Characterizing short stature by insulin-like growth factor axis status and genetic associations: Results from the prospective, cross-sectional, epidemiogenetic EPIGROW study

Peter Clayton, Mireille Bonnemaire, Pascale Dutailly, Pascal Maisonobe, Laurent Naudin, Emmanuel Pham, Zhidong Zhang, Andrew Grupe, Arunthathi Thiagalingam, Patrice Denèfle, Klaus Kapelari, Martin Borkenstein, Robert Payer, Jean De Schepper, Sylvie Tenoutasse, Raoul Rooman, Margarita Craen, Yves Le Bouc, Michel Colle, Michel PolakEric Mallet, Marc Petrus, Mohamad Maghnie, Stefano Zucchini, Sandro Loche, Malgorzata Wasniewska, Giovanni Battista Pozzan, Gianni Bona, Nella Greggio, Piernicola Garofalo, Marco Cappa, Silivia Vannelli, Boudewijn Bakker, Jurrian Hoekx, Edgar G A H Van Mil, Evelyn Van Pinxteren-Nagler, Dorota Birkholz, Leszek Szewczyk, Corina Galesanu, José Ignacio Labarta, Itxaso Rica Echevarria, Jesús Argente, Gabriel Á Martos-Moren, Maria Caimari, Carlos Pavia Sesma, Elena Gallego Gomez, Charles Buchanan, Helen Storr, Assunta Albanese

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. Design and Setting: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). Participants: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Methods: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Results: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10-5, Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10-10; case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P <2.3 × 10-6) were associated with SS. At P <10-4, single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. Conclusions: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.

Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume98
Issue number6
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Somatomedins
Insulin-Like Growth Factor I
Genes
Insulin-Like Growth Factor Binding Protein 3
Polymorphism
Acids
Single Nucleotide Polymorphism
Nucleotides
Serum
Exome
Protein Kinases
Case-Control Studies
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Characterizing short stature by insulin-like growth factor axis status and genetic associations : Results from the prospective, cross-sectional, epidemiogenetic EPIGROW study. / Clayton, Peter; Bonnemaire, Mireille; Dutailly, Pascale; Maisonobe, Pascal; Naudin, Laurent; Pham, Emmanuel; Zhang, Zhidong; Grupe, Andrew; Thiagalingam, Arunthathi; Denèfle, Patrice; Kapelari, Klaus; Borkenstein, Martin; Payer, Robert; De Schepper, Jean; Tenoutasse, Sylvie; Rooman, Raoul; Craen, Margarita; Bouc, Yves Le; Colle, Michel; Polak, Michel; Mallet, Eric; Petrus, Marc; Maghnie, Mohamad; Zucchini, Stefano; Loche, Sandro; Wasniewska, Malgorzata; Pozzan, Giovanni Battista; Bona, Gianni; Greggio, Nella; Garofalo, Piernicola; Cappa, Marco; Vannelli, Silivia; Bakker, Boudewijn; Hoekx, Jurrian; Van Mil, Edgar G A H; Van Pinxteren-Nagler, Evelyn; Birkholz, Dorota; Szewczyk, Leszek; Galesanu, Corina; Labarta, José Ignacio; Echevarria, Itxaso Rica; Argente, Jesús; Martos-Moren, Gabriel Á; Caimari, Maria; Sesma, Carlos Pavia; Gomez, Elena Gallego; Buchanan, Charles; Storr, Helen; Albanese, Assunta.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 98, No. 6, 06.2013.

