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Insulin-like growth factor 1 genotype, phenotype and breast cancer risk, by racial/ethnic group
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Insulin-like growth factor 1 genotype, phenotype and breast cancer risk, by racial/ethnic group
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INSULIN-LIKE GROWTH FACTOR I GENOTYPE, PHENOTYPE AND
BREAST CANCER RISK, BY RACIAL/ETHNIC GROUP
Copyright 2001
by
Katherine Anne DeLellis
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(MOLECULAR EPIDEMIOLOGY)
May 2002
Katherine Anne DeLellis
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UMI Number: 1411781
Copyright 2001 by
DeLellis, Katherine Anne
All rights reserved.
_ _ ®
UMI
UMI Microform 1411781
Copyright 2003 by ProQuest Information and Learning Company.
All rights reserved. This microform edition is protected against
unauthorized copying under Title 17, United States Code.
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UNIVERSITY O F S O U T H E R N CALIFORNIA
TMC GNAOUATKSCHOOL
UNIVCRSITYFAMR
LOS AM OSISS. CALIFORNIA 10007
This thesis, written by
&)r»£M/A/£- /In** D£ L£Lu,3
under the direction of h£62 — Thesis Committee,
and approved by all its members, has been pre~
sented to and accepted by the Dean of The
Graduate School, in partial fulfillment of the
requirements for the degree of
P a ttf May 10, 2002
IS Z Z ^ fl
\v w sJl*—
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TABLE OF CONTENTS
LIST OF FIGURES AND TABLES iii
ABSTRACT iv
INTRODUCTION 1
BACKGROUND 3
MATERIALS AND METHODS 9
RESULTS 16
DISCUSSION 28
REFERENCES 33
BIBLIOGRAPHY 38
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iii
LIST OF FIGURES AND TABLES
Part I: Insulin-like Growth Factor I Phenotype and (CA)„ Microsatellite Genotype in
133 Postmenopausal Controls
Figure 1. Structure o f the human IGFI gene 5
Table 1. Characteristics and mean plasma IGF1 level (ng/mL) 17
by racial/ethnic group
Table 2. IGF I (CA)„ microsatellite genotype frequencies among 18
subjects tested for plasma IGF 1 level,
by racial/ethnic group
Table 3. Mean plasma IGF 1 level (ng/mL) by (CA)n microsatellite 19
genotype and racial/ethnic group
Part II: IGFI (CA)„ Microsatellite Genotype, IGFI C/T Single Nucleotide
Polymorphism Genotype and Breast Cancer Risk in 741 Postmenopausal Women
Table 4. Characteristics o f subjects in IGFI (CA)n microsatellite 20
genotype and breast cancer risk analysis,
by racial/ethnic group
Table 5. IGFI (CA)„ microsatellite genotype frequencies among 22
controls in the case-control analysis, by racial/ethnic group
Table 6. Risk o f breast cancer associated with IGFI (CA)n 23
microsatellite genotype, by racial/ethnic group
Table 7. Risk o f breast cancer associated with IGFI C/T single 25
nucleotide polymorphism genotype, by racial/ethnic group
Figure 2. Histogram showing linkage disequilibrium between (CA)n 26
repeat length and C or T allele o f C->T at position -533,
for all races combined
Table 8. Investigation o f the association between the IGFI (CA)n 27
microsatellite genotype and breast cancer risk, tested for
effect modification by the IGFI C/T single nucleotide
polymorphism genotype
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ABSTRACT
The insulin-like growth factor (IGF) system has been implicated in the etiology
o f breast cancer. Specifically, the insulin-like growth factor I gene {IGFI) is a
particularly strong candidate gene for a breast cancer susceptibility model because its
product has been shown to have mitogenic and anti-apoptotic effects on breast
epithelial cells and is expressed with appreciable population variability. We
investigated two polymorphisms in the promoter region o f the IGFI gene, a
dinucleotide microsatellite 824 base pairs upstream from the transcription start site and
a single nucleotide polymorphism 533 base pairs upstream o f transcription start site,
for possible associations with plasma IGFI levels (the protein will be referred to as
IG FI) and breast cancer risk in tw o groups o f postmenopausal women. While we did
find a significant difference in mean plasma IGF 1 across racial/ethnic groups, we did
not find any consistent association with genotype or breast cancer risk.
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1
INTRODUCTION
According to the American Cancer Society an estimated 192,200 new cases o f
advanced breast cancer will be reported, 39,900 cases o f ductal carcinoma in situ will
be reported and 40,200 women will die from breast cancer in the United States in
2001. Malignant neoplasms o f the breast are the second leading cause o f death in
women. Only lung cancer will take more female lives in America (1).
The insulin-like growth factor-1 protein has been implicated in breast cancer
due to its mitogenic and anti-apoptotic effect on mammary epithelial cells (2-4).
Epidemiological work, epitomized by a paper from Hankinson et al (5) has shown an
increased risk for breast cancer in premenopausal women with high plasma IGFI (5)
We chose to follow-up on a publication that the 19/19 variant in the gene for IGFI
was associated with low serum IGFI (6). We will refer to the gene as IGFI. We
hypothesized that this same 19/19 genotype, if it is truly a marker for low circulating
IGFI as Rosen put forth (6), would also potentially indicate women who have a
decreased lifetime breast epithelial cell exposure to IGFI and thus decreased
susceptibility to breast cancer. These things in mind we set out with three specific
aims: first to determine whether plasma IGFI levels were associated with
racial/ethnic group in parallel to patterns o f breast cancer risk in the Los Angeles-
Hawaii M ultiethnic Cohort, second to investigate whether the 19/19 genotype was
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2
reliably associated with low plasma IGF 1 levels in postmenopausal women and third
to determine whether the 19/19 genotype might be a marker for low breast cancer risk.
Investigation o f these aims led us to a fourth aim which was to determine whether a
polymorphism downstream o f the (CA)n microsatellite is in linkage disequilibrium
with the 19 allele, whether this downstream genotype is independently associated with
breast cancer risk or whether it is an effect modifier in the relationship between the
(CA)n genotype and breast cancer risk.
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3
BACKGROUND
Epidemiological studies o f the insulin-like growth factors have shown that
IGFI levels are associated with risk for many common disease states. For example
low IGF 1 has been associated with osteoporosis (7), and IGF 1 seems to have an
inverse relationship with some risk factors for cardiovascular disease (8).
