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HIF-1α gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy: a pilot triad-based case-control study

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HIF-1α gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy: a pilot triad-based case-control study

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HIF-1Α GENE POLYMORPHISMS AND RISK OF SEVERE-
SPECTRUM HYPERTENSIVE DISORDERS OF PREGNANCY:
A PILOT TRIAD-BASED CASE-CONTROL STUDY

By
Chen Wei

A Thesis presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirement for the Degree
Master of Science
APPLIED BIOSTATISTICS AND EPIDEMIOLOGY

December 2023

Copyright 2023 Chen Wei
ii

Table of Contents
List of Tables ......................................................................................... iii
Abstract .................................................................................................... 1
Chapter One: Introduction ........................................................................ 3
Chapter Two: Methods ............................................................................. 7
2.1 Subjects ......................................................................................... 7
2.2 Case Definition .............................................................................. 8
2.3 Chart Abstraction .......................................................................... 8
2.4 Questionnaire ................................................................................ 8
2.5 Selection of Gene Markers Polymorphisms .................................. 9
2.6 Sample Collection ......................................................................... 9
2.7 Statistical Analyses ....................................................................... 9
Chapter Three: Results ........................................................................... 12
Chapter Four: Discussion ....................................................................... 20
References .............................................................................................. 23

iii

List of Tables
Table 1: HIF-1a Single Nucleotide Polymorphisms Examined. ................................................................... 5
Table 2: Maternal Demographics and Clinical Characteristics Stratified by Case and Control Status. ..... 12
Table 3: Maternal and child carriage of HIF-1a polymorphisms and risk of HELLP syndrome and
preeclampsia with severe features. .............................................................................................................. 14
Table 4: Parent-of-Origin Effects in HIF-1a Polymorphisms and Risk of HELLP Syndrome and
Preeclampsia with Severe Features (Free Response Model) ...................................................................... 16
Table 5: Maternal and Child Carriage of HIF-1a Haplotypes and Risk of HELLP syndrome and
Preeclampsia with Severe Features. ............................................................................................................ 17
Table 6: Parent-of-Origin Effects for HIF-1a Haplotypes and Risk of HELLP Syndrome and Preeclampsia
with Severe Features. .................................................................................................................................. 18
Table 7: Percentage of Imputed Data Using the Expectation Maximization Algorithm by Case-Control
Status for Each Polymorphism. ................................................................................................................... 18

1

Abstract
Background: Hypoxia inducible factor 1 subunit alpha (HIF-1α) regulates cellular responses to
hypoxia by activating transcription of many downstream genes involved in angiogenesis, cell
proliferation, and survival. Overexpression of HIF-1α is associated with abnormal placental trophoblast
invasion and angiogenesis in Hypertensive Disorders of Pregnancy (HDP), as well as fetal growth
restriction. Our primary goal is to evaluate the putative association between polymorphisms and
haplotypes in parental and child HIF-1α genes and the risk of severe-spectrum HDP. Secondarily, we
evaluated the effects of a single-dose vs. double-dose of the variant allele and parent-of-origin
heritability using a free response genetic model.
Methods: Case (n = 179) and control (n = 34) mother-father-child triads were recruited
by an internet-based method. Medical records were reviewed to verify clinical diagnosis of self-
reported HDP cases and completed for 71% of cases. Severe HDP was defined as either HELLP
syndrome or preeclampsia with severe features. DNA was genotyped for four polymorphisms
in the HIF-1α gene using TaqMan assays: rs4902080, rs2057492, rs11549465, and rs10144958.
To examine the association between minor alleles and severe HDP, relative risks, and 95%
confidence intervals were estimated using log-linear models, adjusting for the correlation
between familial genotypes. Data were analyzed using the Haplin package from R.
Results: We found that polymorphisms in the gene for HIF-1α are associated with
severe HDP in a Caucasian population. We observed an increased relative risk for HDP with
double dose carriage of the T allele for SNP rs4902080 in both the mother [6.96 (1.24,38.60),
p=0.028] and child [5.77 (1.18, 29.20), p=0.031] as well as increased relative risk among
children carrying a double dose of the T allele for SNPrs10144958 [5.52 (1.04, 30.70),
2

