Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage

Digna R. Velez Edwards; Todd L. Edwards; Michael J. Bray; Eric Torstenson; Sarah Jones; Martha J. Shrubsole; Harvey J. Muff; Katherine E. Hartmann

doi:10.1038/s41598-017-10150-2

Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage

Digna R. Velez Edwards, Todd L. Edwards, Michael J. Bray, Eric Torstenson, Sarah Jones, Martha J. Shrubsole, Harvey J. Muff, Katherine E. Hartmann

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 × 10^-4) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.

Original language	English
Article number	9874
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-10150-2
State	Published - Dec 1 2017

Bibliographical note

Publisher Copyright:
© 2017 The Author(s).

Funding

Field research was supported by grants from the National Institute of Child and Human Development (R01HD043883 and R01HD049675). Additional funds were provided by the Building Interdisciplinary Research Careers in Women's Health career development program (K12HD043483), training grant 5T32MG080178-09, and supported in part by the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH. This study was supported through the National Cancer Institute grants P50CA95103, R01AT004660, and R01CA121060. The TCPS was conducted by the Survey and Biospecimen Shared Resource supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A portion of this material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System. Field research was supported by grants from the National Institute of Child and Human Development (R01HD043883 and R01HD049675). Additional funds were provided by the Building Interdisciplinary Research Careers in Women’s Health career development program (K12HD043483), training grant 5T32MG080178– 09, and supported in part by the Vanderbilt CTSA grant UL1 RR024975-01 from NCRR/NIH. This study was supported through the National Cancer Institute grants P50CA95103, R01AT004660, and R01CA121060. The TCPS was conducted by the Survey and Biospecimen Shared Resource supported in part by the Vanderbilt-Ingram Cancer Center (P30CA68485). The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. A portion of this material is the result of work supported with resources and the use of facilities at the VA Tennessee Valley Healthcare System.

Funders	Funder number
Building Interdisciplinary Research Careers in Women's Health career development program
Building Interdisciplinary Research Careers in Women’s Health career development program	5T32MG080178– 09
NIH/NCRR
VA Tennessee Valley Healthcare System
Vanderbilt CTSA	UL1 RR024975-01
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	P50CA95103, R01CA121060, R01AT004660
National Childhood Cancer Registry – National Cancer Institute
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research	R01HD049675, R01HD043883, K12HD043483
NIH National Institute of Child Health and Human Development National Center for Medical Rehabilitation Research
Vanderbilt Ingram Cancer Center	P30CA68485
Vanderbilt Ingram Cancer Center

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title = "Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage",

abstract = "This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63\% of cases and 62\% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95\% CI 0.19-0.60, p = 2.45 × 10-4) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95\% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95\% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95\% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.",

author = "\{Velez Edwards\}, \{Digna R.\} and Edwards, \{Todd L.\} and Bray, \{Michael J.\} and Eric Torstenson and Sarah Jones and Shrubsole, \{Martha J.\} and Muff, \{Harvey J.\} and Hartmann, \{Katherine E.\}",

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AU - Velez Edwards, Digna R.

AU - Edwards, Todd L.

AU - Bray, Michael J.

AU - Torstenson, Eric

AU - Jones, Sarah

AU - Shrubsole, Martha J.

AU - Muff, Harvey J.

AU - Hartmann, Katherine E.

PY - 2017/12/1

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N2 - This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 × 10-4) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.

AB - This study evaluates the relationship between single nucleotide polymorphisms (SNPs) in nonsteroidal anti-inflammatory drug (NSAID) metabolism and related pathways and spontaneous abortion (SAB, gestation < 20 weeks) risk. Women were enrolled in Right from the Start (2004-2010) prospective cohort. Periconceptional NSAIDs reported through the sixth week of pregnancy were obtained from study interviews. We evaluated 201 SNPs in 600 European American women. Interaction analyses between NSAID use and SNPs were conducted using logistic regression, adjusted for confounders. We also evaluated prostaglandin E2 urinary metabolite (PGE-M) in an independent population for association with SNPs using linear regression. NSAID use was reported by 63% of cases and 62% controls. The most significant interaction was at prostacyclin synthase (PGIS) rs5602 (OR = 0.34, 95% CI 0.19-0.60, p = 2.45 × 10-4) and was significant after a Bonferroni correction. NSAID users were protected from SAB (OR = 0.78, 95% CI 0.56-1.10), while non-NSAID users were at increased risk (OR = 2.11, 95% CI 1.35-3.29) in rs5602 stratified analyses. rs5602 also associated with increased PGE-M levels (Beta = 0.09, 95% CI -0.002-0.19, p = 0.033). We identified an association between a PGIS variant and SAB risk that is modified by NSAIDs use during pregnancy and directly associated with increased levels of PGE metabolites. This suggests the potential use of genetic information to guide pharmaceutical intervention to prevent adverse pregnancy outcomes.

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Nonsteroidal Anti-inflammatory Drug Interaction with Prostacyclin Synthase Protects from Miscarriage

Abstract

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