Uncommonly high levels o f IG FI are a consequence o f a rare condition called
acromegaly (9), a chronic grow th hormone excess. Acromegalics have been reported
to be at increased risk for colon and rectal cancer (10), and while several studies have
implicated IGFI in colorectal cancer (11, 12). IGFI has also been implicated in
cancer o f the prostate, lung and breast. In 1998 Chan and colleagues [8] found that
men with IGFI values in the highest quartile had 2.4 times the risk for prostate cancer
than men in the lowest quartile (95% Cl 1.2, 4.7) and Hankinson et al (5) found an
increased risk for breast cancer in premenopausal women with high prediagnostic
plasma IGFI (5). Byrne and colleagues [10] subsequently reported that control women
with high IGFI had higher mammographic density than women in the lower IGFI
group. The peptides comprising the IGF system were first investigated in the early
1970’s and were named somatomedins because they were found to mediate the
somatogenic effects o f growth hormone (GH) (13). The somatomedin family of
proteins originally had six members including basic somatomedin, somatomedin A,
somatomedin B, somatomedin C, two molecules with non-suppressible insulin-like
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4
activity (NSILA) and one with multiplication-stimulating activity (MSA). It has since
been determined that basic somatomedin, somatomedins A, somatomedin C, and
NSILA-I are all the same peptide hormone, now known as insulin-like growth factor 1
(IGFI). NSILA-II and MSA are now known as insulin-like growth factor 2 (IGF2)
(14). IGFI and 2 were renamed upon elucidation o f their high sequence homology to
the insulin protein.
Characterization o f the IGFI protein and the IGFI gene locus has occurred
within the last twenty-five years. The two-dimensional structure o f the IGF 1 protein
was characterized in 1978 by Rinderknecht and Flumbel (15) (Figure 1). IGFI is a
single chain polypeptide o f 70 amino acids and a molecular mass of 7.65 kD. The
IGFI gene was localized in 1984 to chromosome 12q22-24 (16, 17). The human gene
spans 45 kilobase pairs (kb) and is comprised o f five exons (18, 19). The IGFI gene
produces two stable mRNAs that each produces a precursor protein. These are called
IGFIA and IGFIB. The tw o precursors differ in their 3' ends but both code for the
same 70 amino acid protein (18). IGFI is highly conserved across species in general
(20).
The IGFI protein is ubiquitous in the human body and its role is critical to
normal growth and development. It is synthesized mainly in the liver in response to
growth hormone and is expressed in tissues including the brain, bone marrow, prostate
epithelium and breast epithelium. IGFI acts to promote grow th in its target tissues
through an IGFI specific tyrosine kinase receptor (21).
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5
Figure 1. Structure o f the human IGFI gene
5’ 3’
2 3 4 5
A depiction of the IGFI gene that spans roughly 45 kilobase pairs. Exons are
depicted in boxes. Coding regions are solid, non-coding regions are cross-hatched.
Alternative RNA processing results in two distinct IGFI peptides. The DNA
sequence of exons 1 through 4 encodes a 195 amino-acid precursor peptide (IGF IB).
The DNA sequence of exons 1, 2, 3 and 5 encode a 153 amino-acid precursor peptide
(IGFIA). Both precursor peptides contain the same 70 amino acid IGFI found in
serum, but their carboxyl terminal ends are different.
IGFI availability to tissues depends not only on circulating and tissue IGFI
levels but also on the concentration o f several IGFI binding proteins. There are
reportedly six IGF binding proteins (IGFBPs) that bind to IGFI with high affinity.
IGFBP3 is the main binding protein in the blood. IGFBP3 binds to the growth factor
and to an 88 kD protein termed the acid-labile subunit (ALS) to make the stable
ternary complex that is the main circulating form o f IG F I. Together these two
proteins carry roughly 80% of the IGFI peptides in normal adult serum (22).
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6
Prevented by its size from leaving the vascular compartment, the ternary complex has
a half-life o f 12-15 hours. This is in contrast to the free IGFI peptide, which has a
half-life o f around 10 minutes (23). Thus the molar ratio IGFI IGFBP3 has been
hypothesized to be a better measure o f bio-available IG FI and some association
studies have used this ratio in place o f IGFI alone (24). Furthermore it has been
shown that IGFBP3 may have an inhibitory effect on cell growth by an IGFI
independent pathway (25). The exact functions and mechanisms o f each of the
binding proteins are not yet completely understood. In general the IGFBP's function is
to regulate IGFI distribution and either enhance or inhibit IGFI action.
The insulin-like growth factor pathway has been shown to possess significant
cross-talk with other well-defined intracellular signaling pathways. Binding of IGF 1
to the IGFI receptor (IGF1R) stimulates receptor auto-phosphorylation, activating the
tyrosine kinase domain. This spurs phosphorylation o f downstream effectors and sets
off a cascade o f events that leads to activation o f proteins such as MAPK, GRB2 and
PI3 kinase (26). Through various pathways IGFI is involved in cell cycle progression,
cell proliferation, anti-apoptosis, cell differentiation and hormone secretion.
IGFI plays a role in embryonic and fetal grow th and development. It also
regulates uterine and placental growth. Transgenic mice with null mutations o f IGFI
have reduced birth weights, organ hypoplasia and delayed bone development. Some
animals with very low or null IGFI die at birth and those that survive have growth
deficiencies (27, 28).
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7
IGFI has a mitogenic and anti-apoptotic effect on several cell lines, including
mammary epithelial cells (2, 3). The IGFI receptor (IGF1R) is abundant in breast
epithelial cells (2) and is over-expressed in breast tumor cells (29). In 1994 Westley
and May showed that IGFI acts in conjunction with estrogen to prom ote breast cell
proliferation. They showed that IGFI has a direct proliferative effect on breast
epithelial cells and hypothesized a role for IGF 1 in mediating the effect o f estrogen on
breast cells (4). Kleinberg and colleagues supported this work in a 1998 paper in
which they observed that the full effect o f IGFI was not seen in the absence o f
estradiol (3).
Epidemiological research has shown that IGFI levels decrease with age after a
peak at puberty (30), tailing off significantly after menopause (31). IGFI has been
shown to decrease with decreasing physical activity (32) and increasing body mass
index (33, 34), although these observations are not very consistent in the literature.
There is no cyclic variation in IGFI during the normal menstrual cycle but IGFI is
suppressed by oral contraceptive use (35). Transdermal delivery o f ERT does not
have this effect (36) on IGFI. IGFI seems to be suppressed by anti-estrogens such as
tamoxifen (37).
In 1998 Rosen and colleagues published a finding that low IGFI was
associated with Idiopathic Osteoporosis (IOM ) in Caucasian men and women, and
furthermore provided a candidate for a genetic marker of circulating IGF 1
concentration. They reported that a simple (CA) dinucleotide repeat in the IGFI gene
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8
was correlated with low serum IGFI levels in Caucasian men and premenopausal
Caucasian women and with risk for IOM (38). We chose to investigate this
polymorphism in a multi-ethnic group o f postmenopausal women. First we performed
a cross-sectional study o f 133 women without breast cancer in order to investigate the
IGFI variation across races and with class o f (CA)n microsatellite genotype.