p=0.047]. The C allele for SNPs rs2057482 and rs11549465 was found to be decreased relative
risk for HDP in a single dose model when carried by either mother [rs2057482: 0.34
(0.28,0.54), p<0.001]; rs11549465: 0.23 (0.14,0.38), p<0.001] or child [rs2057482: 0.44 (0.28,
0.68), p<0.001; rs11549465: 0.31 (0.19, 0.50)]. We did not observe parent-of-origin (POO)
effects as both maternal and paternal C alleles for SNPs rs2057482 and rs11549465 decreased
relative risk of severe HDP. However, we did observe that, for double carriers of the rs4902080
T allele, there was an increased relative risk of HELLP+sPE [6.93 (1.36, 35.20), p=0.020].
Among those carrying a single copy of the C-c-c-G haplotype (rs4902080- rs2057482-
rs11549465- rs10144958) (n=147), there was decreased relative risk compared to the C-T-T-G
haplotype in both the mother [0.28 (0.16, 0.50), p<0.001] and child [0.36 (0.20, 0.63), p<0.001].
There was no evidence of a POO effect in either individual variants or haplotypes.
Conclusions: Our results demonstrate that polymorphism changes and haplotypes in the
HIF-1α gene of mothers, fathers, and children are associated with the risk of severe-spectrum
hypertensive disorders of pregnancy in a Caucasian population.

3

Chapter One: Introduction
Hypertensive Disorders of Pregnancy (HDP) occurs in 3-5% of all pregnant women [1]
and can have severe short- and long-term consequences for both mother and child. Specifically,
short-term complications in mothers include multi-organ dysfunction, placental abruption,
seizures, and death [1]–[4]. In turn, their newborns are frequently growth-restricted and/or
premature, with associated complications including neonatal ICU admission and low birth
weight [5], [6]. Survivors of HDP have an increased long-term risk of cardiovascular disease
[7] while children born out of affected pregnancies have more neurologic and metabolic disease
than children resulting from healthy pregnancies [8] More specifically prenatal exposure to
HDP increases risk for Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder,
and epilepsy [9].
Despite extensive research, the pathogenesis of HDP is poorly understood. A better
understanding of the underlying mechanisms contributing to HDP may lead to improved
preventive or therapeutic treatments[1], [10]. Because HDP is mechanistically heterogeneous, it
is necessary to understand the unique underlying pathways through which a particular woman
has developed HDP. Thus, we focus here on genetic predisposition toward HDP and genes
which impact placental invasion. Shallow trophoblast invasion is a hallmark of HDP [11], [12]
and pregnant women with severe-spectrum disease are more likely to suffer from placental
under-invasion than women who have healthy pregnancies [13] or even less severe HDP [14]. A
number of studies have suggested a possible association between chronic fetal
hypoxia, increased uteroplacental vascular resistance and the placental dysfunction that results
from HDP [15], [16].
Hypoxia inducible factor alpha (HIF-1α) is overexpressed in preeclamptic placentae
4

[17]–[19] and is involved in regulating downstream gene expression in response to changes in
oxygen levels [20], [21]. As a transcription factor located on human chromosome 14q21-q24, it
encodes for 15 exons, resulting in a principal transcript of about 8 kb [22]. In addition to its role
in regulating downstream genes, HIF-1α protein levels are also known to suppress trophoblast
invasion and angiogenesis [23] through regulation of pro-angiogenic factors including vascular
endothelial growth factor (VEGF) [24] ，soluble fms-related tyrosine kinase 1 (sFLT1) [25],
transforming growth factor beta-3 (TGFβ3) [26], [27], and Placental Growth Factor 1 (PIGF1)
[28] among others. HIF-1α also plays a role in placental cell fate [29]. HIF-1α is upregulated
under hypoxic conditions[30]. Mouse models have demonstrated that prolonged expression of
trophoblast-specific HIF-1α leads to a significant decrease in fetal birth weight and placental
abruption in differentiation such as reduced branching morphogenesis and failure to remodel the
maternal spiral arteries, similar to those observed in HDP [11].
Alterations in HIF-1α gene polymorphisms are associated with a variety of human
pathological conditions. Specifically, single nucleotide polymorphisms (SNPs) in HIF-1α have
been associated with treatment response in immune thrombocytopenia (ITP) [31], poor
progression free survival in non-small cell lung cancer [32], cancer susceptibility including lung
cancer [33] as well as Gastrointestinal tract [34], late onset Parkinson’s disease [35], knee
osteoarthritis [36], treatment response in myocardial infarction (MI) [37], and susceptibility to
perimenopausal coronary artery disease (CAD) [38]. Polymorphisms in HIF-1α have been
found to be associated with early onset HDP in Sinhalese women who delivered small for
gestational age infants [39]. However, no association was observed for HIF-1α polymorphisms
and HDP among Korean [40], Mexican [41] and Finnish [42] populations. Harati-Sadegh et al.
found no association with HDP for maternal HIF-1α polymorphisms but an increased risk for
5

