Genetic and Environmental Contributions to Reproductive Characteristics Open Access
Taylor, Kira Creswell (2009)
Published
Abstract
Abstract
Genetic and Environmental Contributions to Reproductive
Characteristics
By Kira C. Taylor
Reproductive traits such as age at menarche, menstrual function,
and perhaps
fertility are heritable, but few specific genes have been
identified that influence these
traits. This dissertation consists of five studies that evaluate
the effects of candidate
genetic and environmental influences and their interactions on
reproductive traits in
women. The first study examined the relative contributions of genes
and environment on
age at menarche and menstrual cycle length. These traits were
heritable, and heritability
varied across levels of an environmental exposure (polybrominated
biphenyls, PBBs).
PBB levels were also inversely associated with estradiol and
follicle stimulating hormone
levels in a subset of this population. Three candidate gene studies
were conducted in a
prospective cohort study of women office workers. Variation in the
progesterone receptor
gene was associated with age at menarche and menstrual cycle
length. Inhibin gene
polymorphisms were not associated with menstrual function. Heavy
alcohol use (>1
drink/day) and smoking were significant predictors of longer time
to pregnancy in this
population, but only among carriers of the "slow" acetylator
haplotype of the enzyme N-
acetyltransferase-2. This dissertation emphasizes the need to
incorporate genetic
information about metabolic enzymes when studying the effects of
xenobiotics on human
health. The results support the utility of candidate gene studies
when there is prior
evidence. This dissertation also adds to a growing body of
literature characterizing the
endocrine-disrupting properties of brominated flame retardants.
Table of Contents
TABLE OF CONTENTS
CHAPTER 1: INTRODUCTION AND
BACKGROUND................................................1
1.1 Introduction
............................................................................................1
1.2 Age at Menarche
......................................................................................1
1.2.1 Biology and Epidemiology
......................................................................1
1.2.2 Genetic Influences on Age at Menarche
...................................................5
1.2.3 The Progesterone Receptor: A Candidate Gene for Age at
Menarche .............8
1.3 Menstrual function
...................................................................................11
1.3.1 Biology and Epidemiology
.....................................................................11
1.3.2 Genetic Influences on Menstrual Function
...............................................13
1.4
Fecundability...........................................................................................13
1.4.1 Biology and Epidemiology
.....................................................................13
1.4.2 Genetic Influences
..............................................................................15
1.5 Summary
................................................................................................15
1.6 Figure
.....................................................................................................17
1.7 References
..............................................................................................18
CHAPTER 2: HERITABILITY OF AGE AT MENARCHE AND
MENSTRUAL
CYCLE LENGTH IN A POPULATION EXPOSED TO A BROMINATED
FLAME RETARDANT
........................................................................................31
2.1 Abstract
..................................................................................................31
2.2 Introduction
..............................................................................................33
2.3
Methods....................................................................................................35
2.3.1 Population
............................................................................................35
2.3.2 PBB Measurements
................................................................................36
2.3.3 Determination of Relatedness
..................................................................37
2.3.4 Determination of Shared
Household...........................................................37
2.3.5Covariates
............................................................................................38
2.3.6 Heritability Analyses
...............................................................................38
2.3.7 Determination of Heritability by Concentrations
of PBB Exposure .....................40
2.4 Results
.......................................................................................................41
2.5 Discussion
...................................................................................................42
2.6 Acknowledgments
.........................................................................................46
2.7 Figures and Tables
........................................................................................47
2.8 References
..................................................................................................54
CHAPTER 3: POLYBROMINATED BIPHENYL EXPOSURE
AND
REPRODUCTIVE HORMONE LEVELS
....................................................................58
3.1 Abstract
.....................................................................................................58
3.2 Introduction
................................................................................................60
3.3
Methods.......................................................................................................62
3.3.1 Population
..............................................................................................62
3.3.2 Exposure Assessment
...............................................................................63
3.3.3 Covariate Assessment
..............................................................................64
3.3.4 Assessment of Urinary Hormone Levels
.......................................................64
3.3.5 Analyses
................................................................................................65
3.4 Results
........................................................................................................66
3.5 Discussion
....................................................................................................69
3.6 Acknowledgments
..........................................................................................71
3.7 Figures and Tables
.........................................................................................73
3.8 References
...................................................................................................79