Concurrently we performed a case-control study o f 741 women to determine whether
the (CA)n genotype was associated with risk for postmenopausal breast cancer. We
then proceeded to sequence the gene 1000 base pairs downstream o f the dinucleotide
repeat in an effort to find a potentially more relevant genetic marker for breast cancer
risk.
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9
MATERIALS AND METHODS
Study Subjects
We set out to determine how IGFI phenotype is associated with racial/ethnic group
and IGFI genotype. For this analysis we had originally planned to obtain IGFI levels
and IGF1 genotype information on 200 control women selected from each o f the four
major racial/ethnic groups in the Hawaii and Los Angeles Multiethnic Cohort. These
include African-American (AA), Japanese-American (JA), Latin-American (LA) and
Non-Latino W hite (NLW). We selected women with no prior history o f cancer who
were postmenopausal and had not taken hormone therapy within two weeks o f blood
draw. We successfully obtained both IGFI measurements and genotypes on 133
women, see the section on IGFI Plasma Levels for details (Table 1). Postmenopausal
women were defined in three ways. Women were determined to be postmenopausal if
they were over the age o f 55 and had reported that their periods had stopped. They
were also determined to be postmenopausal if they were 55 or younger if their periods
had stopped and they had not undergone a hysterectomy. Finally women were
determined to be postmenopausal if they were 55 or younger if their periods had
stopped and if they had undergone a bilateral oophorectomy.
Secondly to assess whether there is an association between (CA)n genotype and
breast cancer risk we performed a case-control analysis for which we selected 400
cases and 400 controls over age 49 from the same four racial/ethnic groups as
described above. 56 women reported having a prevalent breast or uterine cancer on
their questionnaire and
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10
were thus excluded from the analysis. Three women were missing weight or height
values. This left us with 368 cases and 373 controls for whom we successfully
attained a genotype and complete questionnaire information, and who did not report
prevalent hormone-related cancer. O f these 320 had invasive breast cancer o f stage
one and above (Table 4). 47 o f the 373 controls in this case-control dataset are also
included in the controls-only phenotype analysis o f IGFI level and genotype described
above.
IGFI Plasma Levels
Plasma IGFI was quantified in the Reproductive Endocrine Research Laboratory at
USC. We first requested IGFI measurements by ELISA assay. The ELISA
measurements were performed in two batches. Preliminary analysis revealed low
correlation between batches and upon investigation the maker o f the ELISA kit
informed us that they had discovered a problem their kits, which might lead to low
inter-batch correlation. The low reproducibility o f the ELISA results prompted us to
request IGFI plasma assay by the RIA method. The radioimmunoassay for the
determination o f IGFI in human plasma o r serum by the Nichols Institute, San Juan
Capistrano, California was used. After the ELISA assays we had plasma available on
145 o f the 200 women. Ten o f those 145 were excluded from the analysis due to
prevalent breast or uterine cancer and tw o were excluded due to missing weight or
height information, leaving 133 for the analysis. The intra-assay coefficients o f
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11
variation for the RIA assay range from 2.4 to 3.0%, while the inter-assay coefficient o f
variation ranged from 5.2 to 8.4% (39) (40, 41).
(CA)„ Microsatellite Polymorphism Genotyping
Genotyping o f the (CA)„ microsatellite for both groups was performed using PAGE
gel electrophoresis. We performed PCR amplification o f the DNA region surrounding
the microsatellite repeat in question using identical primers to those used in the study
by Rosen et al.(6) and were obtained from the USC/Norris Core Sequencing Lab.
Their sequences were as follows 5’GCTAGCCAGCTGGTGGTGTTATT 3’ and 3’
ACCACTCTGGGAGAAGGGTA 5’. All PCR was performed using a PTC-100
Thermocycler (MJ Research, Waltham MA). We extracted DNA from the buffy coats
o f peripheral blood samples using the Puregene genomic DNA isolation kit. The
genotyping protocol was very close to that used in Rosen’s study. 20 nanograms o f
DNA template, 1.25 pmols o f each primer, 0.25 (iM o f each deoxynucleotide
triphosphate, 2.5 (J.M MgCh, 2% dimethyl sulfoxide, 1.5 U Taq polymerase (Promega)
and manufacturer’s recommended buffers were combined in 25 |il reactions. The
forward primer was labeled with 33P using T4 polynucleotide kinase (Amersham-
Pharmacia). A “touch down” PCR cycling protocol was used which consisted o f 35
cycles total. The program started with a 45 second denaturation at a temperature o f
94°C. The first cycle continued with a 30 second annealing phase at 64°C and
finished with a 30 second 72°C extension. The annealing tem perature was decreased
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12
by one degree in each o f the next nine cycles, and then was held at 55°C for 25 cycles.
Denaturation at 94°C for 45 seconds, and extension at 72°C for 30 seconds was
consistent throughout the entire program. The final extension was held for 5 minutes
at 72°C. The radiolabeled, denatured PCR product was screened on a polyacrylamide
gel by electrophoresis. Autoradiographs were exposed for 12-18 hours. Two
investigators scored all genotypes independently and random samples were rerun
periodically to check consistency across the entire sample.
In order to orient the genotype information attained from the PAGE gel
electrophoresis assay in terms o f the number o f dinucleotide repeats, we sequenced a
number o f homozygote samples using an ABI 3700 automatic sequencer Two
independent investigators read the output and were able to identify the 19/19
genotype, thus orienting the others in relation to the 19. The same 19/19 homozygote
control and a 21/21 homozygote control were run on each genotyping gel.
Downstream Sequencing, Identification o f two SNPs
W e sequenced approximately one kilobase between the (CA) microsatellite and the
IGFI translation start site. This region was first amplified in two overlapping
segments. The first set o f primers was forward 5’AATTGTTTGCCCCCCA3’ and
reverse 5’ GAACCCTGTCAC3’. The second set o f primers was forward
5’CCCATCCCCCATATTCCT3’ and reverse 5’GTGCTGCTTTTGTGATTTC3’.
The PCR conditions were as follows: 94 C for 45 seconds followed by 56 C (first
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13
reaction) or 52 C (second reaction), with a final extension at 72 C for 30 seconds.
Total reaction volume was 25 ul. This was comprised o f 20 nanograms o f template
DNA, lOOng o f each primer, 250 mol/L o f each deoxynucleotide triphosphate, 2 .0
nmol ofM gC l2 and 0.5 U Taq polymerase (Promega, Madison WI) with the
manufacturer’s recommended buffers. PCR products were purified with a multiscreen
96 well filter plate (Millipore, Bedford MA). Sequencing was performed in 25 cycles.