HDP association with placental (fetal) double or single copy of the T allele in rs11549465 [19].
Current literature examines primarily maternal susceptibility associated with specific
single nucleotide polymorphisms (SNPs) [39]–[42], although it would be expected that
placental/fetal genotype may also be an important factor [19]. An Imprinting and parent-of-
origin effects [43] of the HIF-1α gene has not yet been determined and may also contribute to
HDP risk. The primary aim of this study is to evaluate the putative association between HIF 1-α
polymorphisms and haplotypes in all triad members and risk of severe-spectrum HDP.
Secondarily, we will evaluate the effects of a single-dose vs. double-dose of the variant allele,
examine both multiplicative and free-response genetic models, and parent-of-origin effects.
Table 1: HIF-1a Single Nucleotide Polymorphisms Examined.
Single
Nucleotide
Polymorphism
(rs#)
Position Consequence Allee
Change
Synonymous vs.
Nonsynonymous
Significant
Association
rs4902080 chr14:61741287
(GRCh38.p14)
HIF-1𝑎 :
Intron Variant
T>C Not applicable None
rs2057482 chr14:61747130
(GRCh38.p14)
HIF-1𝑎 :
Intron Variant
C>T Not applicable Mediation of
lipids in
myocardial
infarction [37]

Perimenopausal
CAD [38]
rs11549465 chr14:61740839
(GRCh38.p14)
HIF-1𝑎 :
Missense
Variant
C>T missense
variation
nonsynonymous
(Pro582Ser)
Treatment
response in
immune
thrombocytopenia
[31]

Lung cancer [33]

Digestive cancer
[34]
Late onset
Parkinson’s
disease [35]

6

Knee
osteoarthritis [36]

Preeclampsia [19],
[39]
rs10144958 chr14:61691980
(GRCh38.p14)
HIF-1𝑎 :
Intron Variant
G>T Not Applicable None

7

Chapter Two: Methods
2.1 Subjects
This triad-based (mother-father-baby) case-control study included 213 triads (179 cases and 34
controls), resulting in 605 samples (96 controls and 509 cases) available for analysis (sample size varies
between SNPs). Cases were women with self-identified HELLP syndrome who were subsequently
verified by medical record abstraction (71% verified). Participants were recruited online from one of
two HELLP-focused websites (www.hellpsyndromesociety.org or
https://www.facebook.com/pages/Hellp-Syndrome-Research-at-USC/163745723652843). Controls
were friends of participants who had a child within 5 years of the index pregnancy and reported having
had an unaffected pregnancy.
All study participation occurred via email or the postal service. Interested women
contacted the Principal Investigator (MLW) to learn more about the study. Those who opted to
participate were mailed the consent forms, questionnaires, and saliva-based DNA sample
collection kits (DNA GenoTek, Ottawa, Canada). Paid self-addressed envelopes were included
in the study packet. Participants were contacted via email to review the informed consent prior
to enrollment and were given the opportunity to ask questions. Consent was obtained for
affected and unaffected women, their partners, maternal grandparents, and the index child.
Samples from mothers, fathers, and children were included in this study.
Women under the age of 18 were not included; no other exclusion criteria were applied.
This study was approved by the University of Southern California (USC) Health Science
Campus (HSC) Institutional Review Board (HS-06-00111). Informed consent was obtained for
all study participants providing samples and/or questionnaire data.

8

2.2 Case Definition
Cases were classified as HELLP syndrome if medical records were available to confirm
the following criteria: hemolysis (schistocytes, burr cells, or LDH > 600); elevated levels of liver
enzymes (AST > 70 and/or ALT > 70); and low platelet count (platelets < 100 K). Those
participants meeting two of the three criteria were classified as having severe-spectrum HDP.
Women with significant hypertension (≥160/110 on two occasions, at least 6 hours apart) and
proteinuria (500 mg/dL/24 h or +3 dipstick on two occasions, at least 6 hours apart) were also
classified as having severe PE, with or without abnormal laboratory measurements. Last, women
for whom all necessary laboratory assays to confirm HELLP syndrome were not available were
classified as having severe-spectrum HDP. Of the 127 (71%) case charts that were reviewed, all
were verified to have at least severe spectrum HDP.
2.3 Chart Abstraction
Medical records were requested from the delivery hospital and obstetrician who
provided prenatal care for all cases. One of the investigators (MLW) reviewed available medical
records to confirm each diagnosis. Records were abstracted using a standardized data
abstraction form, which included information about prenatal visits, comorbidities, obstetric
history, and delivery.
2.4 Questionnaire
All participants completed a standardized risk factor questionnaire, which included
questions about their medical history, reproductive and sexual history, family history, and the
affected pregnancy.