CHAPTER 4: INHIBIN POLYMORPHISMS AND MENSTRUAL
CYCLE
CHARACTERISTICS...83
4.1 Abstract
........................................................................................................83
4.2 Introduction
...................................................................................................85
4.3
Methods.........................................................................................................87
4.3.1 Population
................................................................................................87
4.3.2 Selection of Single Nucleotide Polymorphisms
..................................................88
4.3.3 DNA Extraction and Genotyping
....................................................................89
4.3.4 Menstrual Cycle Length Analysis
...................................................................89
4.3.5 Menstrual Cycle Variability Analysis
...............................................................90
4.4 Results
..........................................................................................................91
4.5 Discussion
......................................................................................................94
4.6 Acknowledgments
............................................................................................98
4.7 Figures and Tables
...........................................................................................99
4.8 References
....................................................................................................108
CHAPTER 5: ASSOCIATIONS OF PROGESTERONE
RECEPTOR
POLYMORPHISMS WITH AGE AT MENARCHE AND MENSTRUAL CYCLE
LENGTH............113
5.1 Abstract
........................................................................................................113
5.2 Introduction
...................................................................................................115
5.3
Methods.........................................................................................................116
5.3.1 Population
................................................................................................116
5.3.2 Selection of Single Nucleotide Polymorphisms
..................................................117
5.3.3 DNA Extraction and Genotyping
....................................................................118
5.3.4
Age at Menarche Analyses
...........................................................................119
5.3.5 Menstrual Function Analysis
.........................................................................121
5.4 Results
..........................................................................................................122
5.5 Discussion
......................................................................................................126
5.6 Acknowledgments
............................................................................................130
5.7 Figures and Tables
...........................................................................................131
5.8 References
.....................................................................................................144
5.9 Appendices
.....................................................................................................148
5.A The Daily Diary Used in the Mount Sinai Study of Women Office
Workers.................148
5.B Linkage Disequilibrium-Tagging SNPs in the Extended Gene Region
of PGR.................149
5.C SNPs and Primers Chosen for PGR Genotyping for the Beckman
SNPstream System.....152
5.D Genotyping Success According to DNA Concentration Cutoffs
...............................155
5.E Mean Age at Menarche According to Race and Ethnicity
......................................156
5.F Mean Age at Menarche During the Study Period According to Year
of Birth...............157
5.G Multiple Linear Regression Results for the Effect of the
rs1042838 Variant
(Homozygous TT vs. Other) on Age at Menarche
................................................158
5.H Distribution of Menstrual Cycle Lengths According to rs1042838
Genotype ..............159
CHAPTER 6: ASSOCIATIONS OF ALCOHOL, SMOKING, AND
CAFFEINE
WITH FECUNDABILITY: EFFECT MODIFICATIONS BY NAT2
........................................160
6.1 Abstract
.........................................................................................................160
6.2 Introduction
....................................................................................................162
6.3
Methods..........................................................................................................164
6.3.1 Population
.................................................................................................164
6.3.2 Exposure Information
..................................................................................165
6.3.3 NAT2
Genotyping.........................................................................................166
6.3.4 Analyses....................................................................................................168
6.4 Results............................................................................................................169
6.5 Discussion........................................................................................................173
6.6 Acknowledgments..............................................................................................178
6.7 Figures and Tables.............................................................................................180
6.8 References.......................................................................................................189
6.9 Appendices.......................................................................................................194
6.A Participation in MSSWOW and the Prospective Pregnancy Study..............................194
6.B Three SNPs genotyped in NAT2..........................................................................195
6.C Follow-Up Characteristics of Women Attempting Pregnancy and Women Not
Attempting Pregnancy..........................................................................................196
CHAPTER 7: DISCUSSION........................................................................................197
7.1 Discussion.........................................................................................................197
7.2 Future Directions.................................................................................................201
7.3 Conclusion.........................................................................................................202
7.4 References.........................................................................................................203
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