title: A potential novel spontaneous preterm birth gene, AR, identified by linkage and association analysis of X chromosomal markers.
abstract: Preterm birth is the major cause of neonatal mortality and morbidity. In many cases, it has severe life-long consequences for the health and neurological development of the newborn child. More than 50% of all preterm births are spontaneous, and currently there is no effective prevention. Several studies suggest that genetic factors play a role in spontaneous preterm birth (SPTB). However, its genetic background is insufficiently characterized. The aim of the present study was to perform a linkage analysis of X chromosomal markers in SPTB in large northern Finnish families with recurrent SPTBs. We found a significant linkage signal (HLOD = 3.72) on chromosome locus Xq13.1 when the studied phenotype was being born preterm. There were no significant linkage signals when the studied phenotype was giving preterm deliveries. Two functional candidate genes, those encoding the androgen receptor (AR) and the interleukin-2 receptor gamma subunit (IL2RG), located near this locus were analyzed as candidates for SPTB in subsequent case-control association analyses. Nine single-nucleotide polymorphisms (SNPs) within these genes and an AR exon-1 CAG repeat, which was previously demonstrated to be functionally significant, were analyzed in mothers with preterm delivery (n = 272) and their offspring (n = 269), and in mothers with exclusively term deliveries (n = 201) and their offspring (n = 199), all originating from northern Finland. A replication study population consisting of individuals born preterm (n = 111) and term (n = 197) from southern Finland was also analyzed. Long AR CAG repeats (≥ 26) were overrepresented and short repeats (≤ 19) underrepresented in individuals born preterm compared to those born at term. Thus, our linkage and association results emphasize the role of the fetal genome in genetic predisposition to SPTB and implicate AR as a potential novel fetal susceptibility gene for SPTB.
authors.affiliation: Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
authors.forename: Minna K
authors.initials: MK
authors.lastname: Karjalainen
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Huusko
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.forename: Jenni
authors.initials: J
authors.lastname: Sotkasiira
authors.forename: Aino
authors.initials: A
authors.lastname: Luukkonen
authors.forename: Kari
authors.initials: K
authors.lastname: Teramo
authors.forename: Jevon
authors.initials: J
authors.lastname: Plunkett
authors.forename: Verneri
authors.initials: V
authors.lastname: Anttila
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Ritva
authors.initials: R
authors.lastname: Haataja
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
mesh_terms: D016022:Case-Control Studies; D041321:Chromosomes, Human, X / Q000235:genetics*; D005190:Family; D005260:Female; D005333:Fetus / Q000473:pathology; D005387:Finland; D056726:Genetic Association Studies; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D008126:Lod Score; D016015:Logistic Models; D008297:Male; D008957:Models, Genetic; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047928:Premature Birth / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D015203:Reproducibility of Results; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: C410798:AR protein, human; D005819:Genetic Markers; D053631:Interleukin Receptor Common gamma Subunit; D011944:Receptors, Androgen