The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses

Insights into pathogenesis

Federica Sgariglia, Elena Pedrini, Jonathan P. Bradfield, Tricia R. Bhatti, Pio D'Adamo, John P. Dormans, Aruni T. Gunawardena, Hakon Hakonarson, Jacqueline T. Hecht, Luca Sangiorgi, Maurizio Pacifici, Motomi Enomoto-Iwamoto, Struan F A Grant

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)123-127
Number of pages5
JournalBone
Volume72
DOIs
Publication statusPublished - Mar 1 2015

Fingerprint

Multiple Hereditary Exostoses
Type 2 Diabetes Mellitus
Alleles
Catenins
Exostoses
Growth Plate
Modifier Genes
Osteochondroma
Wnt Signaling Pathway
Genome-Wide Association Study
Genomics
Italy
Cartilage
Canada
Orthopedics
Single Nucleotide Polymorphism
Odds Ratio
Genotype
Genome
Staining and Labeling

Keywords

  • Exostosin (EXT)
  • Hereditary Multiple Exostoses (HME)
  • Osteochondroma
  • Transcription factor 7 like 2 (TCF7L2)
  • Type 2 diabetes (T2D)

ASJC Scopus subject areas

  • Physiology
  • Endocrinology, Diabetes and Metabolism
  • Histology

Cite this

The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses : Insights into pathogenesis. / Sgariglia, Federica; Pedrini, Elena; Bradfield, Jonathan P.; Bhatti, Tricia R.; D'Adamo, Pio; Dormans, John P.; Gunawardena, Aruni T.; Hakonarson, Hakon; Hecht, Jacqueline T.; Sangiorgi, Luca; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi; Grant, Struan F A.

In: Bone, Vol. 72, 01.03.2015, p. 123-127.

Research output: Contribution to journalArticle

Sgariglia, F, Pedrini, E, Bradfield, JP, Bhatti, TR, D'Adamo, P, Dormans, JP, Gunawardena, AT, Hakonarson, H, Hecht, JT, Sangiorgi, L, Pacifici, M, Enomoto-Iwamoto, M & Grant, SFA 2015, 'The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses: Insights into pathogenesis', Bone, vol. 72, pp. 123-127. https://doi.org/10.1016/j.bone.2014.11.024
Sgariglia, Federica ; Pedrini, Elena ; Bradfield, Jonathan P. ; Bhatti, Tricia R. ; D'Adamo, Pio ; Dormans, John P. ; Gunawardena, Aruni T. ; Hakonarson, Hakon ; Hecht, Jacqueline T. ; Sangiorgi, Luca ; Pacifici, Maurizio ; Enomoto-Iwamoto, Motomi ; Grant, Struan F A. / The type 2 diabetes associated rs7903146 T allele within TCF7L2 is significantly under-represented in Hereditary Multiple Exostoses : Insights into pathogenesis. In: Bone. 2015 ; Vol. 72. pp. 123-127.
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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.",
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T2 - Insights into pathogenesis

AU - Sgariglia, Federica

AU - Pedrini, Elena

AU - Bradfield, Jonathan P.

AU - Bhatti, Tricia R.

AU - D'Adamo, Pio

AU - Dormans, John P.

AU - Gunawardena, Aruni T.

AU - Hakonarson, Hakon

AU - Hecht, Jacqueline T.

AU - Sangiorgi, Luca

AU - Pacifici, Maurizio

AU - Enomoto-Iwamoto, Motomi

AU - Grant, Struan F A

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N2 - 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.

AB - 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.

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