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Am J Perinatol 2024; 41(01): 044-052
DOI: 10.1055/s-0041-1740072
Original Article

Do Genetic Variants Modify the Effect of Smoking on Risk of Preeclampsia in Pregnancy?

Anna E. Bauer    *
1   Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Christy L. Avery
1   Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
2   Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Min Shi
3   Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina
,
Clarice R. Weinberg
3   Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina
,
Andrew F. Olshan
1   Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Quaker E. Harmon
4   Epidemiology Branch, National Institute of Environmental Health Sciences, Durham, North Carolina
,
Jingchun Luo
5   Mammalian Genotyping Core, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Jenny Yang
6   Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Tracy Manuck
7   Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
,
Michael C. Wu
8   Biostatistics and Biomathematics Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
,
Kari Klungsøyr
9   Division for Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway
10   Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
,
Lill Trogstad
9   Division for Mental and Physical Health, Norwegian Institute of Public Health, Oslo, Norway
,
Per Magnus
11   Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
,
Stephanie M. Engel
1   Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
› Author Affiliations
Funding This research was supported in part by NICHD R01HD058008 and the Intramural Research Program of the NIH, NIEHS Z01-ES103086. AEB was supported in part by NICHD T32 HD052468. The Norwegian Mother, Father and Child Cohort Study is supported by the Norwegian Ministry of Health, contract N01-ES-75558 with the NIH/NIEHS, NIH/NINDS (grant no.1 U01 NS 047537-01), and the Norwegian Research Council/FUGE (grant no. 151918/S10). This work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700.
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Abstract

Objective Maternal smoking is associated with as much as a 50% reduced risk of preeclampsia, despite increasing risk of other poor pregnancy outcomes that often co-occur with preeclampsia, such as preterm birth and fetal growth restriction. Researchers have long sought to understand whether this perplexing association is biologically based, or a result of noncausal mechanisms. We examined whether smoking-response genes modify the smoking-preeclampsia association to investigate potential biological explanations.

Study Design We conducted a nested case–control study within the Norwegian Mother, Father and Child Birth Cohort (1999–2008) of 2,596 mother–child dyads. We used family-based log-linear Poisson regression to examine modification of the maternal smoking-preeclampsia relationship by maternal and fetal single nucleotide polymorphisms involved in cellular processes related to components of cigarette smoke (n = 1,915 with minor allele frequency ≥10%). We further investigated the influence of smoking cessation during pregnancy.

Results Three polymorphisms showed overall (p < 0.001) multiplicative interaction between smoking and maternal genotype. For rs3765692 (TP73) and rs10770343 (PIK3C2G), protection associated with smoking was reduced with two maternal copies of the risk allele and was stronger in continuers than quitters (interaction p = 0.02 for both loci, based on testing 3-level smoking by 3-level genotype). For rs2278361 (APAF1) the inverse smoking-preeclampsia association was eliminated by the presence of a single risk allele, and again the trend was stronger in continuers than in quitters (interaction p = 0.01).

Conclusion Evidence for gene–smoking interaction was limited, but differences by smoking cessation warrant further investigation. We demonstrate the potential utility of expanded dyad methods and gene–environment interaction analyses for outcomes with complex relationships between maternal and fetal genotypes and exposures.

Key Points

  • Maternal and fetal genotype may differentially influence preeclampsia.

  • Smoking-related genes did not strongly modify smoking–preeclampsia association.

  • Smoking cessation reduced strength of gene by smoking interactions.

Keywords

carbon monoxide - detoxification - gene–environment interaction - genetics - MoBa - mother–child dyad - nitric oxide - Norwegian Mother Father and Child Cohort Study - preeclampsia - pregnancy - smoking

* Present Address: Department of Psychiatry, Perinatal Psychiatry Program, School of Medicine, University of North Carolina at Chapel Hill, CB# 7160, Chapel Hill, NC 27599-7160. MS, CRW, and QEH are employees of US federal agency, National Institute of Environmental Health Sciences.


Supplementary Material



Publication History

Received: 22 September 2020

Accepted: 03 October 2021

Article published online:
28 November 2021

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