title: PAX9 and TGFB3 are linked to susceptibility to nonsyndromic cleft lip with or without cleft palate in the Japanese: population-based and family-based candidate gene analyses.
abstract: The prevalence of nonsyndromic cleft lip with or without cleft palate (CL/P) and cleft palate only (CPO) are believed to be higher in the Japanese than in Americans, Europeans or Africans. The purpose of this study was to investigate, in a Japanese population, relationships between CL/P or CPO and seven candidate genes (TGFB3, DLX3, PAX9, CLPTM1, TBX10, PVRL1, TBX22) that showed positive associations in other populations and are expressed in the oral/lip region in developing mice. We first searched for mutations in these genes among 112 CL/P and 16 CPO patients, and found a heterozygous missense mutation (640A > G, S214G) in exon 3 of PAX9 in two sibs with CL/P and their phenotypically normal mother from a Japanese family. A population-based case-control analysis and a family-based transmission disequilibrium test (TDT), using single nucleotide polymorphisms (SNPs), and two-SNP haplotypes of the genes, between the 112 CL/P cases with their parents and 192 controls indicated a significant association at one SNP site, IVS1 + 5321, in TGFB3 with a P-value of 0.0016. Population-based haplotyping revealed that the association was most significant for haplotype "A/A" consisting of IVS1 + 5321 and IVS1 - 1572; TDT also gave a P-value of 0.0252 in this haplotype.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.|Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Eisaburo
authors.initials: E
authors.lastname: Ichikawa
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.|Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nakano
authors.affiliation: Division of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Sadanori
authors.initials: S
authors.lastname: Akita
authors.affiliation: Division of Plastic and Reconstructive Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Hirano
authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kinoshita
authors.affiliation: Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kondo
authors.affiliation: Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kishino
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tokyo Dental College, Chiba, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiyama
authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.affiliation: Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. kyoshi@net.nagasaki-u.ac.jp.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Kawaguchi, Japan. kyoshi@net.nagasaki-u.ac.jp.
authors.forename: Koh-Ichiro
authors.initials: KI
authors.lastname: Yoshiura
mesh_terms: D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007564:Japan; D008297:Male; D008969:Molecular Sequence Data; D051764:PAX9 Transcription Factor / Q000737:chemistry / Q000235:genetics*; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D016212:Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D053782:Transforming Growth Factor beta3
chemical_list: D051764:PAX9 Transcription Factor; C497323:PAX9 protein, human; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3