Cycles had three steps, starting at 96 C for 22 seconds, followed by 54 C for 5 seconds
and then 60 C for 240 seconds. Results were analyzed using the ABI Prism 3700
DNA Analyzer (PE Biosystems, Foster City CA).
-T533C SNP Genotyping
Alleles for the SNP polymorphism C->T at position -533 (-T533C) from the
transcription start site o f the IGFI gene were identified using the fluorogenic 5'-
nuclease assay (TaqM an Assay) (42). The allelic discrimination assay was performed
using a Taxman PCR Core Reagent Kit (Applied Biosystems, Foster City, CA)
according to manufacturers instructions.
The oligonucleotide primers for amplification o f the polymorphic region were
GC029for (5'-GCCCCTCCATAGGTTCTAGGA-3') and
GC029rev (5'-CGGGTGACCCCTTGTCC-3'). The fluorogenic
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14
oligonucleotide probes used to detect each o f the alleles were
GC029FAM (5'-AGATCACACCCCTCACTTGGCAAC-3') labeled with 6-FAM and
GC029CY3 (5'-AGATCACACCTCTCACTTGGCAAC-3') labeled with CY3
(BioSearch Technologies, Novato, CA).
PCR amplification was performed in a thermal cycler (M W G Biotech, High
Point, NC) with an initial step o f 95C for 10 minutes followed by 50 cycles o f
95C/25sec and 63C/lmin. The fluorescence profile o f each well was measured in an
ABI 7900HT Sequence Detection System (Applied Biosystems) and the results
analyzed with Sequence Detection Software (Applied Biosystems). Experimental
samples were compared to 16 controls to identify the 3 genotypes at this locus (TT,
CT, and CC). Any samples that were outside the parameters defined by the controls
were identified as non-informative.
Data Analysis
Plasma IGF 1 levels were square root transformed to produce an approximate normal
distribution. We looked at data using log and square-root transformations and we
present the anti-square root in all tables but both approaches resulted in the same
trend. Analysis o f variance was used to test mean differences by IGFI genotype (No
19, One 19, 19/19) and by racial/ethnic group, while adjusting for age, and BMI.
Means presented are least squares means. Odds ratios for association between the
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15
genotype and breast cancer risk were calculated using logistic regression. Odds ratios
were calculated for the IGFI genotype categorized by the number o f 19 alleles (C A 19)
as described above. Estimates were adjusted for age, BM I and racial/ethnic group
when not stratified by race. Analysis o f effect modification was performed using the
Epilog software package, while all other analyses were performed in SAS (43).
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16
RESULTS
Insulin-like Growth Factor I Genotype, Phenotype and Race
Table 1 shows characteristics for the 133 postmenopausal women in the phenotype
analysis. African-Americans tended to be older, with a mean age o f 68.5 years, and
Latin-Americans tended to be younger. Their mean age was 62.8 years The p-value
specifically for the difference between mean age for African-Americans and Latin-
Americans was statistically significant (p=0.0003), as was the overall p-value for
difference across all four racial/ethnic groups (p=0.001). Body size characteristics
also differed significantly across racial/ethnic group with Latin-Americans on the high
end o f the body mass index (BM1) scale (29.2), and Japanese-Americans on the low
end (24.6). The p-value for this specific difference was statistically significant
(p<0.002) as was the p-value for the test across all four racial/ethnic groups
(p=0.0002).
Mean plasma IGFI levels differed significantly across racial/ethnic strata.
After adjustment for age and BMI African-Americans had the highest plasma
concentration o f IGFI (190.9 ng/mL) and Latin-Americans had the lowest mean
plasma IGFI level (136.0 ng/mL). Japanese-American and Non-Latino W hite women
had plasma IG FI levels intermediate o f these tw o groups, with age and BMI adjusted
means o f 152.2 and 146.2 ng/mL respectively (Table 1). The adjusted mean for the
African-Americans was significantly different from that o f every other group
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17
(p<0.05), but the other three groups were not significantly different from each other
(data not shown).
The distribution o f genotypes for the (CA)n dinucleotide repeat for the group o f
133 controls is shown in Table 2. In Non-Latino Whites and Latin-Americans the
19/19 homozygote is the most common genotype (39.4 and 48.7% respectively), but
for African-Americans the 19/18 is the most common (25.0% ) and in Japanese-
Americans the most common genotype is the 21/19 (33.3%). There is no evidence for
departure from Hardy-Weinberg equilibrium in any o f the racial/ethnic groups.
Table 1. Characteristics and mean plasma IGFI level (ng/mL) by racial/ethnic group
Variable
African-
American
Japanese-
American
Non-Latino
White
Latin-
American
X2
(p-homo)
No. subjects (%) 36 (27) 27(20) 33 (25) 37(28)
Mean age, years 68.5 67.0 67.8 62.8 0.001
Mean height, inches 64.1 60.0 64.2 62.6 <0.0001
Mean weight, pounds 166.8 125.3 147.3 162.4 <0.0001
Mean BMI, kg/m2 28.6 24.6 25.1 29.2 0.0002
Mean plasma IGFI:
(ng/mL)1
p(Anova)
Crude 176.2
(154.8,199.0)
150.2
(127.5, 174.7)
142.3
(122.3, 163.8)
127.6
(109.7, 146.8)
0.011
Adjusted
(for age and BMI)
190.9
(167.4,216.1)
152.2
(128.4, 178.0)
146.2
(125.2, 168.9)
136.0
(117.2, 156.3)
