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

Do 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

Adverse Pregnancy Outcomes and Incident Heart Failure in the Women's Health Initiative

Importance: Some prior evidence suggests that adverse pregnancy outcomes (APOs) may be associated with heart failure (HF). Identifying unique factors associated with the risk of HF and studying HF subtypes are important next steps. Objective: To investigate the association of APOs with incident HF overall and stratified by HF subtype (preserved vs reduced ejection fraction) among postmenopausal women in the Women's Health Initiative (WHI). Design, Setting, and Participants: In 2017, an APO history survey was administered in the WHI study, a large multiethnic cohort of postmenopausal women. The associations of 5 APOs (gestational diabetes, hypertensive disorders of pregnancy [HDP], low birth weight, high birth weight, and preterm delivery) with incident adjudicated HF were analyzed. In this cohort study, the association of each APO with HF was assessed using logistic regression models and with HF subtypes using multinomial regression, adjusting for age, sociodemographic characteristics, smoking, randomization status, reproductive history, and other APOs. Data analysis was performed from January 2020 to September 2021. Exposures: APOs (gestational diabetes, HDP, low birth weight, high birth weight, and preterm delivery). Main Outcomes and Measures: All confirmed cases of women hospitalized with HF and HF subtype were adjudicated by trained physicians using standardized methods. Results: Of 10292 women (median [IQR] age, 60 [55-64] years), 3185 (31.0%) reported 1 or more APO and 336 (3.3%) had a diagnosis of HF. Women with a history of any APO had a higher prevalence of hypertension, diabetes, coronary heart disease, or smoking. Of the APOs studied, only HDP was significantly associated with HF with a fully adjusted odds ratio (OR) of 1.75 (95% CI, 1.22-2.50), and with HF with preserved ejection fraction in fully adjusted models (OR, 2.06; 95% CI, 1.29-3.27). In mediation analyses, hypertension explained 24% (95% CI, 12%-73%), coronary heart disease 23% (95% CI, 11%-68%), and body mass index 20% (95% CI, 10%-64%) of the association between HDP and HF. Conclusions and Relevance: In this large cohort of postmenopausal women, HDP was independently associated with incident HF, particularly HF with preserved ejection fraction, and this association was mediated by subsequent hypertension, coronary heart disease, and obesity. These findings suggest that monitoring and modifying these factors early in women presenting with HDP may be associated with reduced long-term risk of HF.. © 2021 American Medical Association. All rights reserved.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Ethnic differences in the relationship between birth weight and type 2 diabetes mellitus in postmenopausal women

AimThe objective of this study is to examine the relationship between self-reported birth weight and the adult occurrence of type 2 diabetes mellitus in a large multi-ethnic population of women.MethodsBaseline data from the Women's Health Initiative Observational Study [n=75,993] was used to examine the association between participant birth weight category and prevalent type 2 diabetes mellitus. Models were adjusted for age, ethnicity, body mass index and other pertinent risk factors. Sub-analyses were performed stratifying by ethnicity.ResultsThere was a strong inverse association between birth weight and type 2 diabetes mellitus with a birth weight of <6 pounds (lbs) (OR: 1.16, 95% CI: 1.01, 1.33) significantly associated with an increased risk of type 2 diabetes mellitus and a birth weight of ≥10 lbs (OR: 0.72, 95% CI: 0.57, 0.92) associated with a decreased risk of type 2 diabetes mellitus compared to women who reported their birth weight between 7 and 8 lbs 15 ounces (oz). Stratifying by ethnicity, the inverse association between birth weight and type 2 diabetes mellitus was only apparent in White women, but not Black, Hispanic or Asian women.ConclusionLower birth weight was associated with increased T2D risk in American White and Black post-menopausal women

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

STUDY QUESTION: Do 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? SUMMARY ANSWER: We 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. WHAT IS KNOWN ALREADY: Menarche 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. STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. MATERIALS, SETTING, METHODS: SNPs 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. MAIN RESULTS AND THE ROLE OF CHANCE: We 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. LIMITATIONS, REASONS FOR CAUTION: Lack 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. WIDER IMPLICATIONS OF THE FINDINGS: The 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. STUDY FUNDING/COMPETING INTEREST(S): The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest