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1.  High blood pressure during pregnancy is associated with future cardiovascular disease: an observational cohort study 
BMJ Open  2013;3(7):e002964.
The study aimed to determine if having a hypertensive disorder of pregnancy (HDP) is a risk factor for future cardiovascular disease (CVD), independent of age and body mass index (BMI).
Data were sourced from the baseline questionnaire of the 45 and Up Study, Australia, an observational cohort study.
Participants were randomly selected from the Australian Medicare Database within New South Wales.
A total of 84 619 women were eligible for this study, of which 71 819 were included. These women had given birth between the ages of 18 and 45 years, had an intact uterus and ovaries, and had not been diagnosed with high blood pressure prior to their first pregnancy.
HDP was associated with higher odds of having high blood pressure (<58 years: adjusted OR 3.79, 99% CI 3.38 to 4.24; p<0.001 and ≥58 years: 2.83, 2.58 to 3.12; p<0.001) and stroke (<58 years: 1.69, 1.02 to 2.82; p=0.008 and ≥58 years: 1.46, 1.13 to 1.88; p<0.001) in later life. Women with HDP had a younger age of onset of high blood pressure (45.6 vs 54.8 years, p<0.001) and stroke (58 vs 62.5 years, p<0.001). Women who had HDP and whose present day BMI was <25 had significantly higher odds of having high blood pressure, compared with women who were normotensive during pregnancy (<58 years: 4.55, 3.63 to 5.71; p<0.001 and ≥58 years, 2.94, 2.49 to 3.47; p<0.001). Women who had HDP and a present day BMI≥25 had significantly increased odds of high blood pressure (<58 years: 12.48, 10.63 to 14.66; p<0.001 and ≥58 years, 5.16, 4.54 to 5.86; p<0.001), compared with healthy weight women with a normotensive pregnancy.
HDP is an independent risk factor for future CVD, and this risk is further exacerbated by the presence of overweight or obesity in later life.
PMCID: PMC3731716  PMID: 23883883
2.  Past oral contraceptive use and self-reported high blood pressure in postmenopausal women 
BMC Public Health  2015;15:54.
Studies have reported current hormonal contraceptive use is associated with adverse cardiovascular outcomes, including high blood pressure. The aim of this study was to determine the association between past hormonal contraception use and high blood pressure in Australian postmenopausal women.
Women were recruited from the 45 and Up Study, an observational cross-sectional study, conducted from February 2006 to December 2009, NSW Australia. All of the variables used in this study were derived from self-reported data. These women reported being postmenopausal, having an intact uterus, and had given birth to one or more children. Odds ratios and 99% confidence intervals for the association between past hormonal contraceptive use and current treatment for high blood pressure, stratified by current age (<58 yrs, 58–66 yrs, and ≥67 yrs) were estimated using logistic regression, adjusted for income, country of origin, BMI, smoking, alcohol, exercise, family history of high blood pressure, menopausal hormone therapy use, number of children, whether they breastfed, and age of menopause.
A total of 34,289 women were included in the study. No association between past hormonal contraception use and odds of having high blood pressure were seen in any of the age groups (<58 yrs: odds ratio (OR) 1.1, 99% confidence interval (CI) 0.8 to 1.5, p = 0.36; 58–66 yrs: OR 0.9, 99% CI 0.7 to 1.1, p = 0.11; and ≥67 yrs: OR 0.9, 99% CI 0.8 to 1.0. p = 0.06). In women with a history of hormonal contraception use, no association between duration of hormonal contraception use and high blood pressure was observed.
Past hormonal contraception use and duration of use is not associated with high blood pressure in postmenopausal women.
PMCID: PMC4327952  PMID: 25636949
Hormonal contraception; High blood pressure; Postmenopausal women
3.  Identification of genes with altered expression in male and female Schlager hypertensive mice 
BMC Medical Genetics  2014;15:101.
Numerous studies have shown sex differences in the onset and severity of hypertension. Despite these sex-differences the majority of animal studies are carried out in males. This study investigated expression changes in both male and female hypertensive mouse kidneys to identify common mechanisms that may be involved in the development of hypertension.
The Schlager hypertensive mouse model (BPH/2J) and its normotensive control (BPN/3J) were used in this study. Radiotelemetry was performed on 12 to 13 week old BPH/2J and BPN/3J male and female animals. Affymetrix GeneChip Mouse Gene 1.0 ST Arrays were performed in kidney tissue from 12 week old BPH/2J and BPN/3J male and female mice (n = 6/group). Genes that were differentially expressed in both male and female datasets were validated using qPCR.