9

2.5 Selection of Gene Markers Polymorphisms
We selected the following four single nucleotide polymorphisms (SNP) within the HIF-1𝛼
gene: rs4902080, rs2057492, rs11549465, and rs10144958. Table 1 provides details on the four
selected SNPs. Each SNP selected exhibited at least one of the criteria below:
1. Known to be functional, based on published functional data.
2. Associated with an outcome in one or more peer-review publications.
3. Located in a coding region of the gene and results in a non-synonymous amino acid
substitution.
4. Located in a non-coding region or regulatory region of the gene.
5. Located in an intronic region, which is evolutionarily conserved between placental
mammals and humans.
2.6 Sample Collection
DNA samples were collected via buccal swabs (n=127) or saliva (n=478) (DNA Genotek,
Ottawa, Canada). The DNA sampling method did not affect the genotyping failure rate.
Samples obtained from buccal swabs were extracted using QIAamp DNA Mini kits, per the
manufacturer’s protocol (Qiagen, Valencia, CA). Saliva samples were extracted using ethanol
precipitation, per the manufacturer’s protocol (DNA Genotek, Ottawa, Canada). Genotyping
was performed using TaqMan assays (7900HT Sequence Detection System, Applied
Biosystems, Foster City, California, USA). A detailed protocol and outline of laboratory
techniques have been described previously [44].
2.7 Statistical Analyses
Demographic and clinical characteristics are presented as mean and standard deviation for
numeric variables with normal distribution, count with frequency for categorical variables and
10

medians for numeric variables without normal distribution, stratified according to case or
control status. We used a log-linear method, implemented in the R package Haplin [45] to
analyze case parent–triad data. Weinberg et al. described this log-linear method as based on a
maximum likelihood of case-parent-triad data, with stratification of the parental mating type
[46]. Haplin is a flexible and robust software for genetic epidemiological analyses that
implements log-linear models to estimate relative risks (RR), 95% confidence intervals, and
tests the null hypothesis of RR = 1 [45]. Haplin estimates the effect for single or double
alleles, free-response and multiplicative dose-response models, and derives likelihood ratio
𝑋 2
tests (LRTs) of linkage disequilibrium (LD) [47]. The unknown phase of haplotypes and
missing samples (father or child) were accounted for by the Expectation-Maximization (EM)
algorithm implemented in Haplin [45], [48].
We estimated single- and double-dose effects for mothers, fathers, and babies. We also
evaluated free response and multiplicative models, assessed haplotypes, and evaluated parent-
of-origin (POO) effects. Only the free response models are presented since the multiplicative
models assume double dose and single dose are functionally linked, and thus deemed
inappropriate for evaluating the effects of a single-dose vs. double-dose of the variant allele
independently [47]. A sensitivity analysis was conducted to examine the impact of imputed
genotypic information by re-running the analysis excluding imputed data. We found no
substantive differences when excluding imputed data and therefore, we present the results with
imputations to preserve sample size. All SNPs had less than 10% imputed data. Imputed
percentage by SNP is presented in Table 7.
The most common allele and haplotype were used as the referent groups for all RRs. The
effects of single-dose (heterozygous) and double-dose (homozygous) variant alleles and
11

haplotypes were estimated. Rare haplotypes (frequency <5%) were excluded from analysis,
resulting in a comparison of two haplotypes. A two-sided significance level of α=0.05 was used.
All analyses were conducted using R software (version 4.2.2)[49].
Further details on the Haplin package are available on CRAN (https://cran.r-
project.org/web/packages/Haplin/index.html) and the manual is available on the following
website https://cran.r-project.org/web/packages/Haplin/Haplin.pdf. This study was conceived as
a pilot study and thus, no a priori power calculation was made.

12

Chapter Three: Results
A total of 179 self-identified case triads (509 cases) and 34 control triads (96 controls) were
included in the study (Figure 1). Among the cases, only the index child was included in the
analysis when samples were available for more than one child. Medical records were reviewed
for 71% (n=127) of cases and all confirmed diagnosis of severe-spectrum PE or HELLP
Syndrome. Among the cases, 72.1% (n=129) were classified as pre-eclampsia with severe
features, and 27.9% (n=50) were HELLP syndrome. All self-reported but unverified cases
(n=52, 29%) were considered to have severe-spectrum HDP since all reviewed cases met at
least that definition. Table 1 provides details on the four selected SNPs.
Maternal demographics and clinical characteristics are presented in Table 2. The average
maternal age among controls was 32.3 ± 3.9 and 31.1 ± 4.0 among cases. Almost all cases and
controls were white (98.4% and 100%, respectively). Gestational age at delivery was lower in
cases than controls (33.0 ± 4.5 vs. 39.6 ± 1.7, respectively. A higher proportion of cases were
nulliparous (88.4%) vs. controls (50%). Among cases, there was a notable clinical elevation in
lactate dehydrogenase [Median: 601.5 (IQR: 337.0- 1306.3)], aspartate aminotransferase
[Median: 253.0 (IQR:115.3- 447.5)], alanine aminotransferase [204.0 (IQR:117.0- 354.0)], and
a decrease in platelets (60.0 (37.0, 99.5)). Infant birthweight among cases indicated a decrease
compared with the normal range (1942.5 (1181.5, 2786.5)).
Table 2: Maternal Demographics and Clinical Characteristics Stratified by Case and Control
Status.
variable
1
N
2
Control (n=34) N
2
Case (n=179)