0.0005
1 The associated 95% confidence intervals are given in parentheses.
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18
Table 2. IGF I (CA)„ microsatellite genotype frequencies among subjects tested for
plasma IGF1 level, by racial/ethnic group
Genotype African- Japanese- Non-Latmo Latin.American
American Amencan White
N (%) N (%) N (%) N (%)
22/19 0(0) 0(0) 2(6.1) 1 (2.7)
21/21 I (2.8) 2 (7.4) 0(0) 0 (0 )
21/20 I (2.8) 4(14.8) 1 (3.0) 1 (2.7)
21/19 5(13.9) 9(33.3) 5(15.2) 3(8.1)
21/18 2(5.6) 1 (3.7) 0(0) 1 (2.7)
21/17 I (2.8) 1 (3.7) 1 (3.0) 0 (0 )
20/20 1 (2.8) 0(0) 1 (30) 2(5.4)
20/19 4(11.1) 2 (7.4) 8 (24.2) 8(21.6)
20/18 2(5.6) 0(0) 0(0) I (2.7)
19/19 5(13.9) 2 (7.4) 13(39.4) 18(48.7)
19/18 9(25.0) 1 (3.7) 2(6.1) 1 (2.7)
19/17 0(0) 4(14.8) 0(0) 1 (2.7)
19/16 2(5.6) 0(0) 0(0) 0 (0 )
18/18 1 (2.8) I (3.7) 0 (0) 0 (0 )
18/17 2(5.6) 0(0) 0(0) 0 (0)
No 19 11(21.1) 9(33.3) 3(9.1) 5(13.5)
One 19 20 (55.6) 16(59.3) 17(51.5) 14(37.8)
19/19 5(13.9) 2 (7.4) 13(39.4) 18(48.7)
We also compared mean plasma IGF1 concentration for the three (CA)n
microsatellite genotype categories. With our limited sample size we found that
although Latin-Americans, who in general had the highest frequency of the 19/19
homozygote genotype, the lowest mean IGF1 level and exhibited a pattern in which
the lowest mean plasma IGF1 level occurred in subjects with the 19/19 genotypes, had
mean plasma IGF1 levels that did not differ in a statistically significant manner
between microsatellite genotypes (Table 3). None o f the other racial/ethnic groups
exhibited any discernible pattern in IGF1 levels stratified by microsatellite genotype.
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19
Table 3. Mean plasma IGF1 level (ng/mL) by (CA)n inicrosatellite genotype and
racial/ethnic group
Genotype African-American Japanese Non-Latino White Latin-American
Amencan
156.1 152.1 158.4 122.5
(119.8, 197.2) (114.6, 194.9) (105.9, 221.4) (68.5, 192.0)
186.2 147.0 135.9 155.1
(156.1,218.7) (118.9, 178.1) (114.4, 159.4) (116.4, 199.4)
182.7 168.2 147.1 109.3
(125.9,250.0) (90.6,269.7) (121.6, 175.1) (80.7, 142.2)
156.4 158.7 152.4 155.8
(124.0, 192.6) (111.9,213.6) (86.3, 237.3) (88.8,241.6)
182.5 168.3 142.2 156.3
(154.3,213.1) (131.7, 209.4) (112.6, 175.3) (118.0, 199.8)
160.6 201.7 151.9 130.8
(111.0,219.3) (109.9, 321.0) (121.0, 186.4) (97.3, 169.3)
Crude No 19
One 19
19/19
Adjusted1 ' No 19
One 19
19/19
‘ The associated 95% confidence intervals are given in parentheses.
b Adjusted for age and BMI
IGF I (CA)n M icrosatellite Genotype and Breast Cancer Risk
Table 4 shows characteristics for the 693 subjects in the case-control analysis. These
women were all between the ages o f 49 and 81. Mean age did not differ across
racial/ethnic group for either cases or controls. Nor did mean age differ between cases
and controls in each racial/ethnic stratum. The patterns o f body size characteristics
including height, weight and BMI in these women were similar to those described
above for the phenotype subjects. .African-Americans had the highest BMI (29.2 for
cases and 28.3 for controls), and Japanese-Americans had the lowest BMI (23 .8 for
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20
cases and 23.4 for controls). Non-Latino White and Latin-Americans fell intermediate
o f these two groups. Although body size differed significantly across races for cases
and controls, the difference between the mean BMI for cases vs controls was not
statistically significantly different in any racial/ethnic group.
Table 4. Characteristics o f subjects in IGF I (CA)n microsatellite genotype and breast
cancer risk analysis, by racial/ethnic group
Variable
African-
American
Japancse-
American
Non-Latino
White
Latin-American p-homo
No. subjects
Mean age
(yrs)
p-diff.
Mean height
(in)
p-diff.
Mean weight
(lbs)
p-diff.
Mean BMI
(kg/m2)
p-diff.
Cases/Controls) (Cases/Controls) (Cases/Controls) (Cases/Controls) (Cases/Controls)
81/91 7 6 /9 4 82/92 81 / 96
68.1/67.9 68.5/68.4 68.9 / 67.6 68.4 / 67.0 0.85/0.47
0.88 0.85 0.15 0.13
64.4 / 64.4 60.9 / 60.6 64.0 / 63.7 6 1 .8/62.2 <0.0001 / <0.0001
0.82 0.47 0.48 0.19
171.9/166.9 125.6/ 122.3 150.9/ 147.4 150.0 / 151.9 <0.0001 / <0.0001
0.36 0.30 0.45 0.69
29.2/28.3 23.8/23.4 26.0/25.6 27.7/27.6 <0.0001 / <0.0001
0.30 0.41 0.58 0.85
The distribution o f genotypes for the (CA)n dinucleotide repeat among controls
in the case-control analysis is shown in Table 5. Again we see that Non-Latino
Whites and Latin-Americans have the highest frequency o f the 19/19 homozygote
genotype (40.2% and 38.5%). While the most common African-American genotype is
the 19/18 (19.8%) and in Japanese-Americans the most common genotype is the 21/19
(24.5%).
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21
The 19/19 genotype was not predictive o f low breast cancer risk in postmenopausal
women o f African-, Japanese- or Latin-American racial/ethnic origin (Table 6). In
Non-Latino Whites the adjusted odds ratio for breast cancer risk associated with the
19/19 homozygote as compared to the baseline 'No 19' genotype was 0.83, but this
protective effect was not statistically significant (95% C l 0.30-2.29). When all races
are combined, the 19 allele seems to be associated w ith an increased risk for breast
cancer. When dichotomized into No 19 vs. Any 19 categories the risk effect is 1.21
(95%CI 0.83, 1.75). For each risk table in this paper we also performed the analysis
using all cases including ductal carcinoma in situ (D C IS), using only low stage breast
cancer (DCIS) and using only advanced breast cancer (stage 2 and above) vs. all
controls (N=373). The results o f these analyses w ere not significantly different from
those presented here.
