Amy J. Park

Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study

STUDY QUESTIONnDo genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?nnnSUMMARY ANSWERnWe replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.nnnWHAT IS KNOWN ALREADYnMenarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.nnnSTUDY DESIGN, SIZE, DURATIONnA total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.nnnMATERIALS, SETTING, METHODSnSNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.nnnMAIN RESULTS AND THE ROLE OF CHANCEnWe replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.nnnLIMITATIONS, REASONS FOR CAUTIONnLack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.nnnWIDER IMPLICATIONS OF THE FINDINGSnThe discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

Interest in cosmetic vulvar surgery and perception of vulvar appearance

OBJECTIVEnThe objective of the study was to determine whether reproductive-age women are more likely to perceive their vulva as abnormal compared with older-aged women.nnnSTUDY DESIGNnWomen aged 18-44 years (group 1) and 45-72 years (group 2) completed a survey on demographics, grooming patterns, vulvar perceptions, and source of information about the vulva.nnnRESULTSnThere was no difference between group 1 and group 2 in how often women looked at their vulva or their perception of having a normal vulva (91% vs 93%, P = .76). Both groups were satisfied with the appearance of their vulva (81% vs 82%, P = .71). A higher percentage in group 2 would consider cosmetic surgery if cost were not an issue versus group 1 (15% vs 8%, P = .05).nnnCONCLUSIONnA womans age does not have an impact on her perception of a normal vulva. The majority of women perceived their vulva to be normal and were satisfied with its appearance. However, older women are more interested in cosmetic vulvar surgery.

Genetic Variation and Reproductive Timing: African American Women from the Population Architecture Using Genomics and Epidemiology (PAGE) Study

Age at menarche (AM) and age at natural menopause (ANM) define the boundaries of the reproductive lifespan in women. Their timing is associated with various diseases, including cancer and cardiovascular disease. Genome-wide association studies have identified several genetic variants associated with either AM or ANM in populations of largely European or Asian descent women. The extent to which these associations generalize to diverse populations remains unknown. Therefore, we sought to replicate previously reported AM and ANM findings and to identify novel AM and ANM variants using the Metabochip (nu200a=u200a161,098 SNPs) in 4,159 and 1,860 African American women, respectively, in the Women’s Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) studies, as part of the Population Architecture using Genomics and Epidemiology (PAGE) Study. We replicated or generalized one previously identified variant for AM, rs1361108/CENPW, and two variants for ANM, rs897798/BRSK1 and rs769450/APOE, to our African American cohort. Overall, generalization of the majority of previously-identified variants for AM and ANM, including LIN28B and MCM8, was not observed in this African American sample. We identified three novel loci associated with ANM that reached significance after multiple testing correction (LDLR rs189596789, pu200a=u200a5×10−08; KCNQ1 rs79972789, pu200a=u200a1.9×10−07; COL4A3BP rs181686584, pu200a=u200a2.9×10−07). Our most significant AM association was upstream of RSF1, a gene implicated in ovarian and breast cancers (rs11604207, pu200a=u200a1.6×10−06). While most associations were identified in either AM or ANM, we did identify genes suggestively associated with both: PHACTR1 and ARHGAP42. The lack of generalization coupled with the potentially novel associations identified here emphasize the need for additional genetic discovery efforts for AM and ANM in diverse populations.

Genetic determinants of pelvic organ prolapse among African American and Hispanic women in the Women's Health Initiative

Current evidence suggests a multifactorial etiology to pelvic organ prolapse (POP), including genetic predisposition. We conducted a genome-wide association study of POP in African American (AA) and Hispanic (HP) women from the Women’s Health Initiative Hormone Therapy study. Cases were defined as any POP (grades 1–3) or moderate/severe POP (grades 2–3), while controls had grade 0 POP. We performed race-specific multiple logistic regression analyses between SNPs imputed to 1000 genomes in relation to POP (grade 0 vs 1–3; grade 0 vs 2–3) adjusting for age at diagnosis, body mass index, parity, and genetic ancestry. There were 1274 controls and 1427 cases of any POP and 317 cases of moderate/severe POP. Although none of the analyses reached genome-wide significance (p<5x10-8), we noted variants in several loci that met p<10−6. In race-specific analysis of grade 0 vs 2–3, intronic SNPs in the CPE gene (rs28573326, OR:2.14; 95% CI 1.62–2.83; p = 1.0x10-7) were associated with POP in AAs, and SNPs in the gene AL132709.5 (rs1950626, OR:2.96; 95% CI 1.96–4.48, p = 2.6x10-7) were associated with POP in HPs. Inverse variance fixed-effect meta-analysis of the race-specific results showed suggestive signals for SNPs in the DPP6 gene (rs11243354, OR:1.36; p = 4.2x10-7) in the grade 0 vs 1–3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6x10-7) and SHC3 (rs2209875, OR:0.60; p = 9.3x10-7) in the grade 0 vs 2–3 analyses. While we did not identify genome-wide significant findings, we document several SNPs reaching suggestive statistical significance. Further interrogation of POP in larger minority samples is warranted.

