title: Ancestry informative markers and selected single nucleotide polymorphisms in immunoregulatory genes on preterm labor and preterm premature rupture of membranes: a case control study.
abstract: BACKGROUND
  A genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. The aim of this study was to evaluate the contribution of maternal and fetal SNPs in the IL1B, IL6, IL6R, TNFA, TNFR, IL10, TLR2, TLR4, MMP9, TIMP1 and TIMP2 genes and the influence of ancestry background in the susceptibility to PTL or PPROM in Brazilian women.
  
  
  METHODS
  Case-control study conducted at a tertiary hospital in São Paulo State, Brazil. We included women with PTL or PPROM and their babies (PTL: 136 women and 88 babies; PPROM: 65 women and 44 babies). Control group included 402 mother-babies pairs of term deliveries. Oral swabs were collected for identification of AIMs by fragment analysis and SNPs by Taqman® SNP Genotyping Assays and PCR. Linkage Disequilibrium and Hardy-Weinberg proportions were evaluated using Genepop 3.4. Haplotypes were inferred using the PHASE algorithm. Allele, genotype and haplotype frequencies were compared by Fisher's exact test or χ (2) and Odds Ratio. Logistic regression was performed. Clinical and sociodemographic data were analyzed by Fisher's exact test and Mann-Whitney.
  
  
  RESULTS
  PTL was associated with European ancestry and smoking while African ancestry was protective. The fetal alleles IL10-592C (rs800872) and IL10-819C (rs1800871) were also associated with PTL and the maternal haplotype TNFA-308G-238A was protective. Maternal presence of IL10-1082G (rs1800896) and TLR2A (rs4696480) alleles increased the risk for PPROM while TNFA-238A (rs361525) was protective. Family history of PTL/PPROM was higher in cases, and time to delivery was influenced by IL1B-31T (rs1143627) and TLR4-299G (rs4986790).
  
  
  CONCLUSIONS
  There is an association between European ancestry and smoking and PTL in our Brazilian population sample. The presence of maternal or fetal alleles that modify the inflammatory response increase the susceptibility to PTL and PPROM. The family history of PTL/PPROM reinforces a role for genetic polymorphisms in susceptibility to these outcomes.
authors: Department of Pathology, Botucatu Medical School, São Paulo State University - UNESP, Distrito de Rubião Júnior, 18618-970, Botucatu, São Paulo, Brazil. bru_rar@hotmail.com.
authors: Bruna Ribeiro de Andrade
authors: BR
authors: Ramos
authors: Department of Pathology, Botucatu Medical School, São Paulo State University - UNESP, Distrito de Rubião Júnior, 18618-970, Botucatu, São Paulo, Brazil. nieledm@gmail.com.
authors: Niele Dias
authors: ND
authors: Mendes
authors: Blood Transfusion Center, Botucatu Medical School, São Paulo State University - UNESP, Botucatu, São Paulo, Brazil. alineaki@gmail.com.
authors: Aline Aki
authors: AA
authors: Tanikawa
authors: Department of Genetics, Biological Sciences Institute, Pará Federal University - UFPA, Belém, Pará, Brazil. marcosmata52@yahoo.com.br.
authors: Marcos Antônio Trindade
authors: MA
authors: Amador
authors: Department of Genetics, Biological Sciences Institute, Pará Federal University - UFPA, Belém, Pará, Brazil. sidneysantos@ufpa.br.
authors: Ney Pereira Carneiro
authors: NP
authors: dos Santos
authors: Department of Genetics, Biological Sciences Institute, Pará Federal University - UFPA, Belém, Pará, Brazil. sidneysantos@ufpa.br.
authors: Sidney Emanuel Batista
authors: SE
authors: dos Santos
authors: Department of Pathology, Botucatu Medical School, São Paulo State University - UNESP, Distrito de Rubião Júnior, 18618-970, Botucatu, São Paulo, Brazil. erick.castelli@gmail.com.
authors: Erick C
authors: EC
authors: Castelli
authors: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA. switkin@med.cornell.edu.
authors: Steven S
authors: SS
authors: Witkin
authors: Department of Pathology, Botucatu Medical School, São Paulo State University - UNESP, Distrito de Rubião Júnior, 18618-970, Botucatu, São Paulo, Brazil. mgsilva@fmb.unesp.br.
authors: Márcia Guimarães
authors: MG
authors: da Silva
mesh_terms: D000328:Adult; D000483:Alleles; D044383:Black People / Q000235:genetics; D001938:Brazil; D016022:Case-Control Studies; D016207:Cytokines / Q000235:genetics*; D005260:Female; D005322:Premature Rupture of Fetal Membranes / Q000235:genetics*; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000235:genetics; D007752:Obstetric Labor, Premature / Q000235:genetics*; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D012907:Smoking / Q000009:adverse effects; D051195:Toll-Like Receptor 2 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; D005819:Genetic Markers; C508609:IL10 protein, human; C495342:TLR2 protein, human; C439524:TNF protein, human; D051195:Toll-Like Receptor 2; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10