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Table 5. IGF I (CA)„ microsatellite genotype frequencies among controls in the case-
control analysis, by racial/ethnic group
Genotype African-American Japanese-American Non-Latino White Latin-American
N (%) N (%) N (%) N (%)
23/19 1(1.1) 1(1.1) 0(0) 0(0)
23/18 1 (11)
0 (0 ) 0(0) 0(0)
23/17 0(0) 1(1.1) 0(0) 0(0)
22/21 0(0) 1(1.1) 0(0) 1(1.0)
22/20 1(1.1) 0 (0 ) 0(0) 0(0)
22/19 2 (2.2) 1 ( l.l ) 3(3.3) 1(1.0)
22/17 0(0) 0 (0 ) 1(1.1) 0(0)
21/21 1 (11) 5(5.3) 0(0) 3(3.1)
21/20 I (1.1) 5 (5.3) 2(2.2) 4 (4.2)
21/19 7(7.7) 23 (24.5) 9(9.8) 16(16.7)
21/18 2 (2.2) 9(9.6) 0(0) 2(2.1)
21/17 1(1.1) 4 (4 .3 ) 0(0) 0(0)
21/16 3(3.3) 0 (0 ) 0(0) 0(0)
20/20 4 (4.4) 0 (0 ) 3(3.3) 5(5.2)
20/19 7(7.7) 13(13.8) 25 (27.2) 19(19.8)
20/18 9(9.9) 1(1.1) 2(2.2) 0(0)
20/17 0(0) 1 (1.1) 0(0) 1(10)
20/16 5(5.5) 0 (0 ) 0(0) 0(0)
20/15 0(0) 1(1.1) 0(0) 0(0)
19/19 13(14.3) 11(11.7) 37 (40.2) 37(38.5)
19/18 18(19.8) 7(7.5) 7(7.6) 4(4.2)
19/17 2 (2.2) 6 (6.4) 2 (2.2) 1(10)
19/16 2(2.2)
0 (0 ) 0(0) 0(0)
19/15 0(0) 0 (0 ) 0(0) 1(10)
19/11 0(0) 0 (0 ) 1(1.1) 1(10)
18/18 8 (8.8) 3(3.2) 0(0) 0(0)
18/17 1(1.1)
1 (1-1) 0(0) 0(0)
18/16 1(1.1) 0 (0 ) 0(0) 0(0)
17/16 1(1.1) 0 (0 ) 0 (0) 0(0)
No 19 39 (42.9) 32 (34.0) 8(8.7) 16(16.7)
One 19 39 (42.9) 51 (54.3) 47(51.1) 43 (44.8)
19/19 13(14.3) 11 (11.7) 37 (40.2) 37(38.5)
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23
Table 6. Risk o f breast cancer associated with IGF I (CA)n microsatellite genotype, by
racial/ethnic group
RACE GENOTYPE CA(%) CO(%) OR 95%CI* OR 95%CIb p-trend
African- No 19 24(30) 39(43) 1.00 1.00
American One 19 46(57) 39(43) 1.92 (0.99, 3.72) 2.00(1.00,4.00)
19/19 11(14) 13(14) 1.38 (0.53,3.56) 1.41 (0.52,3.82) 0.21
Japanese- No 19 27 (36) 32 (34) 1.00 1.00
American One 19 35 (46) 51(54) 0.81 (0.42, 1.59) 0.79 (0.39, 1.58)
19/19 14(18) 11(12) 1.51 (0.59, 3.87) 1.49 (0.57,3.89) 0.64
Non-Latino No 19 12(15) 8(9) 1.00 1.00
White One 19 26 (32) 47(51) 0.37(0.13, 1.02) 0.38(0.13, 1 08)
19/19 44 (54) 37 (40) 0.79 (0.29, 2.15) 0.83 (0.30, 2.29) 0.44
Latin- No 19 7 (9 ) 16(17) 1.00 1.00
Amencan One 19 46 (57) 43 (45) 2.44 (0.92, 6.52) 2.49 (0.91,6.83)
19/19 28(35) 37(39) 1.73 (0.63,4.77) 1.98 (0.70, 5.66) 0.46
All Races No 19 70 (22) 95 (26) 1.00 1.00
Combined One 19 153 (48) 180 (48) 1.15(0.79, 1.68) 1.12 (0.76, 1.66)c
19/19 97(30) 98(26) 1.34 (0.89,2.04) 1.41 (0.90, 2.21)1 0.13C
■ “ crude
badj usted for age and BMI as categorical variables
“ “ adjusted for age, BMI and race
IGF1 -T533C Genotype and Breast Cancer Risk
Suspecting that the 19 allele might be in linkage disequilibrium with a more pertinent
functional marker, perhaps within the nearby promoter region o f the gene, we
sequenced downstream o f the (CA) repeat towards the translation start site o f the gene
and found two single nucleotide polymorphisms. One was a single nucleotide
polymorphism (C“> T ) 291 bases downstream from the (CA)„ and 533 bases
upstream o f the transcription start site. The other was aT *> A single nucleotide
polymorphism 493 bases downstream o f the (CA)„and 331 bases upstream o f the
transcription start site. These two single nucleotide polymorphisms are in virtually
perfect linkage disequilibrium with each other (data not shown). We chose to study
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24
the C->T SNP at position -533 from the translation start site and set out to determine
if this SNP is in linkage disequilibrium with the 19 or other allele in (CA)„
dinucleotide repeat and whether this SNP might be a better predictor o f breast cancer
risk.
Table 7 shows the results of the case-control analysis for the -T533C genotype
and risk o f breast cancer. The TT genotype is non-significantly associated with risk
for high-stage breast cancer in African-Americans, Japanese-American and Non-
Latino Whites [OR.AA(adj ) = 1.38 (95% Cl 0.37, 5.25), ORM(adj.) = 1.61 (95% Cl
0.83, 3.10) and ORNLw(adj) = 1.39 (95% Cl 0.35, 5.54)]. Among Latin-Americans
the adjusted odds ratio was virtually null [OR^\(adj.) = 0.94 (95% Cl 0.43, 2.07)].
There is no evidence for departure from Hardy-Weinberg equilibrium in this -T533C
dataset.
To investigate the possibility o f linkage disequilibrium between the T to C
single nucleotide polymorphism at position -533 (-T533C) and the microsatellite
alleles we compared the (CA)„ repeat length among individuals who are homozygous
for the C or T allele o f -T533C (Figure 2). Figure 2 shows only the alleles belonging
to homozygote subjects because only among these do we know without doubt which
two alleles are linked. The C allele o f the -T533C SNP seems to be a marker for the
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25
21 repeat length, whereas the T is most frequently linked with (CA )i9 . Further support
for this arises upon subsequent analysis o f the heterozygotes. The majority o f the -
T533C heterozygote subjects (77% o f the 116 -T533C heterozygote subjects) have at
least one 21 allele.