Age (years) 29 32.3 ± 3.9 131 31.1 ± 4.0
White race (%) 30 30.0 (100.0) 128 126.0 (98.4)
13

Gestational age at delivery
(weeks)
22 39.6 ± 1.7 125 33.0 ± 4.5
Pre-pregnancy weight (lbs) – _ 108 149.9 ± 33.0
Nulliparity (%) 26 129
Nulliparous 13.0 (50) 114.0 (88.4)
Parous 13.0 (50) 15.0 (11.6)
Parity 24 120
0 11(45.9) 107.0 (89.1)
1 8 (33.3) 8.0 (6.7)
2 or more 5 (20.8) 5 (4.2)
Gravidity 24 121
1 11.0 (45.8) 91.0 (75.2)
2 6.0（25.0 ） 21.0 (17.4)
3 4.0（16.7 ） 5.0 (4.1)
4 or more 3.0（12.5 ） 4.0 (3.3)
Status NA 179
Severe PE _ 129 (72.1)
HELLP Syndrome _ 50 (27.9)
Lactate dehydrogenase,U/L NA _ 64 601.5 (337.0, 1306.3)
Bilirubin, mg/dL NA _ 84 0.9 (0.5, 2.0)
Aspartate
aminotransferase,U/L
NA _ 112 253.0 (115.3, 447.5)
Alanine
aminotransferase,U/L
NA _ 105 204.0 (117.0, 354.0)
Creatinine(mg/dL) NA _ 96 0.8 (0.7, 1.0))
14

Platelet count,per U/L NA _ 113 60.0 (37.0, 99.5)
Birthweight,g NA _ 106 1942.5 (1181.5, 2786.5)
Fetal growth restriction(%) NA _ 118 11.0 (9.3)
Gestational diabetes(%) NA _ 118 8.0 (6.8)
1
Numeric variables are presented as mean (SD) or median (IQR) while categorical variables are
presented as count (frequency)
2
Chart abstractions were completed only for cases; 71% (n=127) of cases were confirmed via
review.

Table 3 presents the maternal and fetal effects of each HIF-1𝑎 SNP for single and
double dose in a free response model; multiplicative models were not significant. We found a
statistically significant increase in risk with carriage of the T allele for SNP rs4902080 in both
maternal [6.96 (95% CI: 1.24, 38.6), p=0.028] and child [5.77 (95% CI: 1.18,29.20), p=0.031]
genotypes in the double dose model, but not the single dose model. We also observed a
statistically significant reduction in risk associated with carriage of the C allele for SNP
rs2057482 in both maternal [0.34 (95% CI: 0.28,0.54), p<0.001] and child [0.44 (95% CI: 0.28,
0.68), p<0.001] samples in the single dose model, but not the double dose model. Carriage of
the C allele for SNP rs11549465 was associated with a significant reduction in risk among both
maternal [0.23 (95% CI: 0.14, 0.38), p<0.001] and child [0.31 (95% CI: 0.19, 0.50), p<0.001]
genotypes in the single dose model only. Lastly, carriage of the T allele in children was
significantly associated with increased risk of HDP for SNP rs10144958 [5.52 (95% CI: 1.04,
30.70), p=0.047] in the double dose model only; the maternal genotype for this SNP was not
significantly associated with HDP.

Table 3: Maternal and child carriage of HIF-1a polymorphisms and risk of HELLP syndrome
15

and preeclampsia with severe features.
SN
P
Min
or
allel
e
Maternal Child
Minor
Allele
Frequen
cy
(%)
Single
dose RR
(95%
CI)
P-
valu
e
Double
dose
RR
(95%
CI)
P-
value
Minor
Allele
Freque
ncy
Single
dose RR
(95% CI)
P-
value
Double
dose RR
(95%
CI)
P-
valu
e
rs4
902
080
T 4.2 1.29
(0.63,
2.62)
0.49 6.96
(1.24,
38.6 ）
0.028 4.7 0.73
(0.34,
1.57)
0.425 5.77
(1.18,
29.20)
0.03
1
rs2
057
482
C 40.8 0.34
(0.28,
0.54)
<0.0
01
1.23
(0.66,
2.28)
0.505 39.2 0.44(0.28,
0.68)
<0.0
01
1.08
(0.56,
2.08)
0.82
7
rs1
154
946
5
C 40.9 0.23
(0.14,
0.38)
<0.0
01
1.05
(0.54,
2.04)
0.891 38.5 0.31
(0.19,
0.50)
<0.0
01
1.29
(0.66,
2.57)
0.46
3
rs1
014
495
8
T 5.0 0.72
(0.35,
1.45)
0.35
8
1.91
(0.23,
17.50)
0.549 5.0 1.06
(0.51,
2.17)
0.875 5.52
(1.04,
30.70)
0.04
7

