Uterine leiomyomata (UL), or fibroids, are a major source of gynecologic morbidity among reproductive-aged women. Relative to white women, black women are 2-3 times more likely to be diagnosed with UL, develop tumors at earlier ages, and have more severe disease at the time of diagnosis. Differences in environmental risk factors and screening behaviors do not explain this racial disparity. Using DNA from the Black Women's Health Study (BWHS), a nationwide follow-up study of 59,000 African American women begun in 1995, we propose to conduct genome-wide assays to identify genetic variants associated with clinically relevant UL. On follow-up questionnaires completed in 1997, 1999, 2001, 2003, and 2005, BWHS participants have reported data on the occurrence of incident UL and on a wide range of UL risk factors. A validation study of UL in the BWHS has demonstrated high accuracy of self-report (>96%). DNA samples have been obtained from over 26,000 BWHS participants, including 2,500 incident cases of UL. We propose to first use admixture mapping of 2,500 UL cases to find genes associated with UL that differ greatly in frequency across European and African populations. Admixture mapping has more power than linkage mapping in families to find genes of moderate effect. It is less expensive per sample than whole-genome association but has similar power to detect variants that differ across populations. Fine mapping in additional cases and matched controls, will be carried out if genome-wide suggestive or significant peaks are detected. If no such peaks are detected, we will carry out a whole-genome scan for UL genes in 768 UL cases and matched controls to detect variants that are not highly differentiated in frequency between African and European populations. Because gene-disease associations may be stronger among younger cases and those with greater symptomatology (markers of disease severity), we will prioritize the selection of younger surgically-confirmed cases. The controls will be restricted to those who reported a recent ultrasound (<5 years ago). Genes associated with UL in the BWHS will be tested in the NIEHS Fibroid Study to assess the robustness of our findings. The large number of incident UL cases in the BWHS will provide high statistical power. The study can be carried out at relatively low cost because the follow-up of BWHS participants and data collection, including the collection of DNA samples, are supported by other grants. The high incidence of UL in black women is a problem of major public health importance. The proposed study may identify genetic risk factors for UL that contribute to the large excess of the disease among black women.

Public Health Relevance

Uterine leiomyomata (UL), or fibroids, are a major source of gynecologic morbidity among black women and account for more than $2.1 billion in U.S. health care costs each year. Using data from the Black Women's Health Study, a large prospective follow-up study of African American women, we propose to carry out genome-wide assays to identify genes that might contribute to the occurrence of clinically relevant UL in black women. The proposed study has great potential to help explain the excess incidence of UL among African American women.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD057966-02
Application #
7750614
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Parrott, Estella C
Project Start
2008-12-15
Project End
2012-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
2
Fiscal Year
2010
Total Cost
$601,754
Indirect Cost
Name
Boston University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Hellwege, Jacklyn N; Jeff, Janina M; Wise, Lauren A et al. (2017) A multi-stage genome-wide association study of uterine fibroids in African Americans. Hum Genet 136:1363-1373
Wise, Lauren A; Palmer, Julie R; Rosenberg, Lynn et al. (2016) FASN, dietary fat intake, and risk of uterine leiomyomata in the Black Women's Health Study. Fertil Steril 106:1136-1141
Wise, Lauren A; Laughlin-Tommaso, Shannon K (2016) Epidemiology of Uterine Fibroids: From Menarche to Menopause. Clin Obstet Gynecol 59:2-24
Wise, Lauren A; Radin, Rose G; Rosenberg, Lynn et al. (2015) History of uterine leiomyomata and incidence of breast cancer. Cancer Causes Control 26:1487-93
Wise, Lauren A; Ruiz-Narváez, Edward A; Haddad, Stephen A et al. (2014) Polymorphisms in vitamin D-related genes and risk of uterine leiomyomata. Fertil Steril 102:503-510.e1
Wise, Lauren A; Palmer, Julie R; Ruiz-Narvaez, Edward et al. (2013) Is the observed association between dairy intake and fibroids in African Americans explained by genetic ancestry? Am J Epidemiol 178:1114-9
Wise, Lauren A; Radin, Rose G; Palmer, Julie R et al. (2012) Association of intrauterine and early life factors with uterine leiomyomata in black women. Ann Epidemiol 22:847-54
Wise, Lauren A; Palmer, Julie R; Reich, David et al. (2012) Hair relaxer use and risk of uterine leiomyomata in African-American women. Am J Epidemiol 175:432-40
Wise, Lauren A; Ruiz-Narvaez, Edward A; Palmer, Julie R et al. (2012) African ancestry and genetic risk for uterine leiomyomata. Am J Epidemiol 176:1159-68
Palmer, Julie R; Boggs, Deborah A; Wise, Lauren A et al. (2011) Parity and lactation in relation to estrogen receptor negative breast cancer in African American women. Cancer Epidemiol Biomarkers Prev 20:1883-91

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