Human Molecular Genetics Advance Access published online on February 14, 2008
Human Molecular Genetics, 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, Department of Medicine, and Center for Human Genetics Research, Vanderbilt University, Nashville, TN, USA 2 The Perinatal Research Center, Nashville, TN, USA
* Correspondence should be addressed to: Scott M. Williams, Ph.D. Center for Human Genetics Research 519 Light Hall Vanderbilt University Nashville, TN 37232 Telephone: 615-322-8036 Fax: 615-343-8619 Email: smwilliams{at}chgr.mc.vanderbilt.edu
Received January 8, 2008; Revised February 12, 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 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 = 4.49x10–3 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 = 1.6x10–3 and African American maternal (rs4601580-rs4845618-rs6687726-rs7549338) p = 2.30x10–3. 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 amniotic fluid concentration, in situations of PTB, result from variation in IL-6 and more importantly IL-6R.