Systolic arterial pressure and heart rate was significantly higher in BPH/2J mice compared with BPN/3J mice in both males and females. Microarray analysis identified 153 differentially expressed genes that were common between males and females (70 upregulated and 83 downregulated). We validated 15 genes by qPCR. Genes involved in sympathetic activity (Hdc, Cndp2), vascular ageing (Edn3), and telomere maintenance (Mcm6) were identified as being differentially expressed between BPH/2J and BPN/3J comparisons. Many of these genes also exhibited expression differences between males and females within a strain.
This study utilised data from both male and female animals to identify a number of genes that may be involved in the development of hypertension. We show that female data can be used to refine candidate genes and pathways, as well as highlight potential mechanisms to explain the differences in prevalence and severity of disease between men and women.
Electronic supplementary material
The online version of this article (doi:10.1186/s12881-014-0101-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4355368  PMID: 25259444
Schlager mouse; Genome wide gene expression
4.  Variability in mRNA expression of fms-like tyrosine kinase-1 variants in normal and preeclamptic placenta 
BMC Research Notes  2014;7:154.
Preeclampsia is a complication of pregnancy characterised by gestational hypertension and proteinuria and is a leading cause of morbidity and mortality in both mothers and infants. Certain anti-angiogenic factors have long been implicated in the pathogenesis of preeclampsia and the placental expression of factors such as soluble fms-like tyrosine kinase-1 (sFLT-1) are often reported in studies of normal and diseased placentae. Despite evidence showing significant differences in placental gene expression by collection site, many studies fail to provide sufficient details on sample selection and collection.
With ourselves and others investigating and reporting on the expression of FLT-1 variants and other genes in the placenta of normotensive and preeclamptic patients, we felt it prudent to examine the variation in expression of FLT-1 variants across human placenta. We examined the differential expression of FLT-1 variants in samples obtained from 12 sites on normal and preeclamptic placentae and found expression to be highly variable between sites. We therefore developed an algorithim to calculate the mean expression for any number of these sites collected and in any combination. The coefficient of variation for all combinations of sites was then used to determine the minimum number of sites required to reduce coefficient of variation to below an acceptable 10%. We found that 10 and 11 sites had to be sampled in the normal and preeclamptic placentae respectively to ensure a representative expression pattern for all FLT-1 variants for an individual placenta.
These findings demonstrate significant variation in expression levels of several commonly investigated genes across sites in both normal and preeclamptic placenta. This highlights both the importance of adequate sampling of human placenta for expression studies and the effective communication of sample selection and collection methods, for data interpretation and to ensure the reproducibility and reliability of results and conclusions drawn.
PMCID: PMC3995530  PMID: 24636199
Placenta; Preeclampsia; sFLT-1; Variability; Sampling
5.  Parent of origin influences the cardiac expression of vascular endothelial growth factor (Vegfa) 
BMC Medical Genetics  2013;14:43.
Vascular endothelial growth factor A (VEGFA) is a major regulator of both physiological and pathological angiogenesis. Associations between polymorphisms in VEGFA and complex disease have been inconsistent. The parent from whom the allele was inherited may account for these inconsistencies. This study examined the parent of origin effect on the expression of murine Vegfa.
Two homozygous, inbred mouse strains A/J (AJ) and 129x1/SvJ (129) were crossed to produce reciprocal AJ129 and 129AJ offspring, respectively. RNA was extracted from cardiac tissue of 6 week old male (n = 8) and female (n = 8) parental, and male and female F1 offspring mice (AJ129 n = 8 and 129AJ n = 8). Vegfa and Hif1a expression levels were measured by qPCR and compared between the F1 offspring from the reciprocal crosses.
We found significant differences in the expression of Vegfa in F1 offspring (AJ129 and 129AJ mice) of the reciprocal crosses between AJ and 129 mice. Offspring of male AJ mice had significantly higher expression of Vegfa than offspring of male 129 mice (p = 0.006). This difference in expression was not the result of preferential allele expression (allelic imbalance). Expression of Hif1a, a transcriptional regulator of Vegfa expression, was also higher in F1 offspring of an AJ father (p = 0.004).
Differences in Vegfa and Hif1a gene expression are likely the result of an upstream angiogenic regulator gene that is influenced by the parent of origin. These results highlight the importance of including inheritance information, such as parent of origin, when undertaking allelic association studies.