Fetal effects of each SNP for single and double dose with POO effects is presented in
Table 4. We found a statistically significant association among the children for rs4902080 [6.93
16

(95% CI: 1.36, 35.20), p=0.020] in the double dose model, indicating an increase in risk
associated with carriage of TT genotype. We also observed a statistically significant association
for SNP rs2057482 paternal samples in the single doses model [0.43 (95% CI: 0.25, 0.72),
p=0.001] and a borderline significant association among maternal samples [0.46 (95% CI: 0.20,
1.06), p=0.068], indicating a protective effect associated with C allele. There was a statistically
significant association for rs11549465 in both maternal [0.17 (95% CI: 0.06, 0.50), p=0.001]
and paternal [0.37 (95% CI: 0.22, 0.64), p<0.001] samples in the single dose model, which
indicated a protective effect associated with C allele. We did not find an association between
rs10144958 and HELLP+sPE in either single or double dose models.
The association between maternal and child haplotypes and HELLP+sPE is presented
in Table 5. For both maternal [0.28 (95% CI: 0.16, 0.50), p<0.001] and child [0.36 (95% CI:
0.20, 0.63), p<0.001] samples, we found a reduced risk of HELLP+sPE among carriers of the
C-c-c-G haplotype compared to the C-T-T-G haplotype in the single dose but not the double
dose model. When evaluating POO effects, we observed a reduction in risk for both maternal
[0.28 (95% CI: 0.09, 0.89), p=0.028] and paternal samples [0.39 (95% CI: 0.20, 0.75), p=0.004]
in single dose, but not double dose models, suggesting no POO effects for this haplotype.
Table 4: Parent-of-Origin Effects in HIF-1a Polymorphisms and Risk of HELLP Syndrome and
Preeclampsia with Severe Features (Free Response Model)
Child
SNP Mino
r
allele
Samp
le
Size
N
Maternal
RR
(95% CI)
p-value Paternal
RR
(95% CI)
p-value Double dose
RR (95% CI)
p-value
17

rs49020
80
T 213 1.32
(0.42,
4.22)
0.628 0.39
(0.10,
1.41)
0.147 6.93
(1.36, 35.20)
0.020
rs20574
82
C 213 0.46
(0.20,
1.06)
0.068 0.43
(0.25,
0.72)
0.001 1.09
(0.52, 2.34)
0.831
rs11549
465
C 213 0.17
(0.06,
0.50)
0.001 0.37
(0.22,
0.64)
<0.001 0.91
(0.39, 2.13)
0.824
rs10144
958
T 213 0.64
(0.18,
2.28)
0.495 1.37
(0.56,
3.32)
0.495 4.80
(0.87, 25.60)
0.072

Table 5: Maternal and Child Carriage of HIF-1a Haplotypes and Risk of HELLP syndrome and
Preeclampsia with Severe Features.
Haplot
ype
Freq
uenc
y (%)
Maternal Child
Single
dose RR
(95% CI)
P-
value
Double
dose RR
(95% CI)
P-
value
Single dose
RR (95%
CI)
P-
value
Double
dose RR
(95% CI)
P-
value
RS4902090- RS2057482- RS11549465- RS10144958 (N=147)
18

C-T-T-
G
58.9 REF REF 0.34
8
REF REF 0.731
C-c-c-
G
41.1 0.28
(0.16,
0.50)
<0.0
01
1.2
(0.55,
2.60)
0.64
8
0.36
(0.20, 0.63)
<0.0
01
1.13
(0.51, 2.55)
0.765

Table 6: Parent-of-Origin Effects for HIF-1a Haplotypes and Risk of HELLP Syndrome and
Preeclampsia with Severe Features.
Child
Haploty
pe
Frequenc
y (%)
Maternal RR
(95% CI)
P-value Paternal
RR (95%
CI)
P-value Double
RR(95% CI)
p-value
RS4902090- RS2057482- RS11549465- RS10144958 (N=147)
C-T-T-
G
59.3 REF REF REF
C-c-c-G 40.7 0.28
(0.09, 0.89)
0.028 0.39
(0.20, 0.75)
0.004 0.99
(0.38, 2.65)
0.988

Table 7: Percentage of Imputed Data Using the Expectation Maximization Algorithm by Case-
Control Status for Each Polymorphism.
19

Imputed N (%)
rs4902080 rs2057482 rs11549465 rs10144958
Case (N= 509) 12 (2.4%) 29 (5.7%) 22 (4.3%) 22 (4.3%)
Control (N =
96) 4 (4.2%) 7 (7.3%) 6 (6.3%) 9 (9.4%)

