Cytokine gene polymorphisms and length of gestation

Abstract

Objective: To estimate whether there is an association between length of gestation and gene polymorphisms that effect transcription of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), or interleukin-1β (IL-1β).

Methods: Blood for DNA analysis was collected from 834 women at high risk enrolled in a randomized, clinical trial of omega-3 fatty acid supplementation for the prevention of recurrent preterm birth. Genotyping was performed for three single nucleotide polymorphisms (SNPs), TNF-α -308, IL-6 -174, and IL-1β +3954. Women with the homozygous minor genotype were compared with women with either the heterozygous or the homozygous major genotype. Kaplan-Meier curves of gestational age at delivery and odds ratios for extreme preterm delivery were adjusted for African-American race and treatment group.

Results: Women who were homozygous for the minor allele at the -308 position in the promoter region of the TNF-α gene had significantly shorter length of gestation than women who were either heterozygous or homozygous for the major allele (adjusted hazard ratio 1.74, 95% confidence interval [CI] 1.04-2.90, P=.03). Among women with this genotype, 20% (3/15) experienced extreme spontaneous preterm delivery (less than 28 weeks of gestation; adjusted odds ratio 7.51, 95% CI 1.84-30.72, P=.005). There was no difference in length of gestation or risk of extreme spontaneous preterm delivery by genotype for the IL-6 -174 or the IL-1β +3954 SNP.

Conclusion: Polymorphism at the -308 position in the TNF-α promoter region is associated with shorter gestation and an increased risk of spontaneous extreme preterm delivery.

Clinical trial registration: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00135902.

Level of evidence: II.

Conflict of interest statement

Financial Disclosure:

The authors did not disclose any potential conflicts of interest.

Figures

Fig. 1

Kaplan-Meier curve. Length of gestation censored at 40 weeks of gestation by tumor necrosis factor (TNF)-α −308 genotype. TNF-α −308 AG/GG represents women heterozygous and homozygous for the usual allele. TNF-α −308 AA represents women homozygous for the minor allele. Harper. Inflammatory Cytokine Gene Polymorphisms. Obstet Gynecol 2011.

Fig. 2

Kaplan-Meier curve. Length of gestation censored at 40 weeks by interleukin (IL)-6–174 genotype. IL-6–174 GC/GG represents women heterozygous and homozygous for the usual allele. IL-6–174 CC represents women homozygous for the minor allele. Harper. Inflammatory Cytokine Gene Polymorphisms. Obstet Gynecol 2011.

Fig. 3

Kaplan-Meier curve. Length of gestation censored at 40 weeks of gestation by interleukin (IL)-1β +3954 genotype. IL-1β +3954 CT/CC represents women heterozygous and homozygous for the usual allele. IL-1β +3954 TT represents women homozygous for the minor allele. Harper. Inflammatory Cytokine Gene Polymorphisms. Obstet Gynecol 2011.