Research output: Contribution to journalArticle

Clayton, P, Bonnemaire, M, Dutailly, P, Maisonobe, P, Naudin, L, Pham, E, Zhang, Z, Grupe, A, Thiagalingam, A, Denèfle, P, Kapelari, K, Borkenstein, M, Payer, R, De Schepper, J, Tenoutasse, S, Rooman, R, Craen, M, Bouc, YL, Colle, M, Polak, M, Mallet, E, Petrus, M, Maghnie, M, Zucchini, S, Loche, S, Wasniewska, M, Pozzan, GB, Bona, G, Greggio, N, Garofalo, P, Cappa, M, Vannelli, S, Bakker, B, Hoekx, J, Van Mil, EGAH, Van Pinxteren-Nagler, E, Birkholz, D, Szewczyk, L, Galesanu, C, Labarta, JI, Echevarria, IR, Argente, J, Martos-Moren, GÁ, Caimari, M, Sesma, CP, Gomez, EG, Buchanan, C, Storr, H & Albanese, A 2013, 'Characterizing short stature by insulin-like growth factor axis status and genetic associations: Results from the prospective, cross-sectional, epidemiogenetic EPIGROW study', Journal of Clinical Endocrinology and Metabolism, vol. 98, no. 6. https://doi.org/10.1210/jc.2012-4283
Clayton, Peter ; Bonnemaire, Mireille ; Dutailly, Pascale ; Maisonobe, Pascal ; Naudin, Laurent ; Pham, Emmanuel ; Zhang, Zhidong ; Grupe, Andrew ; Thiagalingam, Arunthathi ; Denèfle, Patrice ; Kapelari, Klaus ; Borkenstein, Martin ; Payer, Robert ; De Schepper, Jean ; Tenoutasse, Sylvie ; Rooman, Raoul ; Craen, Margarita ; Bouc, Yves Le ; Colle, Michel ; Polak, Michel ; Mallet, Eric ; Petrus, Marc ; Maghnie, Mohamad ; Zucchini, Stefano ; Loche, Sandro ; Wasniewska, Malgorzata ; Pozzan, Giovanni Battista ; Bona, Gianni ; Greggio, Nella ; Garofalo, Piernicola ; Cappa, Marco ; Vannelli, Silivia ; Bakker, Boudewijn ; Hoekx, Jurrian ; Van Mil, Edgar G A H ; Van Pinxteren-Nagler, Evelyn ; Birkholz, Dorota ; Szewczyk, Leszek ; Galesanu, Corina ; Labarta, José Ignacio ; Echevarria, Itxaso Rica ; Argente, Jesús ; Martos-Moren, Gabriel Á ; Caimari, Maria ; Sesma, Carlos Pavia ; Gomez, Elena Gallego ; Buchanan, Charles ; Storr, Helen ; Albanese, Assunta. / Characterizing short stature by insulin-like growth factor axis status and genetic associations : Results from the prospective, cross-sectional, epidemiogenetic EPIGROW study. In: Journal of Clinical Endocrinology and Metabolism. 2013 ; Vol. 98, No. 6.
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abstract = "Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. Design and Setting: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). Participants: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Methods: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Results: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53{\%}, 30{\%}, and 0.8{\%}, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10-5, Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10-10; case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P <2.3 × 10-6) were associated with SS. At P <10-4, single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. Conclusions: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.",
author = "Peter Clayton and Mireille Bonnemaire and Pascale Dutailly and Pascal Maisonobe and Laurent Naudin and Emmanuel Pham and Zhidong Zhang and Andrew Grupe and Arunthathi Thiagalingam and Patrice Den{\`e}fle and Klaus Kapelari and Martin Borkenstein and Robert Payer and {De Schepper}, Jean and Sylvie Tenoutasse and Raoul Rooman and Margarita Craen and Bouc, {Yves Le} and Michel Colle and Michel Polak and Eric Mallet and Marc Petrus and Mohamad Maghnie and Stefano Zucchini and Sandro Loche and Malgorzata Wasniewska and Pozzan, {Giovanni Battista} and Gianni Bona and Nella Greggio and Piernicola Garofalo and Marco Cappa and Silivia Vannelli and Boudewijn Bakker and Jurrian Hoekx and {Van Mil}, {Edgar G A H} and {Van Pinxteren-Nagler}, Evelyn and Dorota Birkholz and Leszek Szewczyk and Corina Galesanu and Labarta, {Jos{\'e} Ignacio} and Echevarria, {Itxaso Rica} and Jes{\'u}s Argente and Martos-Moren, {Gabriel {\'A}} and Maria Caimari and Sesma, {Carlos Pavia} and Gomez, {Elena Gallego} and Charles Buchanan and Helen Storr and Assunta Albanese",
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month = "6",
doi = "10.1210/jc.2012-4283",
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TY - JOUR

