Gene-environment interactions are increasingly understood to be a primary contributing factor in the etiology of cardiovascular disease. Environmental factors include person and societal-level variables. Genome factors include sequence variation and mechanisms controlling genome expression. These regulatory mechanisms are the nexus of gene-environment interactions, and can be transient or adaptive; the latter are termed epigenetics. Some genetic characteristics are highly homogeneous within ethnic groups, due to a combination of geographically derived natural selection and environmental factors. South Asians are a population with disproportionately high cardiovascular disease burden. A prevalence study of cardiovascular risk factors in this population provides evidence that common risk factors are alterations in cholesterol metabolism; specifically low high-density lipoprotein cholesterol with elevated triglycerides. These initial observations led to a second study yielding evidence that abdominal adiposity is not a necessary precursor to the development of this dyslipidemia, challenging previous assumptions. A third study found pro-atherogenic risk profiles in South Asians are present decades earlier than in other populations. While these risk factors have genetic underpinnings, the added effects of a changing environment (i.e., Westernization of South Asians) are not known. MicroRNA are an epigenetic post-transcriptional regulatory mechanism of messenger RNA translation, and are potential biomarkers of pathophysiology and response to interventions. MicroRNA in human blood are differentially expressed in numerous disease conditions, and in vitro studies indicate that microRNA play a role in regulation of cholesterol metabolism in response to the extracellular environment. Methods to quantify microRNA include microarray, in which a large number of microRNA targets are screened. Microarray results are then validated with the more sensitive quantitative polymerase chain reaction method. Using microRNA arrays and a case-control design of pooled bio-specimens, a fourth study identified 16 candidate microRNA biomarkers of this atherogenic profile, which were then verified by quantitative polymerase chain reaction. Several of these are known to target messenger RNA involved in cholesterol metabolism. These results are promising evidence for translational application of microRNA as clinical biomarkers elucidating underlying genetic determinants of atherogenic risk in South Asians. Further research is needed to determine whether microRNA expression in blood is sensitive to cardiovascular risk reduction interventions.

ABSTRACT

An Evaluation of the Molecular Species of CA125 Across the Three Phases of the Menstrual Cycle

CA125, a tumor-associated antigen, is primarily used to monitor epithelial ovarian cancer. However, CA125 alone lacks the sensitivity and specificity necessary for population-based screening in healthy women. Barriers to the development of a screening assay includes the low incidence of the disease, large inter-individual variability in CA125 levels, fluctuations in levels during the phases of the menstrual cycle (i.e., menses, follicular, luteal), ethnicity, menopausal status, and other benign conditions.

Evaluation of the molecular species of serum CA125 is a vital step in understanding the underlying biology of CA125. The specific aims of this study, in a sample of healthy women were: 1) To determine if the molecular species of CA125 differ across the three phases of the menstrual cycle; and 2) To determine if the absolute serum concentrations of CA125 differ across the three phases of the menstrual cycle, using two common commercial CA125 assays.

Healthy, Caucasian women between the ages of 18 and 39 were enrolled using strict criteria to minimize serum CA125 fluctuations. After menstrual cycle regularity was determined using calendars maintained by participants for 3 months, blood samples for analyses of CA125 were collected at three different phases of the menstrual cycle.

Serum levels of CA125 fluctuated across the menstrual cycle, with the highest levels found during menses. The amount of change in CA125 over time (i.e., 0.2 U/ml per day) was identical using both assays, which suggests that the relative changes in CA125 are consistently measured regardless of assay system.

Additionally Western blot analysis yielded seventeen distinct profiles (patterns of species) of CA125. Demographic characteristics and serum CA125 values are not significantly different for each CA125 pattern or at any time point. Consistent with previous studies of CA125, our data show species ranging from 31 to 460 kDa. Most of the referent bands in our data appear at 117 kDa or higher indicating that CA125 may primarily be a high molecular weight species in healthy women with regular menstrual cycles. Future research needs to determine the clinical importance and the molecular composition of these species of CA125.

The purposes of this study were to determine the occurrence rate for preoperative breast pain; describe the characteristics of this pain; evaluate for differences in demographic and clinical characteristics; and evaluate for variations in pro- and anti-inflammatory cytokine genes between women who did and did not report pain. Patients (n=398) were recruited prior to surgery and completed self-report questionnaires to obtain information on pain characteristics. Genotyping was done using the Golden Gate genotyping platform. Of note, 28.2% of the patients reported pain prior to surgery. Women who reported pain were significantly younger (p < 0.001), a higher percentage were non-white (p= 0.018), reported significantly lower Karnofsky Performance Status scores (p = 0.008), were less likely to have gone through menopause (p = 0.012), and had had significantly more biopsies (p=0.006). Carriers of the minor allele for a single nucleotide polymorphism (SNP) in IL1R1 (rs2110726; p = 0.007) were less likely to report breast pain prior to surgery. In contrast carriers of the minor allele for a SNP in IL13 (rs1295686; p= 0.019) were more likely to report breast pain prior to surgery. Findings from this study suggest that pain is a problem for over a quarter of women who are about to undergo breast cancer surgery. Based on the characteristics of the pain and the increased number of biopsies in women who reported pain, as well as the genetic associations found, this pain problem has an inflammatory component.

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