ErgoPART: A Computerized Observational Tool to Quantify Postural Loading in Real-Time During Surgery

OCCUPATIONAL APPLICATIONS Ergonomics postural assessment in real-time (ErgoPART) is a new job analysis tool designed to systematically characterize the postural demands of performing surgery. Tasks, equipment, and procedures that require ergonomic intervention can be identified. ErgoPART can also be used to quantify the benefits of ergonomic interventions that reduce the frequency and duration of non-neutral postures. Preliminary tests, conducted in the context of vaginal surgery, indicate that the tool is easy to learn and may allow broad categories of neck, shoulder, and trunk postures to be coded reliably. ErgoPART is freely available for use. TECHNICAL ABSTRACT Background: Little quantitative information exists regarding the postural demands placed on surgeons in the operating room. One reason for this is the lack of minimally invasive tools available to characterize the duration and frequency of non-neutral postures during surgery. Purpose: The objective of this study was to develop an ergonomics job analysis tool to evaluate, in real-time, the postural requirements of performing surgeries with minimal intrusion to the work, and to complete a preliminary evaluation of the tool. Method: A team of vaginal surgeons first identified the need to systematically observe and characterize body postures during surgery. Ergonomics postural assessment in real-time (ErgoPART) is a computer-based tool that was developed via an iterative design process between these surgeons and ergonomics researchers, and designed to characterize environmental, task, and postural variables during surgical work. A preliminary inter-observer reliability assessment was conducted during one vaginal surgery, involving four observers with varying degrees of ergonomics experience. Results: ErgoPARTs data collection interface facilitates recording of basic information about the surgery, task information, surgeons position with respect to the surgical field, operating room features, and tracking of broad categories of neck, trunk, and shoulder postures. A unique feature is that the computer interface provides visual feedback about the status of postural codes in the form of a virtual mannequin and dynamic color-coded buttons to reduce coding misclassification during observation. Quantitative information about the frequency and duration of non-neutral body posture categories for the entire surgery, and for specific surgical tasks, is available immediately after the observations are completed via Microsoft Excel™ spreadsheets. Measures of inter-observer reliability indicated that the tool may provide a reliable assessment of the duration and frequency of surgeons non-neutral postures during vaginal surgeries. Conclusions: ErgoPART allows multiple body postures to be assessed simultaneously, can be used to study the contributions of the individual, environment, tools, and task demands on working postures, and helps quantify the frequency and duration of non-neutral body postures. More research is planned to further evaluate the inter-observer reliability and methodological validity of the tool.

Postural stress experienced by vaginal surgeons

Increasing attention has been drawn to the prevalence of work-related musculoskeletal disorders (MSDs) among surgeons in various medical specialties; however, the risk of work-related MSDs among gynecologic surgeons has not received much attention. This study aimed to investigate the postural load among gynecologic surgeons for various surgical tasks during vaginal surgery. The frequency and percentage of duration of awkward upper body postures experienced by vaginal surgeons during eleven different vaginal surgical tasks observed during thirteen surgeries were collected using a new observational ergonomic job analysis tool, Ergonomic Posture Assessment in Real Time (ErgoPART). Results indicate that the postural loading is high for many surgical tasks but that the frequency and duration of awkward neck, shoulder, and trunk postures is variable across tasks. Surgeons’ postural load was significantly higher for the transvaginal hysterectomy compared to others. This task, in particular, is a candidate for ergonomics interventions designed to reduce postural stress.