T1 - Characterizing short stature by insulin-like growth factor axis status and genetic associations

T2 - Results from the prospective, cross-sectional, epidemiogenetic EPIGROW study

AU - Clayton, Peter

AU - Bonnemaire, Mireille

AU - Dutailly, Pascale

AU - Maisonobe, Pascal

AU - Naudin, Laurent

AU - Pham, Emmanuel

AU - Zhang, Zhidong

AU - Grupe, Andrew

AU - Thiagalingam, Arunthathi

AU - Denèfle, Patrice

AU - Kapelari, Klaus

AU - Borkenstein, Martin

AU - Payer, Robert

AU - De Schepper, Jean

AU - Tenoutasse, Sylvie

AU - Rooman, Raoul

AU - Craen, Margarita

AU - Bouc, Yves Le

AU - Colle, Michel

AU - Polak, Michel

AU - Mallet, Eric

AU - Petrus, Marc

AU - Maghnie, Mohamad

AU - Zucchini, Stefano

AU - Loche, Sandro

AU - Wasniewska, Malgorzata

AU - Pozzan, Giovanni Battista

AU - Bona, Gianni

AU - Greggio, Nella

AU - Garofalo, Piernicola

AU - Cappa, Marco

AU - Vannelli, Silivia

AU - Bakker, Boudewijn

AU - Hoekx, Jurrian

AU - Van Mil, Edgar G A H

AU - Van Pinxteren-Nagler, Evelyn

AU - Birkholz, Dorota

AU - Szewczyk, Leszek

AU - Galesanu, Corina

AU - Labarta, José Ignacio

AU - Echevarria, Itxaso Rica

AU - Argente, Jesús

AU - Martos-Moren, Gabriel Á

AU - Caimari, Maria

AU - Sesma, Carlos Pavia

AU - Gomez, Elena Gallego

AU - Buchanan, Charles

AU - Storr, Helen

AU - Albanese, Assunta

PY - 2013/6

Y1 - 2013/6

N2 - Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. Design and Setting: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). Participants: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Methods: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Results: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10-5, Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10-10; case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P <2.3 × 10-6) were associated with SS. At P <10-4, single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. Conclusions: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.

AB - Context: Serum IGF-I levels are often low in patients with short stature (SS) without defined etiology. Hence, genetic investigations have focused on the GH-IGF-I axis. Objective: Our objectives were to characterize IGF-I axis status and search for a broader range of genetic associations in children with SS and normal GH. Design and Setting: We conducted a prospective, cross-sectional, epidemiogenetic case-control study in 9 European countries (2008-2010). Participants: Children (n = 275) aged ≥2 years with SS without defined etiology (≤-2.5 height SD score [SDS]) and ≥1 peak GH ≥7 μg/L) were recruited. Methods: Serum IGF-I, IGF-binding protein-3 (IGFBP-3), and acid-labile subunit (ALS) levels were measured in a central laboratory. Candidate gene exome sequencing was performed in this cohort and ethnicity-matched controls. Results: Serum IGF-I, IGFBP-3, and ALS levels were highly correlated, but there was a discrepancy between prevalence of IGF-I, IGFBP-3, and ALS deficiencies (53%, 30%, and 0.8%, respectively). An insertion-deletion (Indel) on the IGF1 gene (P = 1.2 × 10-5, Bonferroni-corrected; case vs control frequency: 0.04 vs 0.112), an Indel on NFKB1 (P = 1.36 × 10-10; case vs control frequency: 0.464 vs 0.272), and 2 single-nucleotide polymorphisms on ZBTB38 (P <2.3 × 10-6) were associated with SS. At P <10-4, single-nucleotide polymorphisms on genes related to protein kinase regulation, MAPK, and Fanconi pathways were also associated with SS. Conclusions: IGF-I deficiency is a common feature in SS without defined etiology; an Indel in the IGF1 gene was associated with SS. However, genes involved in transcriptional regulation (NFKB1 and ZBTB38) and growth factor signaling were also associated, providing further candidates for genetic investigations on individual patients.

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