All (N = 605) 16 (2.6%) 36 (6.0%) 28 (4.6%) 31 (5.1%)

20

Chapter Four: Discussion

We found that polymorphisms in the gene for HIF-1𝛼 are associated with the development of
HELLP+sPE in a Caucasian population for maternal, paternal, and child samples. Specifically, risk of
HELLP+sPE was increased with carriage of the T allele (rs4902080) among both mothers and children
carrying a double copy of the allele. A reduction in risk was noted with carriage of a single C allele for
rs2057482 and rs11549465 in both mothers and children and an increase in risk of HELLP+sPE was
observed among children carrying a double dose of the T allele (rs10144958). The haplotype C-c-c-G
was noted to decrease the risk of HELLP+sPE for both mothers and children carrying a single copy
compared to the C-T-T-G haplotype. No POO effects were observed for either individual SNPs or
haplotypes, as both maternal and paternal copies were associated with the risk of being a case.
Several studies have examined the effect of maternal genotype for rs1154965. In contrast to
our findings, there was no association with HDP in either Finnish [42] Mexican [41], or Korean [40]
populations, possibly owing to limited statistical power. Consistent with our findings, a study of
Sinhalese women reported a decrease in risk associated with carriage of a single T allele in women
who developed early-onset HDP and who delivered a small-for-gestational-age infants (OR=0.3 (95%
CI: 0.1, 0.7), p=0.003) [39]. Last, Harati-Sadegh et al. found that carriage of at least one T allele
significantly increased the risk of HDP and the TT genotype was associated with increased HIF-1𝛼
expression in women with HDP [19] None of the other polymorphisms we studied have been
examined with respect to HDP risk.
HIF-1α is a vital component of the cellular oxygen-sensing machinery, is a major regulator of
trophoblast differentiation [11], and orchestrates the transcriptional activation of over 100 downstream
genes that govern essential processes for tumor and trophoblast cell survival, progression, invasion,
and angiogenesis [20]. Our observation that the CT genotype of variants rs2057482 and rs11549465
21

reduces the risk of HELLP+sPE may suggest that these variants could lead to increased HIF1-𝛼
expression, or improved transcriptional activity, thereby promoting angiogenesis and placental
invasion [16]–[18], both of which are central factors in the pathogenesis of PE [1]–[4], [11], [16].
In addition, confidence intervals for double dose effects were wider likely due to lower
sample size in these groups and thus potential inability to reach statistical significance even if a
biological effect exists (Type II error). Thus, a small number of participants carrying a double
dose of the variant can make estimates of double versus single dose unstable [50]. Furthermore,
we noted that, for some variants, we found that the single dose altered the risk of HELLP+sPE
whereas the double dose of the variant allele did not. One possible explanation is a maternal-fetal
interaction or an imprinted gene effect. In this case, a single copy of the SNP in the fetus might
trigger a maternal response that increases the risk of HELLP and PE, but having two copies in the
fetus doesn't further alter the maternal response [51].
This study has several limitations. First, two (rs2057482 and rs11549465) of the four
SNPs investigated showed deviations from hardy weinberg equilibrium [52] (HWE), which may
indicate mating selection, inbreeding, or other factors [53]. However, deviations from HWE can
also be caused by maternal-fetal interactions [50] since they increase the complexity of the genetic
model and can lead to inaccurate estimation of variant frequency and distribution. As we would
expect the maternal and fetal genomes to interact in a genomically complex condition such as
pregnancy, maternal-fetal interaction may explain deviations from HWE. Second, we could only
obtain records to confirm 71% of the cases’ diagnosis, though all reviewed charts confirmed a
diagnosis of at least severe-spectrum HDP. Thus, unconfirmed cases who were classified as
severe-spectrum HDP may have been cases of HELLP Syndrome and thus, misclassified.
However, since all severe cases were combined in this analysis, there should have been no
22

substantive impact on our results. Similarly, we did not perform chart reviews on controls; all
self-reported not having experienced HDP in their matched pregnancy. If some women with HDP
were inadvertently included in the control group, the resulting RR would be attenuated.
Additionally, our population was almost entirely Caucasian, thereby limiting the generalizability
of our results to other populations. Last, we recruited participants online and all affected women
do not have equal internet access. Thus, our population also had a higher socioeconomic status
(SES) than the overall population of women with HDP.
The study also has several strengths. First, it encompasses the assessment of mother-
father-baby triads, enabling the estimation of genetic influences for each family member and
allowing for the examination of POO effects. In addition, while we were unable to obtain records
for all cases, the fact that, for the 71% of cases with available medical records, all were verified
to have a diagnosis of either severe-spectrum HDP or HELLP Syndrome and therefore were
considered severe HDP. Future studies should include a larger sample size from a more diverse
population and verification of case-control status for all participants.
In conclusion, polymorphisms within the HIF-1α gene appear to be associated with risk
of severe-spectrum HDP in both mother and child samples. These findings suggest a possible
maternal-fetal interaction, though our sample size was insufficient to model this effect. No POO
effects were observed.

