title: The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses: insights into pathogenesis.
abstract: Hereditary Multiple Exostoses (HME) is an autosomal-dominant disorder characterized by benign cartilage tumors (exostoses) forming near the growth plates, leading to severe health problems. EXT1 and EXT2 are the two genes known to harbor heterozygous loss-of-function mutations that account for the vast majority of the primary genetic component of HME. However, patients present with wide clinical heterogeneity, suggesting that modifier genes play a role in determining severity. Our previous work has pointed to an imbalance of β-catenin signaling being involved in the pathogenesis of osteochondroma formation. TCF7L2 is one of the key 'gate-keeper' TCF family members for Wnt/β-catenin signaling pathway, and TCF7L2 and EXT2 are among the earliest associated loci reported in genome wide appraisals of type 2 diabetes (T2D). Thus we investigated if the key T allele of single nucleotide polymorphism (SNP) rs7903146 within the TCF7L2 locus, which is strongly over-represented among T2D cases, was also associated with HME. We leveraged genotype data available from ongoing GWAS efforts from genomics and orthopedic centers in the US, Canada and Italy. Collectively 213 cases and 1890 controls were analyzed and, surprisingly, the T allele was in fact significantly under-represented in the HME patient group [P = 0.009; odds ratio = 0.737 (95% C.I. 0.587-0.926)]; in addition, the direction of effect was consistent within each individual cohort. Immunohistochemical analyses revealed that TCF7L2 is differentially expressed and distributed in normal human growth plate zones, and exhibits substantial variability in human exostoses in terms of staining intensity and distribution. In summary, the data indicate that there is a putative genetic connection between TCF7L2 and EXT in the context of HME. Given this observation, we suggest that these loci could possibly modulate shared pathways, in particular with respect to β-catenin, and their respective variants interplay to influence HME pathogenesis as well as T2D.
authors.affiliation: Division of Orthopedic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Federica
authors.initials: F
authors.lastname: Sgariglia
authors.affiliation: Department of Medical Genetics and Skeletal Rare Diseases, IRCCS Rizzoli Orthopaedic Institute (IOR), Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pedrini
authors.affiliation: Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Bradfield
authors.affiliation: Department of Pathology & Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Tricia R
authors.initials: TR
authors.lastname: Bhatti
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
authors.forename: Pio
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: Division of Orthopedic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Dormans
authors.affiliation: Division of Orthopedic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Aruni T
authors.initials: AT
authors.lastname: Gunawardena
authors.affiliation: Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.affiliation: Department of Pediatrics, Division of Pediatric Research, The University of Texas Medical School at Houston, Houston, TX USA.
authors.forename: Jacqueline T
authors.initials: JT
authors.lastname: Hecht
authors.affiliation: Department of Medical Genetics and Skeletal Rare Diseases, IRCCS Rizzoli Orthopaedic Institute (IOR), Bologna, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Sangiorgi
authors.affiliation: Division of Orthopedic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pacifici
authors.affiliation: Division of Orthopedic Surgery, Department of Surgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
authors.forename: Motomi
authors.initials: M
authors.lastname: Enomoto-Iwamoto
authors.affiliation: Center for Applied Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: grants@chop.edu.
authors.forename: Struan F A
authors.initials: SF
authors.lastname: Grant
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002356:Cartilage / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005097:Exostoses, Multiple Hereditary / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D016017:Odds Ratio; D015831:Osteochondroma / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism; D000099058:Exostosin 1
chemical_list: C495270:CTNNB1 protein, human; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1
keywords: Exostosin (EXT); Hereditary Multiple Exostoses (HME); Osteochondroma; Transcription factor 7 like 2 (TCF7L2); Type 2 diabetes (T2D)