Table 7. Risk o f breast cancer associated with IG Fl -T533C single nucleotide
polymorphism genotype, by racial/ethnic group
RACE GENOTYPE CA(%) CO(%) OR' (95%C1)* O R' (95%CI)b
African- TT 66 (94) 75(93) 1.32 (0.36,4.88) 1.38 (0.37, 5.25)
American Other 4(6) 6(7)
Japanese- TT 40(58) 36 (45) 1.69 (0.88, 3.23) 1.61 (0.83, 3.10)
American Other 29 (42) 44 (55)
Non-Latino TT 66 (94) 72 (92) 1.38 (0.37, 5.09) 1.39 (0.35,5.54)
White Other 4(6) 6 (8)
Latin- TT 51(75) 63 (77) 0.91 (0.43, 1.92) 0.94 (0.43, 2.07)
American Other 17(25) 19(23)
All Races TT 223(80) 244 (77) 1.26(0.85, 1.87) 1.31 (0.85,2.04)
Combined Other 54 (20) 73 (23)
' reference group is the 'Other' Category
"crude
b adjusted for age and BMI as categorical variables
"adjusted for age, BMI and race
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26
Figure 2. Comparison o f the (CA)n repeat length among individuals who are
homozygous for the C or the T allele o f -T533C
Homozygotes for C (left) and T (right) alleles
24
23
22
i
21 c
20
A C \
19
18
— -
17
■
16
■
15
14
13
12
11
Number of Alleles (each bar = 200 alleles)
Finally there is modest evidence for modest effect modification by -T533C
genotype on the association between (CA)„ microsatellite genotype and breast cancer
risk (Table 8). There is also weak evidence for effect modification in the other
direction, by the (CA)n genotype on the association between -T533C genotype and
breast cancer risk (data not shown). This table is particularly interesting in light o f the
fact that for all races and -T533C genotypes combined, the risk for breast cancer
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among those persons with at least one 19 allele is 1.21 (95% C l 0.83, 1.75). Thus
there appears to be a modest increased risk o f breast cancer associated with the 19
allele o f the (CA)n repeat. This effect seems to be further enhanced by linkage with
the T alleles o f -T533C as seen in Table 8. However because the C allele o f -T533C
so uncommon in Non-Latino Whites and African-Americans these results only apply
to the Japanese and Latina-Americans.
Table 8. Investigation o f the association between the IG F I (CA)„ microsatellite
genotype and breast cancer risk, tested for effect modification by the IGF I -T533C
single nucleotide polymorphism genotype
# Cases # Controls Adjusted OR* (95% Cl)
-T533C SNP Genotype = TT
C C A X , Genotvpe
Other 33(15) 48(20) 1.00
Any 19 190 (85) 198(80) 1.39 (0.83, 2.36)
-T533C SNP Genotype = Other
(Not TT)
(CAl, Genotvpe
Other 24 (44) 38(51) 1.00
Any 19 30 (56) 37 (49) 1.14 (0.54, 2.38)
p-interaction 0.87*
* OR and p-value adjusted for age, BMI and race as categorical variables.
Reference category for OR is Other'.
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28
DISCUSSION
In the current study we estimated associations between IGF1 phenotype and
genotype with postmenopausal breast cancer. This study is important in light o f
previous studies that have implicated IGF1 in breast carcinogenesis. W e hoped to
clarify the relationship between IGF1 and breast cancer using a multi-ethnic candidate
gene approach to identify a marker for circulating IGF 1 level and thus breast cancer
susceptibility. This multi-ethnic approach is a clear strength o f this w ork because it
allows us to assess the functionality o f polymorphisms by assessing the consistency of
associations across racial/ethnic groups. W e set out to determine whether there is a
racial/ethnic pattern to IGF I levels, whether this (CA)„ microsatellite polymorphism is
a marker for plasma IGF1 levels, and whether the polymorphism is a marker for breast
cancer susceptibility. We also investigated the possibility that the 19 allele o f this
polymorphism might be in linkage disequilibrium with an allele in a downstream
single nucleotide polymorphism (-T533C), and whether this might be a better
predictor for breast cancer risk or whether this genotype may modify the effect o f the
(CA)„.
Several prior epidemiological studies concerning circulating IGF1 levels have
provided evidence for an association between high IGF1 and breast cancer risk (5, 44).
However the subjects in these studies were o f restricted racial/ethnic background and
the effects were limited to premenopausal women. Relatively little is known about
how IGF1 effects breast cancer risk in postmenopausal women and even less is known
about the variation o f this effect across racial/ethnic groups. We were able to observe
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29
a strong racial/ethnic trend in plasma IGF1 levels. While there is a chance that this
may be a mere reflection o f lifestyle habits and not causally related to breast cancer
risk, this finding is interesting in light o f recent data from the M EC (Pike, in press).
Pike and colleagues have shown that the pattern o f breast cancer risk in the MEC
flows from Hawaiians at highest risk, through African-Americans, Japanese, Non-
Latina Whites to Latin-Americans, with Mexican-born Latinas at the low end. This
looks much like the pattern we found in mean plasma IGF1 level across racial/ethnic
group. Among the four major racial/ethnic groups comprising the Los Angeles-
Hawaii Multiethnic Cohort that were studied here, African-Americans are at the
highest risk for breast cancer, followed by Japanese-Americans, Non-Latino Whites
and Latin-Americans in order.
The (CA)n genotype frequencies were quite varied across races and the 19/19
only indicated low plasma IGF1 concentration, though not statistically significant, in
the group with the highest frequency o f the 19/19 homozygote, the Latin-Americans.
It is interesting to note that in this group o f 133 controls the 19/19 genotype was most
common genotype in Non-Latino and Latin-Americans. The 21/19 is the most
com mon genotype among Japanese-Americans and the 19/18 is the most common
am ong African-Americans. What is commonly referred to in the literature as the
common genotype at this locus is clearly not so in every racial/ethnic group. These
patterns held for the larger group o f subjects in our case-control analysis as well
(Tables 2 and 5).
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30
The results o f the case-control study, although not statistically significant,
showed that the (CA)i9 homozygote genotype might be associated with modest low
risk for breast cancer among the Non-Latino White population as we had hypothesized
based upon Rosen's publication (6). But the 19/19 genotype did not predict low breast
cancer risk in the other three racial/ethnic groups. In these groups and in all
racial/ethnic groups combined, the (CA)i9 allele appears to predict risk for rather than
protection from breast cancer.
This finding was enhanced by the addition o f the second SNP to the data. The
T allele of -T533C seems to slightly modify the risk effect o f the 19 allele in the two
groups for which the C is common. Because the C allele is so rare in Japanese and
Latinas it is impossible to generalize from those data. The inconsistency o f the
association between the 19 allele and breast cancer risk in the four ethnic groups
suggests that this is not the most relevant variant in this gene.
Between the (CA)„ and upon identification and investigation o f the second
SNP, the T->C polymorphism 533 bases upstream o f the ATG, we have found no
clear marker for breast cancer risk, either alone or as possible effect modifiers of each
other. The TT genotype o f this second polymorphism does seem to show more
consistency as a marker o f high breast cancer risk in the three racial/ethnic groups
excluding the Latin-Americans. This SNP will be further investigated in an expanded
case-control dataset. M oreover we will expand our investigation o f candidate genes in
the growth hormone-IGF pathway.
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31
W e decided to analyze these data as a nested case-control study rather than a
case-cohort design, which would be more appropriate. This was done because o f
problems attaining necessary variables. However, analytical work done by members
o f our group suggests that the case-cohort analyses would not have affected the results
substantially (Pearce, dissertation).
