title: CXCR3 Polymorphism and Expression Associate with Spontaneous Preterm Birth.
abstract: Spontaneous preterm birth (SPTB) is a major factor associating with deaths and with lowered quality of life in humans. Environmental and genetic factors influence the susceptibility. Previously, by analyzing families with recurrent SPTB in linkage analysis, we identified a linkage peak close to the gene encoding CXCR3. Present objectives were to investigate the association of CXCR3 with SPTB in Finnish mothers (n = 443) and infants (n = 747), to analyze CXCR3 expression levels in human placenta and levels of its ligands in umbilical cord blood, and to verify the influence of Cxcr3 on SPTB-associating cytokines in mice. We detected an association between an intronic CXCR3 polymorphism, rs2280964, and SPTB in infants from families with recurrent preterm births (p = 0.009 versus term controls, odds ratio 0.52, 95% confidence interval 0.32-0.86). The minor allele was protective and undertransmitted to SPTB infants (p = 0.007). In the placenta and fetal membranes, the rs2280964 major allele homozygotes had higher expression levels than minor allele homozygotes; decidual trophoblasts showed strong CXCR3 immunoreactivity. Expression was higher in SPTB placentas compared with those from elective deliveries. Concentration of a CXCR3 ligand, CXCL9, was increased in cord blood from SPTB, and the protective rs2280964 allele was associated with low CXCL9. In CXCR3-deficient mice (Mus musculus), SPTB-associating cytokines were not acutely increased in amniotic fluid after preterm birth-inducing dose of maternal LPS. Our results indicate that CXCR3 contributes to SPTB. Activation of CXCR3 signaling may disturb the maternal-fetal tolerance, and this may promote labor.
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland; minna.k.karjalainen@oulu.fi.
authors.forename: Minna K
authors.initials: MK
authors.lastname: Karjalainen
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Marja
authors.initials: M
authors.lastname: Ojaniemi
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Antti M
authors.initials: AM
authors.lastname: Haapalainen
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Mari
authors.initials: M
authors.lastname: Mahlman
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Annamari
authors.initials: A
authors.lastname: Salminen
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Huusko
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Tomi A
authors.initials: TA
authors.lastname: Määttä
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Tuula
authors.initials: T
authors.lastname: Kaukola
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Julia
authors.initials: J
authors.lastname: Anttonen
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.affiliation: Biocenter Oulu, University of Oulu, 90014 Oulu, Finland;
authors.forename: Ritva
authors.initials: R
authors.lastname: Haataja
authors.affiliation: Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland;
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.affiliation: Center for Pediatric Genomic Medicine, Kansas City, MO 64108;
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Kingsmore
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142; Institute for Molecular Medicine Finland, University of Helsinki, 00014 Helsinki, Finland; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114; Department of Neurology, Massachusetts General Hospital, Boston, MA 02114;
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: Center for Prevention of Preterm Birth, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland; BioMediTech, University of Tampere, 33014 Tampere, Finland; and Department of Pediatrics, Tampere University Hospital, 33521 Tampere, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Rämet
authors.affiliation: PEDEGO Research Center and Medical Research Center Oulu, University of Oulu, 90014 Oulu, Finland; Department of Children and Adolescents, Oulu University Hospital, 90029 Oulu, Finland;
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
mesh_terms: D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010920:Placenta / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D047928:Premature Birth / Q000235:genetics*; D054367:Receptors, CXCR3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C515187:CXCR3 protein, human; C515188:Cxcr3 protein, mouse; D016207:Cytokines; D054367:Receptors, CXCR3