Defining Cervical Elongation: A Prospective Observational Study

OBJECTIVESnOur primary aim was to define cervical elongation (CE) using the following methods: (1) measurement of pathology specimen, (2)xa0physician perception, (3) intraoperative estimate of anterior cervical length, and (4) office Pelvic Organ Prolapse Quantification (POP-Q) points C and D. Our secondary aim was to determine whether these definitions correlate with perioperative outcomes.nnnMETHODSnWomen undergoing vaginal hysterectomy and prolapse repair were enrolled. Office POP-Q measurements were collected. Estimates of cervical length were made based on points C minus D of the POP-Q and by manual exam using the surgeons index and middle fingers. Cervical dimensions were measured from the pathology specimen at the end of the case. CE was defined as one standard deviation (SD) above the mean for each definition. Additional intraoperative data was collected to determine the surgeon perception of cervical anatomy.nnnRESULTSnA total of 90 patients were enrolled during the study period. Our definitions for CE were as follows: (1) 5 cm (70 without and 20 with CE), (2) physician perception (67 without and 23 with CE), (3)xa03.4 cm (79 without and 11 with CE), and (4) 8.3 cm (77 without and 13 with CE). After controlling for uterine weight and the presence of fibroids, the operative time was the only outcome measure that remained elevated for patients with CE using our first definition (42.4 ± 20.1 without vs. 53.8 ± 19.2 with CE, Pxa0= 0.03).nnnCONCLUSIONSnCE using our first definition was associated with a statistically significant increase in operative time in women undergoing hysterectomy at the time of prolapse repair.

Effects of bilateral salpingo-oophorectomy at the time of hysterectomy on pelvic organ prolapse: results from the Women's Health Initiative trial.

ObjectiveThis study aims to estimate the effects of bilateral salpingo-oophorectomy (BSO) at the time of hysterectomy and estrogen therapy on vaginal prolapse. MethodsA retrospective analysis of the Women’s Health Initiative estrogen-alone trial was performed. Women who retained their ovaries were compared with women who had BSO at the time of hysterectomy for the presence of cystocele or rectocele at entry into the study. Based on BSO and hormone therapy (HT) status, participants were categorized into groups. We hypothesized that BSO and prolonged hypoestrogenemia may be associated with an increased risk of prolapse. Univariate and multivariate analyses were used to determine the effects of BSO and HT status on cystocele and rectocele. ResultsOf 10,739 participants in the estrogen-alone trial, 8,879 women were included in the analysis. Older age, higher parity, higher body mass index, higher waist-to-hip ratio, and non–African-American race/ethnicity were associated with increased odds of developing cystocele or rectocele. Women who retained their ovaries had higher rates of cystocele or rectocele at screening (39%) compared with all women who had BSO (31-36%; odds ratio, 1.18; 95% CI, 1.04-1.33). After controlling for multiple variables, our analysis showed that women who retained their ovaries had higher odds of developing cystocele or rectocele compared with women who had BSO and no subsequent HT (odds ratio, 1.23; 95% CI, 1.07-1.41). All other comparisons were nonsignificant. ConclusionsBSO at the time of hysterectomy is not associated with increased risk of cystocele or rectocele. BSO and no subsequent HT may even have a protective effect against cystocele or rectocele.

Incidence of corneal abrasions during pelvic reconstructive surgery

OBJECTIVESnTo compare the incidence of corneal abrasions after robotic/laparoscopic sacral colpopexies versus vaginal apical suspensions, and to determine risk factors associated with the development of corneal abrasions.nnnSTUDY DESIGNnThis retrospective cohort study included all women undergoing robotic/laparoscopic sacral colpopexy or vaginal apical suspensions over a 5-year period. The incidence of corneal abrasions was compared between groups and statistical analysis was performed.nnnRESULTSn5/216 (2.3%) patients developed corneal abrasions in the sacral colpopexy group compared to 1/332 (0.3%) in the vaginal group (p=0.04). Eye protection was more frequently documented in the sacral colpopexy group compared to the vaginal group (98.6% vs. 83.4%, p<0.001). Women in the sacral colpopexy group were younger, with longer operating times, more intravenous fluids, and lower estimated blood loss. Risk factors for corneal abrasion could not be identified due to the low number of patients with corneal abrasions.nnnCONCLUSIONnMore corneal abrasions occurred with laparoscopic and robotic sacral colpopexy compared to vaginal apical suspension procedures. Risk factors could not be identified in this study.

Admixture mapping of pelvic organ prolapse in African Americans from the Women's Health Initiative Hormone Therapy trial

Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women’s Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade ≥2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10-5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.