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

Ayush Giri; Jennifer M. Wu; Renee M. Ward; Katherine E. Hartmann; Amy J. Park; Kari E. North; Mariaelisa Graff; Robert B. Wallace; Gihan Bareh; Lihong Qi; Mary J. O'Sullivan; Alexander P. Reiner; Todd L. Edwards; Digna R.Velez Edwards

doi:10.1371/journal.pone.0141647

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

Ayush Giri
, Jennifer M. Wu
, Renee M. Ward
, Katherine E. Hartmann
, Amy J. Park
, Kari E. North
, Mariaelisa Graff
, Robert B. Wallace
, Gihan Bareh
, Lihong Qi
, Mary J. O'Sullivan
, Alexander P. Reiner
, Todd L. Edwards
, Digna R.Velez Edwards

Producción científica: Article › revisión exhaustiva

25 Citas (Scopus)

Resumen

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<5×10^-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 = 1.0×10^-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 = 2.6×10^-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 = 4.2×10^-7) in the grade 0 vs 1-3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6×10^-7) and SHC3 (rs2209875, OR:0.60; p = 9.3×10^-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.

Idioma original	English
Número de artículo	e0141647
Publicación	PLoS ONE
Volumen	10
N.º	11
DOI	https://doi.org/10.1371/journal.pone.0141647
Estado	Published - nov 6 2015

Nota bibliográfica

Publisher Copyright:
© 2015 Giri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Financiación

This manuscript was prepared in collaboration with investigators of the Women''s Health Initiative, and has been reviewed and/or approved by the Women''s Health Initiative. The following persons are investigators in theWomen''s Health Initiative. Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller Clinical Coordinating Center: Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg Investigators and Academic Centers: (Brigham and Women''s Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston- Salem, NC) Sally Shumaker Women''s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker A list of all investigators who have contributed to WHI science can be found at https:// www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator% 20Long%20List.pdf The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/sites/entrez?db=gap through dbGaP accession phs000200.v9. p3. The Women''s Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Funding for Women''s Health Initiative SHARe genotyping was provided by NHLBI Contract N02-HL-64278. This work was funded by Vanderbilt Clinical and Translational Research Scholar award (5KL2RR024975) to Todd Edwards and by the Building Interdisciplinary Research Careers in Women''s Health career development program (5K12HD04383-11) to Digna R. Velez Edwards. Dr. Jennifer Wu is supported by K23HD068404, Eunice Kennedy Shriver National Institute of Child Health & Human Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Financiadores	Número del financiador
Iowa City/Davenport
Stanford Prevention Research Center
Eunice Kennedy Shriver National Institute of Child Health and Human Development
MedStar Health Research Institute/Howard University
Ohio Water Resources Center, Ohio State University
University at Buffalo
Tucson/Phoenix
Harvard Medical School
Florida AandM University and Florida State University
University of Northern Arizona
University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh
Iowa Environmental Mesonet at Iowa State University
???publication-publication-funding-organisation-not-added???	N01WH022110
National Childhood Cancer Registry – National Cancer Institute	P30CA015704
Vanderbilt Institute for Clinical and Translational Research	5KL2RR024975
National Heart, Lung, and Blood Institute (NHLBI)	R01HL064278
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	K23HD068404
U.S. Department of Health and Human Services	32115, 32118-32119, N01WH22110, 24152, 44221, 32122, 42107-26, 32111-13, 32105-6, 32100-2, 42129-32, 32108-9
National Center for Research Resources	UL1RR024975
Building Interdisciplinary Research Careers in Women''s Health career development program	5K12HD04383-11, K23HD068404

ASJC Scopus subject areas

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Giri, A., Wu, J. M., Ward, R. M., Hartmann, K. E., Park, A. J., North, K. E., Graff, M., Wallace, R. B., Bareh, G., Qi, L., O'Sullivan, M. J., Reiner, A. P., Edwards, T. L., & Edwards, D. R. V. (2015). Genetic determinants of pelvic organ prolapse among African American and Hispanic women in the Women's Health Initiative. PLoS ONE, 10(11), Artículo e0141647. https://doi.org/10.1371/journal.pone.0141647

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abstract = "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<5{\texttimes}10-8), 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 = 1.0{\texttimes}10-7) were associated with POP in AAs, and SNPs in the gene AL132709.5 (rs1950626, OR:2.96; 95\% CI 1.96-4.48, p = 2.6{\texttimes}10-7) 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 = 4.2{\texttimes}10-7) in the grade 0 vs 1-3 analyses and for SNPs around PGBD5 (rs740494, OR:2.17; p = 8.6{\texttimes}10-7) and SHC3 (rs2209875, OR:0.60; p = 9.3{\texttimes}10-7) 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.",

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AU - Hartmann, Katherine E.

AU - Park, Amy J.

AU - North, Kari E.

AU - Graff, Mariaelisa

AU - Wallace, Robert B.

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AU - Qi, Lihong

AU - O'Sullivan, Mary J.

AU - Reiner, Alexander P.

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N1 - Publisher Copyright: © 2015 Giri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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

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