Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer

Katharina Nimptsch, Krasimira Aleksandrova, Heiner Boeing, Jürgen Janke, Young Ae Lee, Mazda Jenab, So Yeon Kong, Konstantinos K. Tsilidis, Elisabete Weiderpass, H. Bas Bueno-De-Mesquita, Peter D. Siersema, Eugène H J M Jansen, Antonia Trichopoulou, Anne Tjønneland, Anja Olsen, Chunsen Wu, Kim Overvad, Marie Christine Boutron-Ruault, Antoine Racine, Heinz Freisling & 26 others Verena Katzke, Rudolf Kaaks, Pagona Lagiou, Dimitrios Trichopoulos, Gianluca Severi, Alessio Naccarati, Amalia Mattiello, Domenico Palli, Sara Grioni, Rosario Tumino, Petra H. Peeters, Ingrid Ljuslinder, Hanna Nyström, Jenny Brändstedt, María José Sánchez, Aurelio Barricarte Gurrea, Catalina Bonet Bonet, María Dolores Chirlaque, Miren Dorronsoro, José Ramõn Quirõs, Ruth C. Travis, Kay Tee Khaw, Nick Wareham, Elio Riboli, Marc J. Gunter, Tobias Pischon

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 μg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 μg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development. What's new? Fetuin-A is a liver protein associated with insulin resistance, but with no defined role yet in colorectal cancer. In this prospective study, the authors uncover a modest linear association between fetuin-A levels and higher risk of colorectal cancer, but this was only observed in male participants. In addition, no association was observed between fetuin-A variants and colorectal cancer risk in a Mendelian randomization analysis, arguing against a direct role of fetuin-A in colorectal carcinogenesis.

Original languageEnglish
Pages (from-to)911-920
Number of pages10
JournalInternational Journal of Cancer
Volume137
Issue number4
DOIs
Publication statusPublished - Aug 15 2015

Fingerprint

alpha-2-HS-Glycoprotein
Colorectal Neoplasms
Glycoproteins
Genes
Mendelian Randomization Analysis
Logistic Models
Confidence Intervals
Liver
Hyperinsulinism

Keywords

  • AHSG
  • colorectal cancer
  • fetuin-A

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Nimptsch, K., Aleksandrova, K., Boeing, H., Janke, J., Lee, Y. A., Jenab, M., ... Pischon, T. (2015). Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer. International Journal of Cancer, 137(4), 911-920. https://doi.org/10.1002/ijc.29448

Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer. / Nimptsch, Katharina; Aleksandrova, Krasimira; Boeing, Heiner; Janke, Jürgen; Lee, Young Ae; Jenab, Mazda; Kong, So Yeon; Tsilidis, Konstantinos K.; Weiderpass, Elisabete; Bueno-De-Mesquita, H. Bas; Siersema, Peter D.; Jansen, Eugène H J M; Trichopoulou, Antonia; Tjønneland, Anne; Olsen, Anja; Wu, Chunsen; Overvad, Kim; Boutron-Ruault, Marie Christine; Racine, Antoine; Freisling, Heinz; Katzke, Verena; Kaaks, Rudolf; Lagiou, Pagona; Trichopoulos, Dimitrios; Severi, Gianluca; Naccarati, Alessio; Mattiello, Amalia; Palli, Domenico; Grioni, Sara; Tumino, Rosario; Peeters, Petra H.; Ljuslinder, Ingrid; Nyström, Hanna; Brändstedt, Jenny; Sánchez, María José; Gurrea, Aurelio Barricarte; Bonet, Catalina Bonet; Chirlaque, María Dolores; Dorronsoro, Miren; Quirõs, José Ramõn; Travis, Ruth C.; Khaw, Kay Tee; Wareham, Nick; Riboli, Elio; Gunter, Marc J.; Pischon, Tobias.

In: International Journal of Cancer, Vol. 137, No. 4, 15.08.2015, p. 911-920.

