short poly-A alleles.
However, we found no significant relationship between the Bsmi polymorphism and
colorectal adenoma. One possible explanation for genetic effects o f the 3 ’UTR
polymorphisms has been suggested to be a direct effect on VDR gene expression at the
transcriptional or translational level. Another possibility is that the polymorphisms are in
linkage disequilibrium with another unknown gene. Our finding that the translation
initiation site polymorphism but not 3’ UTR polymorphism is related to colorectal
1 9
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
adenoma risk may reflect a functional role for the VDR, rather than linkage
disequilibrium with other genes. Since VDR gene expression exhibits a tissue- and/or
developmental-specific pattern (Crofts et al., 1998), more specific functional studies are
needed to explain the inconsistent outcomes of epidemiological studies.
In conclusion, the FokI polymorphism at the VDR start-codon region, but not
Bsmi at the 3’-end was found significantly associated with risk o f large colorectal polyps
in this multiethnic population. The association between VDR variants and colorectal
adenoma risk appears to be modified by calcium and vitamin D status. These findings
reinforce the potential role that VDR may play in the development o f colorectal cancer
and motivate further study of the VDR polymorphisms and their relation to colorectal
cancer.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
REFERENCES
Ames, S.K. Ellis, K.J. Gunn, S JC. Copeland, K.C. and S.A. Abrams. 1999. Vitamin D
receptor gene FokI polymorphism predicts calcium absorption and bone mineral
density in children. Journal o f Bone & Mineral Research 14: 740-746.
Arai, H. Miyamoto, K. Taketani, Y. Yamamoto, H. Iemori, Y. Morita, K. Tonai, T.
Nishisho, T. Mori, S. and E.Takeda. 1997. A vitamin D receptor gene polymorphism
in the translation initiation codon: effect on protein activity and relation to bone
mineral density in Japanese women. Journal o f Bone & M ineral Research 12: 915-
921.
Atkin, W.S. Morson, B.C. and J.Cuzick. 1992. Long-term risk o f colorectal cancer after
excision o f rectosigmoid adenomas. New England Journal o f M edicine 326: 658-
662.
Bischof, M.G. Redlich, K. Schille,r C. Chirayath, M.V. Uskokovic, M. Peterlik, M. and
H.S. Cross. 1995. Growth inhibitory effects on human colon adenocarcinoma-
derived Caco-2 cells and calcemic potential of 1 alpha,25-dihydroxyvitamin D3
analogs: structure-function relationships. Journal o f Pharmacology & Experimental
Therapeutics 275: 1254-1260.
Buras, R.R. Schumaker, L.M. Davoodi, F. Brenne, R.V. Shabahang, M. Nauta, R.J. and
S.R. Evans. 1994. Vitamin D receptors in breast cancer cells. Breast Cancer
Research & Treatment 31: 191-202.
Buset,, M. Lipkin M. Winawer, S. Swaroop, S. and E. Friedman. 1986. Inhibition of
human colonic epithelial cell proliferation in vivo and in vitro by calcium. Cancer
Research 46: 5426-5430.
Clemens, T.L. Adams, J.S. Henderson, S.L. and M.F.Holick. 1982. Increased skin
pigment reduces the capacity o f skin to synthesize vitamin D3. Lancet 1: 74-76.
Cooper, G.S. and D.M. Umbach. 1996. Are vitamin D receptor polymorphisms
associated with bone mineral density? A meta-analysis. Journal o f Bone & M ineral
Research 11: 1841-1849.
Crofts, L.A. Hancock, M.S. Morrison, N.A. and J.A.Eisman.1998. Multiple promoters
direct the tissue-specific expression of novel N-terminal variant human vitamin D
receptor gene transcripts. Proceedings o f the National Academy o f Sciences o f the
United States o f America 95: 10529-10534.
Cross, H.S. Pavelka, M. Slavik, J. and M. Peterlik. 1992. Growth control of human colon
cancer cells by vitamin D and calcium in vitro. Journal o f the National Cancer
Institute 84: 1355-1357.
21
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Cross, H.S. Bajna, E. Bises, G. Genser, D. Kallay, E. Potzi, R. Wenzl, E. Wrba, F. Roka
R. and M. Peterlik. 1996. Vitamin D receptor and cytokeratin expression may be
progression indicators in human colon cancer. Anticancer Research 16: 2333-2337.
