Human Molecular Genetics Advance Access originally published online on February 14, 2008
Human Molecular Genetics 2008 17(11):1619-1630; doi:10.1093/hmg/ddn049
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Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth
1 Division of Cardiovascular Medicine 2 Department of Medicine 3 Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA 4 The Perinatal Research Center, Centennial Women's Hospital, Nashville, TN, USA 5 Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University, New Haven, CT, USA 6 Northern Atlantic Neuro Epidemiologic Alliance, Department of Epidemiology, University of Aarhus, Denmark
* To whom correspondence should be addressed at: Center for Human Genetics Research, 519 Light Hall, Vanderbilt University, Nashville, TN 37232, USA. Tel: +1 6153228036; Fax: +1 6153438619; Email: smwilliams{at}chgr.mc.vanderbilt.edu
Received January 8, 2008; Accepted February 12, 2008
Spontaneous preterm birth (PTB—gestational age <37 weeks) occurs in 
450 000 births annually in the United States and is one of the leading causes of neonatal morbidity and mortality. Risk of PTB is affected by complex gene–environment interactions that are not well understood. We examined the PTB candidate gene, Interleukin 6 (IL-6) and its receptor (IL6-R) in both Caucasian (145 PTB and 194 term maternal; 140 PTB and 179 term fetal) and African-American (76 PTB and 191 term maternal; 66 PTB and 183 term fetal) DNA. Eight single nucleotide polymorphisms (SNPs) in IL-6 and 22 SNPs in IL6R were examined for association with IL-6 amniotic fluid (AF) concentrations, as concentration of IL-6 is a hypothesized risk factor. In addition, IL-6 and IL6-R SNPs were analyzed for associations with PTB. Haplotype associations were tested by sliding windows. No strong single marker effects were observed in Caucasians; however, in African-American maternal IL-6R marker rs4553185 associated with PTB (allele P = 4.49 x 10–3 and genotype P = 0.01). The strongest haplotype associations were observed in IL-6R with IL-6 cytokine concentration as outcome: Caucasian fetal (rs4601580–rs4845618) P = 1.6 x 10–3 and African-American maternal (rs4601580–rs4845618–rs6687726–rs7549338) P = 2.30 x 10–3. Significant results converged on three regions in the two genes: in IL-6 markers rs1800797, rs1800796 and rs1800795; in IL-6R markers rs4075015, rs4601580, rs4645618, rs6687726 and rs7549338 and markers rs4845623, rs4537545 and rs4845625. In conclusion, our results suggest that IL-6 AF concentration, in situations of PTB, result from variation in IL-6 and more importantly IL-6R.