Research output: Contribution to journalArticle

Nimptsch, K, Aleksandrova, K, Boeing, H, Janke, J, Lee, YA, Jenab, M, Kong, SY, Tsilidis, KK, Weiderpass, E, Bueno-De-Mesquita, HB, Siersema, PD, Jansen, EHJM, Trichopoulou, A, Tjønneland, A, Olsen, A, Wu, C, Overvad, K, Boutron-Ruault, MC, Racine, A, Freisling, H, Katzke, V, Kaaks, R, Lagiou, P, Trichopoulos, D, Severi, G, Naccarati, A, Mattiello, A, Palli, D, Grioni, S, Tumino, R, Peeters, PH, Ljuslinder, I, Nyström, H, Brändstedt, J, Sánchez, MJ, Gurrea, AB, Bonet, CB, Chirlaque, MD, Dorronsoro, M, Quirõs, JR, Travis, RC, Khaw, KT, Wareham, N, Riboli, E, Gunter, MJ & Pischon, T 2015, 'Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer', International Journal of Cancer, vol. 137, no. 4, pp. 911-920. https://doi.org/10.1002/ijc.29448
Nimptsch, Katharina ; Aleksandrova, Krasimira ; Boeing, Heiner ; Janke, Jürgen ; Lee, Young Ae ; Jenab, Mazda ; Kong, So Yeon ; Tsilidis, Konstantinos K. ; Weiderpass, Elisabete ; Bueno-De-Mesquita, H. Bas ; Siersema, Peter D. ; Jansen, Eugène H J M ; Trichopoulou, Antonia ; Tjønneland, Anne ; Olsen, Anja ; Wu, Chunsen ; Overvad, Kim ; Boutron-Ruault, Marie Christine ; Racine, Antoine ; Freisling, Heinz ; Katzke, Verena ; Kaaks, Rudolf ; Lagiou, Pagona ; Trichopoulos, Dimitrios ; Severi, Gianluca ; Naccarati, Alessio ; Mattiello, Amalia ; Palli, Domenico ; Grioni, Sara ; Tumino, Rosario ; Peeters, Petra H. ; Ljuslinder, Ingrid ; Nyström, Hanna ; Brändstedt, Jenny ; Sánchez, María José ; Gurrea, Aurelio Barricarte ; Bonet, Catalina Bonet ; Chirlaque, María Dolores ; Dorronsoro, Miren ; Quirõs, José Ramõn ; Travis, Ruth C. ; Khaw, Kay Tee ; Wareham, Nick ; Riboli, Elio ; Gunter, Marc J. ; Pischon, Tobias. / Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer. In: International Journal of Cancer. 2015 ; Vol. 137, No. 4. pp. 911-920.
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AU - Nimptsch, Katharina

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AU - Janke, Jürgen

AU - Lee, Young Ae

AU - Jenab, Mazda

AU - Kong, So Yeon

AU - Tsilidis, Konstantinos K.

AU - Weiderpass, Elisabete

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AU - Trichopoulou, Antonia

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AU - Olsen, Anja

AU - Wu, Chunsen

AU - Overvad, Kim

AU - Boutron-Ruault, Marie Christine

AU - Racine, Antoine

AU - Freisling, Heinz

AU - Katzke, Verena

AU - Kaaks, Rudolf

AU - Lagiou, Pagona

AU - Trichopoulos, Dimitrios

AU - Severi, Gianluca

AU - Naccarati, Alessio

AU - Mattiello, Amalia

AU - Palli, Domenico

AU - Grioni, Sara

AU - Tumino, Rosario

AU - Peeters, Petra H.

AU - Ljuslinder, Ingrid

AU - Nyström, Hanna

AU - Brändstedt, Jenny

AU - Sánchez, María José

AU - Gurrea, Aurelio Barricarte

AU - Bonet, Catalina Bonet

AU - Chirlaque, María Dolores

AU - Dorronsoro, Miren

AU - Quirõs, José Ramõn

AU - Travis, Ruth C.

AU - Khaw, Kay Tee

AU - Wareham, Nick

AU - Riboli, Elio

AU - Gunter, Marc J.

AU - Pischon, Tobias

PY - 2015/8/15

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N2 - Fetuin-A, also referred to as α2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 μg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 μg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development. What's new? Fetuin-A is a liver protein associated with insulin resistance, but with no defined role yet in colorectal cancer. In this prospective study, the authors uncover a modest linear association between fetuin-A levels and higher risk of colorectal cancer, but this was only observed in male participants. In addition, no association was observed between fetuin-A variants and colorectal cancer risk in a Mendelian randomization analysis, arguing against a direct role of fetuin-A in colorectal carcinogenesis.

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