title: Association between polymorphisms at the GREM1 locus and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population.
abstract: BACKGROUND
  The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population.
  
  
  METHODS
  Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients.
  
  
  RESULTS
  Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts.
  
  
  CONCLUSIONS
  Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology.
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Adrianna
authors.initials: A
authors.lastname: Mostowska
authors.affiliation: Department of Paediatrics, Institute of Mother and Child, Warsaw, Poland.
authors.forename: Kamil K
authors.initials: KK
authors.lastname: Hozyasz
authors.affiliation: University Clinic of Medical Academy in Wroclaw and Department of Plastic Surgery Specialist Medical Center in Polanica Zdroj, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Wójcicki
authors.affiliation: Department of Animal Genetics and Breeding, National Research Institute of Animal Production, Balice, Poland.
authors.forename: Kacper
authors.initials: K
authors.lastname: Żukowski
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Dąbrowska
authors.affiliation: Department of Jaw Orthopaedics, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Lasota
authors.affiliation: Department of Orthodontics, Institute of Dentistry, The Medical University of Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Zadurska
authors.affiliation: Department of Orthodontics, Institute of Dentistry, The Medical University of Warsaw, Poland.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Radomska
authors.affiliation: Department of Jaw Orthopaedics, Medical University of Lublin, Lublin, Poland.
authors.forename: Izabela
authors.initials: I
authors.lastname: Dunin-Wilczyńska
authors.affiliation: Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland.
authors.forename: Paweł P
authors.initials: PP
authors.lastname: Jagodziński
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics* / Q000378:metabolism; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056426:Genetic Loci; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D011044:Poland; D011110:Polymorphism, Genetic
chemical_list: C486399:GREM1 protein, human; D036341:Intercellular Signaling Peptides and Proteins
keywords: GREM1; NSCL/P; functional polymorphism; sequencing