Due to the fact that we do not have pre-diagnostic bloods for all subjects in the
cohort, we were not able to perform a case-control analysis using plasma IGF1 values.
As part o f a newly funded project we intend to draw blood on everyone in the cohort
and thus we will be able in the future to perform such an analysis
The most important weakness o f the current study is the sample size. After
stratification by race and genotype numbers in some strata become quite small, a fact
that detracts from statistical power. Another important element o f this study is that
there is some difficulty in assigning high and low risk genotypes when dealing with
repeat polymorphisms. There is no good basis for deciding what is a high risk allele
and what is a low risk allele. Here we chose to follow the hypothesis that the 19 allele
was the potential low risk allele, but results o f analyses in which we categorized the
genotypes several different ways, were not significant.
There is also potential for random misclassification in genotyping. Although
there is some potential for random misclassification in genotype determination that
would bias our outcom e toward null, our careful control and checking process, plus
negative tests for departure from Hardy-Weinberg equilibrium provide some
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32
confidence in our genotyping. In order to preclude the potential problem o f
population stratification we stratified by race in each o f our analyses.
We have data on the IGF binding protein 3 (IGFBP3) levels in circulation,
however this data is not presented here. IGFBP3 has been shown to be an important
molecular regulator o f free IGF1 in the circulation (45). In investigating these data
using the molar ratio o f IGF1IGFBP3 in a preliminary analysis the outcom e did not
change.
We have data on some relevant covariates, including smoking, alcohol and
other lifestyle factors and plan to include these analyses in future studies. In summary
we have provided evidence that there are ethnic differences in IGF1 levels. There may
be an important variant in the IGFI gene that is responsible for these differences, but it
has not as yet been identified.
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33
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Am J Physiol Regulatory Integrative Comp Physiol, 280: R 1230-1239, 2001.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
35
21. Jones JI and Clemmons DR. Insulin-like growth factors and their binding
proteins: biological actions. Endocrine Reviews, 16:3-34, 1995.
22. Leong SR, Baxter RC, Camerato T, Dai J and Wood WI. Structure and functional
expression o f the acid-labile subunit o f the insulin-like growth factor-binding
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23 Guler HP, Z apf J, Schmid C and Froesch ER. Insulin-like growth factors I and II
in healthy man. Estimations o f half-lives and production rates. Acta
Endocrinologica, 121: 753-8, 1989.
24 Juul A, Main K, Blum WF, Lindholm J, Ranke MB and Skakkebaek NE. The
ratio between serum levels o f insulin-like growth factor (IGF)-I and the IGF
binding proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is
increased in acromegalic patients. Clinical Endocrinology, 41: 85-93, 1994.
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in cell growth, transformation and apoptosis. Biochimica et Biophysica Acta,
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36
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34. Maccario M, Ramunni J, Oleandri SE, Procopio M, G rottoli S, Rossetto R, Savio
P, Aimaretti G, Camanni F and Ghigo E. Relationships between IGF-I and
age, gender, body mass, fat distribution, metabolic and hormonal variables in
obese patients. International Journal o f Obesity & Related Metabolic
Disorders, 23: 612-8, 1999.
35. Westwood M, Gibson JM, Pennells LA and White A. Modification of plasma
insulin-like growth factors and binding proteins during oral contraceptive use
and the normal menstrual cycle. American Journal o f Obstetrics &
Gynecology, 180: 530-6, 1999.
36. Campagnoli C, Biglia N, Altare F, Lanza MG, Lesca L, Cantamessa C, Peris C,
Fiorucci GC and Sismondi P. Differential effects o f oral conjugated estrogens
and transdermal estradiol on insulin-like growth factor 1, growth hormone and
sex hormone binding globulin serum levels. Gynecological Endocrinology, 7:
251-8, 1993.
37. Elkas J, Gray K, Howard L, Petit N, Pohl J and A rm strong A. The effects o f
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regulation o f insulin-like growth factor binding protein-1 in patients with
polycystic ovary syndrome. Journal o f the Society for Gynecologic
Investigation, 2: 743-7, 1995.
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37
41. Carmina E, Gonzalez F, Vidali A, Stanczyk FZ, Ferin M and Lobo RA. The
contributions o f oestrogen and growth factors to increased adrenal androgen
secretion in polycystic ovary syndrome. Human Reproduction, 14: 307-11,
1999.
42. Lee LG, Connell CR and Bloch W. Allelic discrimination by nick-translation
PCR with fluorogenic probes. Nucleic Acids Research, 21: 3761-6, 1993.
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Comparative Biochemistry & Physiology - B: Comparative Biochemistry, 91:
229-35, 1988.
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between serum levels o f insulin-like grow th factor (IGF)-I and the IGF binding
proteins (IGFBP-1, 2 and 3) decreases with age in healthy adults and is
increased in acromegalic patients. Clinical Endocrinology, 41: 85-93, 1994.
Kelly PJ, Eisman JA, Stuart MC, Pocock NA, Sambrook PN and Gwinn TH.
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Leong SR, Baxter RC, Camerato T, Dai J and W ood WI. Structure and functional
expression o f the acid-labile subunit o f the insulin-like growth factor-binding
protein complex. Molecular Endocrinology, 6. 870-6, 1992.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
41
Liu JP, Baker J, Perkins AS, Robertson EJ and Efstratiadis A. Mice carrying null
mutations o f the genes encoding insulin-like grow th factor I (Igf-1) and type 1
IGF receptor (Igflr). Cell, 75: 59-72, 1993.
Maccario M, Ramunni J, Oleandri SE, Procopio M, Grottoli S, Rossetto R, Savio P,
Aimaretti G, Camanni F and Ghigo E. Relationships between IGF-I and age,
gender, body mass, fat distribution, metabolic and hormonal variables in obese
patients. International Journal of Obesity & Related Metabolic Disorders, 23:
612-8, 1999.
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determination o f IGF-1 levels in human plasma or serum, by extraction. In:
Diagnostics, ed. San Juan Capistrano, CA: Nichols Institute Diagnostics, 2000.
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plasma lipids, insulin-like growth factor I and blood pressure: a longitudinal
study. European Journal o f Clinical Investigation, 27: 322-6, 1997.
Pozios KC, Ding J, Degger B, Upton Z and Duan C. IGFs stimulate zebrafish cell
proliferation by activating MAP kinase and PI3-kinase-signaling pathways.
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530-6, 1999.
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
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DeLellis, Katherine Anne
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Insulin-like growth factor 1 genotype, phenotype and breast cancer risk, by racial/ethnic group
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Molecular Epidemiology
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