Interleukin-1 Receptor Antagonist Polymorphism and Birth Timing: Pathway Analysis Among African American Women
Shannon L Gillespie1, Jeremy L Neal, Lisa M Christian
1Shannon L. Gillespie, PhD, MS, RN, is Postdoctoral Researcher, College of Nursing, The Ohio State University, Columbus. Jeremy L. Neal, PhD, CNM, RN, is Assistant Professor, School of Nursing, Vanderbilt University, Nashville, Tennessee. Lisa M. Christian, PhD, is Associate Professor, Department of Psychiatry and Behavioral Health, The Institute for Behavioral Medicine Research, and Department of Obstetrics and Gynecology, Wexner Medical Center, Department of Psychology, The Ohio State University, Columbus. Laura A. Szalacha, EdD, is Professor, College of Nursing, University of Arizona, Tucson. Donna O. McCarthy, PhD, RN, FAAN, is Professor, Marquette University, Milwaukee, Wisconsin. Pamela J. Salsberry, PhD, RN, FAAN, is Professor, Department of Health Behavior and Health Promotion, College of Public Health, The Ohio State University, Columbus.
Insights
African American women with the IL1RN gene GG genotype may experience earlier birth due to reduced inhibition of interleukin-1 beta (IL-1β) production, impacting inflammatory responses and newborn health.
Area of Science:
- Reproductive biology
- Immunology
- Genetics
Background:
- Timing of birth is crucial for newborn health.
- African American women face higher risks of preterm birth, often linked to inflammation.
- Interleukin-1 receptor antagonist (IL-1RN) gene variants are associated with early birth, but pathways remain unclear.
Purpose of the Study:
- To investigate the association between an IL1RN gene variant and birth timing in African American women.
- To determine if this association is mediated by IL-1Ra production or linked to IL-1β production.
- To explore inflammatory pathway differences in relation to birth timing within this demographic.
Main Methods:
- A prospective cohort study of 89 African American women with uncomplicated pregnancies.
- Genotyping of IL1RN single-nucleotide polymorphism (SNP) rs2637988.
- Quantification of lipopolysaccharide-stimulated IL-1Ra and IL-1β production; birth timing determined by medical records.
Main Results:
- Women with the GG genotype had earlier births compared to AA/AG genotypes (p=0.04).
- No mediation effect of IL1RN SNP rs2637988 on birth timing via IL-1Ra production was found.
- GG genotype was linked to reduced IL-1β inhibition (p=0.03), and higher IL-1β was marginally associated with earlier birth (p=0.05).
Conclusions:
- The GG genotype of IL1RN may increase early birth risk due to impaired IL-1β inhibition, potentially initiating inflammatory responses.
- Further research into inflammatory pathways among African American women is crucial for identifying risk markers and interventions for early birth.
Background:
Timing of birth is a major determinant of newborn health. African American women are at increased risk for early birth, particularly via the inflammatory pathway. Variants of the IL1RN gene, which encode the interleukin-1 receptor antagonist (IL-1Ra) protein, are implicated in early birth. The biological pathways linking these variables remain unclear. Evidence also suggests that inflammatory pathways differ by race; however, studies among African American women are lacking.
Objectives:
We assessed whether an IL1RN variant was associated with timing of birth among African American women and whether this relationship was mediated by lower anti-inflammatory IL-1Ra production or related to a decrease in inhibition of proinflammatory IL-1β production.
Methods:
A candidate gene study using a prospective cohort design was used. We collected blood samples at 28-32 weeks of gestation among African American women experiencing an uncomplicated pregnancy (N = 89). IL1RN single-nucleotide polymorphism (SNP) rs2637988 was genotyped, and lipopolysaccharide-stimulated IL-1Ra and IL-1β production was quantified. Medical record review determined timing of birth.
Results:
Women with GG genotype gave birth earlier than women with AA/AG genotypes (b* = .21, p = .04). There was no indirect effect of IL1RN SNP rs2637988 allele status on timing of birth through IL-1Ra production, as evidenced by a nonsignificant product of coefficients in mediational analyses (ab = .006, 95% CI [-0.05, 0.13]). Women with GG genotype showed less inhibition of IL-1β production for a unit positive difference in IL-1Ra production than women with AA/AG genotypes (b* = .93, p = .03). Greater IL-1β production at 28-32 weeks of pregnancy was marginally associated with earlier birth (b* = .21, p = .05).
Discussion:
Women with GG genotype may be at risk for earlier birth because of diminished IL-1β inhibition, allowing for initiation of a robust inflammatory response upon even mild immune challenge. Study of inflammatory contributions to early birth among African American women may be key to identifying potential prognostic markers of risk and targeted preventive interventions.
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