Significant interpopulation differentiation at candidate loci may underlie ethnic disparities in the prevalence of uterine fibroids

Phthalates are associated with multiple, adverse reproductive outcomes including increased risk of uterine leiomyoma (fibroids). Phthalates can interact with epigenetic modifications including microRNAs (miRNAs), which help regulate processes crucial to fibroid pathogenesis. However, no prior study has examined the influence of phthalates on miRNA expression in fibroid tumors. We conducted a preliminary, cross-sectional study to examine the associations between phthalate exposures and miRNA expression levels in fibroid tumors and to explore potential effect modification by race/ethnicity. We quantified expression levels of 754 miRNAs in fibroid tumor samples and analyzed spot urine samples for phthalate metabolites collected from 45 pre-menopausal women undergoing surgery for fibroid treatment at an academic hospital. Associations between miRNA levels in fibroids and phthalate biomarkers were evaluated using linear regression adjusting for age, race/ethnicity, and body mass index (BMI). Statistical tests were adjusted for multiple comparisons. We also performed in silico Ingenuity Pathway Analysis to identify the biological pathways that are regulated by phthalate-associated miRNAs. Mono-hydroxybutyl phthalate and mono(2-ethyl-5-hydroxyhexyl) phthalate were positively associated with miR-10a-5p (β = 0.76, 95% CI = [0.40, 1.11]) and miR-577 (β = 1.06, 95% CI = [0.53, 1.59]), respectively. A total of 8 phthalate-miRNA associations varied by race/ethnicity (qinteraction < 0.10). Pathway analysis revealed that mRNA gene targets of phthalate-associated miRNAs were significantly associated with multiple fibroid-related processes including angiogenesis, apoptosis, and proliferation of connective tissues. Collectively, these data suggest that exposures to some phthalates are associated with miRNA in fibroids, and that associations may vary by race/ethnicity. Validation of these findings may provide insight into mechanisms underlying associations between phthalates and fibroids and contribute to novel hypotheses regarding racial/ethnic disparities in fibroids.

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247: Relationships of uterine fibroids to racial/ethnic disparities in severe maternal morbidity

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2019.11.263 ◽

2020 ◽

Vol 222 (1) ◽

pp. S170-S171

Author(s):

Irogue Igbinosa ◽

Stephanie A. Leonard ◽

Yasser Y. El-Sayed ◽

Deirdre J. Lyell

Keyword(s):

Maternal Morbidity ◽

Uterine Fibroids ◽

Ethnic Disparities ◽

Severe Maternal Morbidity ◽

Racial Ethnic

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Evidence That Geographic Variation in Genetic Ancestry Associates With Uterine Fibroids

10.21203/rs.3.rs-500189/v1 ◽

2021 ◽

Author(s):

Jacob M. Keaton ◽

Elizabeth A Jasper ◽

Jacklyn N. Hellwege ◽

Sarah H. Jones ◽

Eric S. Torstenson ◽

...

Keyword(s):

African Ancestry ◽

Cumulative Risk ◽

Uterine Fibroids ◽

Ethnic Disparities ◽

European Ancestry ◽

East African ◽

Risk Alleles ◽

Northern European ◽

Genetic Mechanisms ◽

Ancestry Proportions

Abstract Uterine fibroids disproportionately impact African American (AA) women. Evidence suggests AA women have earlier onset and higher cumulative risk. This risk disparity may be due an imbalance of risk alleles in one parental geographic subpopulation relative to others. We investigated ancestry proportions for the 1000 Genomes phase 3 populations clustered into 6 geographic groups for association with fibroid traits in AA women (n=583 cases, 797 controls) and European American (EA) women (n=1,195 cases, 1,164 controls). Global ancestry proportions were estimated using ADMIXTURE. Dichotomous (fibroids status and multiple fibroid status) and continuous outcomes (volume and largest dimension) were modeled for association with ancestry proportions using logistic and linear regression adjusting for age. Effect estimates are reported per 10% increase in genetically inferred ancestry proportion. Among AAs, West African (WAFR) ancestry was associated with fibroid risk, East African ancestry was associated with risk of multiple fibroids, Northern European (NEUR) ancestry was protective for multiple fibroids, Southern European ancestry was protective for fibroids and multiple fibroids, and South Asian (SAS) ancestry was positively associated with volume and largest dimension. In EAs, NEUR ancestry was protective for fibroids, SAS ancestry was associated with fibroid risk, and WAFR ancestry was positively associated with volume and largest dimension. These results suggest that a proportion of fibroid risk and fibroid trait racial disparities are due to genetic differences between geographic groups. Further investigation at the local ancestry and single variant levels may yield novel insights about disease architecture and genetic mechanisms underlying ethnic disparities in fibroid risk.

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