Curran, J.E. Vaughan, T. Lea, R.A. Weinstein, S.R. Morrison, N.A. and L.R. Griffiths.
1999. Association o f A vitamin D receptor polymorphism with sporadic breast
cancer development. International Journal o f Cancer 83: 723-726.
Emerson, J.C. and N.S. Weiss. 1992. Colorectal cancer and solar radiation. Cancer
Causes & Control 3: 95-99.
Evans, S.R. Nolla, J. Hanfelt, J. Shabahang, M. Nauta, R J. and I.B. Shchepotin.1998.
Vitamin D receptor expression as a predictive marker of biological behavior in
human colorectal cancer. Clinical Cancer Research 4: 1591-1595.
Gallagher, J.C. Riggs, B.L. Eisman, J. Hamstra, A. Amaud, S.B. and H.F. DeLuca. 1979.
Intestinal calcium absorption and serum vitamin D metabolites in normal subjects
and osteoporotic patients: effect of age and dietary calcium. Journal o f Clinical
Investigation 64: 729-736.
Garland, C.F. Shekelle, R.B. Barrett-Connor, E. Criqui, M.H. Rossof, A.H. and O. Paul.
1985. Dietary vitamin D and calcium and risk o f colorectal cancer: a 19-year
prospective study in men. Lancetl : 307-309.
Garland, C.F. Comstock, G.W. Garland, F.C. Helsing, K J. Shaw, E.K. and E.D.Gorham.
1989. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study.
Lancet 2:1176-1178.
Gennari, L. Becherini, L. Mansani, R. Masi, L. Falchetti, A. Morelli, A. Colli, E.
Gonnelli, S. Cepollaro, C. and M.L. Brandi. 1999. FokI polymorphism at translation
initiation site of the vitamin D receptor gene predicts bone mineral density and
vertebral fractures in postmenopausal Italian women. Journal o f Bone & M ineral
Research 14: 1379-1386.
Giuliano, A.R. Franceschi, R.T. and R.J. Wood. 1991. Characterization of the vitamin D
receptor from the Caco-2 human colon carcinoma cell line: effect of cellular
differentiation. Archives o f Biochemistry & Biophysics 285: 261-269.
Gross, C. Eccleshall, T.R. Malloy, P J . Villa, M.L. Marcus, R. and D. Feldman. The
presence o f a polymorphism at the translation initiation site of the vitamin D
receptor gene is associated with low bone mineral density in postmenopausal
Mexican-American women. Journal o f Bone & M ineral Research 11: 1850-1855.
Gross, C. Krishnan, A.V. Malloy, P J. Eccleshall, T.R. Zhao, X.Y. and D. Feldman. 1998.
The vitamin D receptor gene start codon polymorphism: a functional analysis o f
FokI variants. Journal o f Bone & M ineral Research 13: 1691-1699.
22
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Harris, S.S. Eccleshall, T.R. Gross, C. Dawson-Hughes, B. and D. Feldman. 1997. The
vitamin D receptor start codon polymorphism (FokI) and bone mineral density in
premenopausal American black and white women. Journal o f Bone & M ineral
Research 12: 1043-1048.
Harris, S.S. and B. Dawson-Hughes. 1998. Seasonal changes in plasma 25-
hydroxyvitamin D concentrations of young American black and white women.
American Journal o f Clinical Nutrition 67: 1232-1236.
Holick, M.F. MacLaughlin, J.A. Clark, M.B. Holick, S.A. Potts, J.T Jr. Anderson, R.R.
Blank, I.H. Parrish, J.A. and P. Elias. 1980. Photosynthesis o f previtamin D3 in
human skin and the physiologic consequences. Science 210: 203-205.
Ingles, S.A. Ross, R.K. Yu, M.C. Irvine, R.A. La Pera, G. Haile, R.W. and R.A. Coetzee
1997a. Association o f prostate cancer risk with genetic polymorphisms in vitamin D
receptor and androgen receptor. Journal o f the N ational Cancer Institute 89: 166-
170.
Ingles, S.A. Haile, R.W. Henderson, B.E. Kolonel, L. Nakaichi Shi, Han, C.Y. Yu, M.C.
Ross, R.K. and G.A. Coetzee. 1997b. Strength o f Linkage Disequilibrium between
Two Vitamin D Receptor Markers in Five Ethnic Groups: Implications for
Association Studies. Cancer Epidemiology, Biomarkers & Prevention 6:93-98.
Ingles, S.A. Coetzee, G.A. Ross, R.K. Henderson, B.E. Kolonel, L.N. Crocitto, L. Wang,
W. and R.W. Haile. 1998. Association o f Prostate Cancer with Vitamin D Receptor
Haplotypes in African-Americans. Cancer Research 58:1620-1623.
Kim, E.C. and P. Lance. 1997. Colorectal polyps and their relationship to cancer.
[Review] Gastroenterology Clinics o f North America 26: 1-17.
Lin, H.J. Probst-Hensch, N.M. Ingles, S.A. Han, C.Y. Lin, B.K. Lee, D.B. Frankl, H.D.
Lee, E.R. Longnecker, M.P. andR.W. Haile. 1995. Glutathione transferase
(GSTM1) null genotype, smoking, and prevalence o f colorectal adenomas. Cancer
Research 55: 1224-1226.
Lointier, P. Meggouh, F. Dechelotte, P. Pezet, D. Ferrier, C. Chipponi, J. and S. Saez.
1991. 1,25-Dihydroxyvitamin D3 receptors and human colon adenocarcinoma.
British Journal o f Surgery 78: 435-439
Lucotte, G. Mercier, G. and A. Burckel. 1999. Fok I polymorphism at the human vitamin
D receptor gene locus in Europeans and Africans. Clinical Genetics 55: 281-282.
Ma, J. Stampfer, M.J. Gann, P.H. Hough, H.L. Giovannucci, E. Kelsey, K.T. Hennekens,
C.H. and D J. Hunter. 1998. Vitamin D receptor polymorphisms, circulating vitamin
23
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
D metabolites, and risk of prostate cancer in United States physicians. Cancer
Epidemiology, Biomarkers & Prevention 7: 385-390.
Martinez, M.E. and W.C. Willett. 1998. Calcium, vitamin D, and colorectal cancer: a
review o f the epidemiologic evidence. [Review] Cancer Epidemiology, Biomarkers
& Prevention 7: 163-168.
Matsuoka, L.Y. Wortsman, J. Haddad, J.G. Kolm, P. and B.W. Hollis. 1991. Racial
pigmentation and the cutaneous synthesis of vitamin D. Archives o f Dermatology
127: 536-538.
Morrison, N.A. Qi, J.C. Tokita, A. Kelly, P.J. Crofts, L. Nguyen, T.V. Sambrook, P.N.
and J.A. Eisman. 1994. Prediction o f bone density from vitamin D receptor alleles.
Nature 367: 284-287.
Niimi, T. Tomita, H. Sato, S. Kawaguchi, H. Akita, K. Maeda ,H. Sugiura ,Y. and R.
Ueda. 1999. Vitamin D receptor gene polymorphism in patients with sarcoidosis.
American Journal o f Respiratory & Critical Care M edicine 160: 1107-1109.
Peehl, D.M. Skowronski, R.J. Leung, G.K. Wong, S.T. Stamey, T.A. and D.Feldman.
1994. Antiproliferative effects o f 1,25-dihydroxyvitamin D3 on primary cultures of
human prostatic cells. Cancer Research 54: 805-810.
Potter, J.D. Slattery, M.L. Bostick, R.M. and S.M. Gapstur. 1993. Colon cancer: a review
o f the epidemiology. [Review] Epidemiologic Reviews 15: 499-545.
Shabahang, M. Buras, R.R. Davoodi, F. Schumake,r L.M. Nauta, R J. and S.R. Evans.
1993. 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma
cell line differentiation and growth inhibition. Cancer Research 53: 3712-3718.
Studzinski, G.P. McLane, J.A. and M.R. Uskokovic. 1993. Signaling pathways for
vitamin D-induced differentiation: implications for therapy of proliferative and
neoplastic diseases. [Review] Critical Reviews in Eukaryotic Gene Expression 3:
279-312.
Sturzenbecker, L. Scardaville, B. Kratzeisen, C. Katz, M. Abarzua, P. and J. McLane.
1994. Isolation and analysis of cDNA encoding a naturally-occurring truncated form
o f the human vitamin D receptor. In: Bouillon R, Norman AW, Thomasset M (eds.)