23

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Abstract (if available)

Abstract Background: Hypoxia inducible factor 1 subunit alpha (HIF-1α) regulates cellular responses to hypoxia by activating transcription of many downstream genes involved in angiogenesis, cell proliferation, and survival. Overexpression of HIF-1α is associated with abnormal placental trophoblast invasion and angiogenesis in Hypertensive Disorders of Pregnancy (HDP), as well as fetal growth restriction. Our primary goal is to evaluate the putative association between polymorphisms and haplotypes in parental and child HIF-1α genes and the risk of severe-spectrum HDP. Secondarily, we evaluated the effects of a single-dose vs. double-dose of the variant allele and parent-of-origin heritability using a free response genetic model.

Methods: Case (n = 179) and control (n = 34) mother-father-child triads were recruited by an internet-based method. Medical records were reviewed to verify clinical diagnosis of self-reported HDP cases and completed for 71% of cases. Severe HDP was defined as either HELLP syndrome or preeclampsia with severe features. DNA was genotyped for four polymorphisms in the HIF-1α gene using TaqMan assays: rs4902080, rs2057492, rs11549465, and rs10144958. To examine the association between minor alleles and severe HDP, relative risks, and 95% confidence intervals were estimated using log-linear models, adjusting for the correlation between familial genotypes. Data were analyzed using the Haplin package from R.

Results: We found that polymorphisms in the gene for HIF-1α are associated with severe HDP in a Caucasian population. We observed an increased relative risk for HDP with double dose carriage of the T allele for SNP rs4902080 in both the mother [6.96 (1.24,38.60), p=0.028] and child [5.77 (1.18, 29.20), p=0.031] as well as increased relative risk among children carrying a double dose of the T allele for SNPrs10144958 [5.52 (1.04, 30.70), p=0.047]. The C allele for SNPs rs2057482 and rs11549465 was found to be decreased relative risk for HDP in a single dose model when carried by either mother [rs2057482: 0.34 (0.28,0.54), p<0.001]; rs11549465: 0.23 (0.14,0.38), p<0.001] or child [rs2057482: 0.44 (0.28, 0.68),p<0.001; rs11549465: 0.31 (0.19, 0.50)]. We did not observe parent-of-origin (POO) effects as both maternal and paternal C alleles for SNPs rs2057482 and rs11549465 decreased relative risk of severe HDP. However, we did observe that, for double carriers of the rs4902080 T allele, there was an increased relative risk of HELLP+sPE [6.93 (1.36, 35.20), p=0.020]. Among those carrying a single copy of the C-c-c-G haplotype (rs4902080- rs2057482- rs11549465- rs10144958) (n=147), there was decreased relative risk compared to the C-T-T-G haplotype in both the mother [0.28 (0.16, 0.50), p<0.001] and child [0.36 (0.20, 0.63), p<0.001]. There was no evidence of a POO effect in either individual variants or haplotypes.

Conclusions: Our results demonstrate that polymorphism changes and haplotypes in the HIF-1α gene of mothers, fathers, and children are associated with the risk of severe-spectrum hypertensive disorders of pregnancy in a Caucasian population.

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Creator Wei, Chen (author)

Core Title HIF-1α gene polymorphisms and risk of severe-spectrum hypertensive disorders of pregnancy: a pilot triad-based case-control study

School Keck School of Medicine

Degree Master of Science

Degree Program Applied Biostatistics and Epidemiology

Degree Conferral Date 2023-12

Publication Date 09/06/2023

Defense Date 09/06/2023

Publisher Los Angeles, California (original), University of Southern California (original), University of Southern California. Libraries (digital)

Tag HELLP syndrome,HIF1A,HiF-1α,hypertensive disorders of pregnancy,OAI-PMH Harvest,parent-of-origin effects,polymorphism,preeclampsia

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Wilson, Melissa (committee chair), Grubbs, Brendan (committee member), Pickering, Trevor (committee member)

Creator Email cwei9403@usc.edu,weichen970227@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-oUC113302958

Unique identifier UC113302958

Identifier etd-WeiChen-12321.pdf (filename)

Legacy Identifier etd-WeiChen-12321

Document Type Thesis

Format theses (aat)

Rights Wei, Chen

Internet Media Type application/pdf

Type texts

Source 20230906-usctheses-batch-1091 (batch), University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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Repository Name University of Southern California Digital Library

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