PMCID: PMC3626619  PMID: 23560444
Parent of origin; Epigenetics; Vascular endothelial growth factor
6.  Magnetic Resonance Imaging Detects Placental Hypoxia and Acidosis in Mouse Models of Perturbed Pregnancies 
PLoS ONE  2013;8(3):e59971.
Endothelial dysfunction as a result of dysregulation of anti-angiogenic molecules secreted by the placenta leads to the maternal hypertensive response characteristic of the pregnancy complication of preeclampsia. Structural abnormalities in the placenta have been proposed to result in altered placental perfusion, placental oxidative stress, cellular damage and inflammation and the release of anti-angiogenic compounds into the maternal circulation. The exact link between these factors is unclear. Here we show, using Magnetic Resonance Imaging as a tool to examine placental changes in mouse models of perturbed pregnancies, that T2 contrast between distinct regions of the placenta is abolished at complete loss of blood flow. Alterations in T2 (spin-spin or transverse) relaxation times are explained as a consequence of hypoxia and acidosis within the tissue. Similar changes are observed in perturbed pregnancies, indicating that acidosis as well as hypoxia may be a feature of pregnancy complications such as preeclampsia and may play a prominent role in the signalling pathways that lead to the increased secretion of anti-angiogenic compounds.
PMCID: PMC3608595  PMID: 23555853
7.  Menopausal Hormone Therapy Is Associated with Having High Blood Pressure in Postmenopausal Women: Observational Cohort Study 
PLoS ONE  2012;7(7):e40260.
The relationship between menopausal hormone therapy (MHT) and cardiovascular risk remains controversial, with a number of studies advocating the use of MHT in reducing risk of cardiovascular diseases, while others have shown it to increase risk. The aim of this study was to determine the association between menopausal hormone therapy and high blood pressure.
Methods and Findings
A total of 43,405 postmenopausal women were included in the study. Baseline data for these women were sourced from the 45 and Up Study, Australia, a large scale study of healthy ageing. These women reported being postmenopausal, having an intact uterus, and had not been diagnosed with high blood pressure prior to menopause. Odds ratios for the association between MHT use and having high blood pressure were estimated using logistic regression, stratified by age (<56 years, 56–61 years, 62–70 years and over 71 years) and adjusted for demographic and lifestyle factors. MHT use was associated with higher odds of having high blood pressure: past menopausal hormone therapy use: <56 years (adjusted odds ratio 1.59, 99% confidence interval 1.15 to 2.20); 56–61 years (1.58, 1.31 to 1.90); 62–70 years (1.26, 1.10 to 1.44). Increased duration of hormone use was associated with higher odds of having high blood pressure, with the effect of hormone therapy use diminishing with increasing age.
Menopausal hormone therapy use is associated with significantly higher odds of having high blood pressure, and the odds increase with increased duration of use. High blood pressure should be conveyed as a health risk for people considering MHT use.
PMCID: PMC3394783  PMID: 22808129
8.  Association of Y chromosome haplogroup I with HIV progression, and HAART outcome 
Human genetics  2009;125(3):281-294.
The host genetic basis of differential outcomes in HIV infection, progression, viral load set point and highly active retroviral therapy (HAART) responses was examined for the common Y haplogroups in European Americans and African Americans. Accelerated progression to acquired immune deficiency syndrome (AIDS) and related death in European Americans among Y chromosome haplogroup I (Y-I) subjects was discovered. Additionally, Y-I haplogroup subjects on HAART took a longer time to HIV-1 viral suppression and were more likely to fail HAART. Both the accelerated progression and longer time to viral suppression results observed in haplogroup Y-I were significant after false-discovery-rate corrections. A higher frequency of AIDS-defining illnesses was also observed in haplogroup Y-I. These effects were independent of the previously identified autosomal AIDS restriction genes. When the Y-I haplogroup subjects were further subdivided into six I subhaplogroups, no one subhaplogroup accounted for the effects on HIV progression, viral load or HAART response. Adjustment of the analyses for population stratification found significant and concordant haplogroup Y-I results. The Y chromosome haplogroup analyses of HIV infection and progression in African Americans were not significant. Our results suggest that one or more loci on the Y chromosome found on haplogroup Y-I have an effect on AIDS progression and treatment responses in European Americans.
PMCID: PMC2885350  PMID: 19169712

Results 1-8 (8)