Vitamin D: A Pluripotent Steroid Hormone: Structural Studies, M olecular
Endocrinology, and Clinical Applications. W. deGruyter, New York, NY, U.S.A.,
pp. 112.
Taylor, J.A. Hirvonen, A. Watson, M. Pittman, G. Mohler, J.L. and D.ABell. 1996.
Association o f prostate cancer with vitamin D receptor gene polymorphism. Cancer
Research 56: 4108-4110.
24
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Wargovich, M J. Eng, V.W. and H.L. Newmark. 1984. Calcium inhibits the damaging
and compensatory proliferative effects o f fatty acids on mouse colon epithelium.
Cancer Letters 23: 253-258
Williams, C.B. and L. Bedenne. 1990. Management of colorectal polyps: is all the effort
worthwhile? [Review] Journal o f Gastroenterology & Hepatology 5 Suppl 1: 144-
165.
Zmuda, J.M. Cauley, J.A. Danielson, M.E. Theobald, T.M. and R.E. Ferrell. 1999.
Vitamin D receptor translation initiation codon polymorphism and markers of
osteoporotic risk in older African-American women. Osteoporosis International 9:
214-219
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Linked assets
University of Southern California Dissertations and Theses
Conceptually similar
PDF
CYP17 polymorphism and risk for colorectal adenomas
PDF
Dietary fats, fat metabolizing genes, and the risk of breast cancer
PDF
Androgen receptor gene and prostate -specific antigen gene in breast cancer
PDF
Colorectal cancer risks in Singapore Chinese: Polymorphisms in the insulin-like growth factor-1 and the vitamin D receptor
PDF
A large-scale genetic association study of prostate cancer in a multi-ethnic population
PDF
BRCA1 mutations and polymorphisms in African American women with a family history of breast cancer identified through high throughput sequencing
PDF
beta3-adrenergic receptor gene Trp64Arg polymorphism and obesity-related characteristics among African American women with breast cancer: An analysis of USC HEAL Study
PDF
Determinants of mammographic density in African-American, non-Hispanic white and Hispanic white women before and after the diagnosis with breast cancer
PDF
Genetic risk factors in breast cancer susceptibility: The multiethnic cohort
PDF
Breast cancer in the multiethnic cohort study: Genetic (prolactin pathway genes) and environmental (hormone therapy) factors
PDF
Association between body mass and benign prostatic hyperplasia in Hispanics: Role of steroid 5-alpha reductase type 2 (SRD5A2) gene
PDF
Assessment of fatigue as a late effect of therapy among survivors of childhood leukemia
PDF
Androgens and breast cancer
PDF
A case/parental/sibling control study of Ewing's sarcoma/peripheral primitive neuroectodermal tumor (pPNET)
PDF
Association between latchkey status and smoking behavior in middle school children
PDF
Single-nucleotide polymorphisms in 17beta-hydroxysteroid dehydrogenase type III and prostate cancer risk
PDF
A linear model for measurement errors in oligonucleotide microarray experiment
PDF
Cluster analysis of p53 mutational spectra
PDF
Descriptive epidemiology of thyroid cancer in Los Angeles County, 1972-1995
PDF
Infrequent androgen receptor mutations in primary prostate tumors from men residing in Singapore and Los Angeles
Asset Metadata
Creator
Wang, Jun
(author)
Core Title
Association of vitamin D receptor gene polymorphisms with colorectal adenoma
School
Graduate School
Degree
Master of Science
Degree Program
Molecular Epidemiology
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
health sciences, oncology,health sciences, public health,OAI-PMH Harvest
Language
English
Contributor
Digitized by ProQuest
(provenance)
Advisor
Ingles, Sue Ann (
committee chair
), Coetzee, Gerhard (
committee member
), Haile, Robert W. (
committee member
)
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c16-36449
Unique identifier
UC11342221
Identifier
1405256.pdf (filename),usctheses-c16-36449 (legacy record id)
Legacy Identifier
1405256.pdf
Dmrecord
36449
Document Type
Thesis
Rights
Wang, Jun
Type
texts
Source
University of Southern California
(contributing entity),
University of Southern California Dissertations and Theses
(collection)
Access Conditions
The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...
Repository Name
University of Southern California Digital Library
Repository Location
USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA
Tags
health sciences, oncology
health sciences, public health