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Open Access Research article

Effect of interleukin-6 polymorphism on risk of preterm birth within population strata: a meta-analysis

Wilfred Wu1, Erin A S Clark2, Gregory J Stoddard3, W Scott Watkins1, M Sean Esplin2, Tracy A Manuck2, Jinchuan Xing14, Michael W Varner2 and Lynn B Jorde1*

Author Affiliations

1 Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA

2 Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

3 Study Design and Biostatistics Center, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA

4 Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

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BMC Genetics 2013, 14:30  doi:10.1186/1471-2156-14-30

Published: 25 April 2013

Abstract

Background

Because of the role of inflammation in preterm birth (PTB), polymorphisms in and near the interleukin-6 gene (IL6) have been association study targets. Several previous studies have assessed the association between PTB and a single nucleotide polymorphism (SNP), rs1800795, located in the IL6 gene promoter region. Their results have been inconsistent and SNP frequencies have varied strikingly among different populations. We therefore conducted a meta-analysis with subgroup analysis by population strata to: (1) reduce the confounding effect of population structure, (2) increase sample size and statistical power, and (3) elucidate the association between rs1800975 and PTB.

Results

We reviewed all published papers for PTB phenotype and SNP rs1800795 genotype. Maternal genotype and fetal genotype were analyzed separately and the analyses were stratified by population. The PTB phenotype was defined as gestational age (GA) < 37 weeks, but results from earlier GA were selected when available. All studies were compared by genotype (CC versus CG+GG), based on functional studies.

For the maternal genotype analysis, 1,165 PTBs and 3,830 term controls were evaluated. Populations were stratified into women of European descent (for whom the most data were available) and women of heterogeneous origin or admixed populations. All ancestry was self-reported. Women of European descent had a summary odds ratio (OR) of 0.68, (95% confidence interval (CI) 0.51 – 0.91), indicating that the CC genotype is protective against PTB. The result for non-European women was not statistically significant (OR 1.01, 95% CI 0.59 - 1.75). For the fetal genotype analysis, four studies were included; there was no significant association with PTB (OR 0.98, 95% CI 0.72 - 1.33). Sensitivity analysis showed that preterm premature rupture of membrane (PPROM) may be a confounding factor contributing to phenotype heterogeneity.

Conclusions

IL6 SNP rs1800795 genotype CC is protective against PTB in women of European descent. It is not significant in other heterogeneous or admixed populations, or in fetal genotype analysis.

Population structure is an important confounding factor that should be controlled for in studies of PTB.

Keywords:
Preterm birth; Preterm delivery; Premature birth; Premature delivery; Genetic polymorphism; Genetic variant; Single nucleotide polymorphism; SNP; Interleukin-6; Cytokine; Population structure; HapMap project; Phenotype heterogeneity