Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses

Nazlisadat Seyed Khoei; Mazda Jenab; Neil Murphy; Barbara L. Banbury; Robert Carreras-Torres; Vivian Viallon; Tilman Kühn; Bas Bueno-De-Mesquita; Krasimira Aleksandrova; Amanda J. Cross; Elisabete Weiderpass; Magdalena Stepien; Andrew Bulmer; Anne Tjønneland; Marie Christine Boutron-Ruault; Gianluca Severi; Franck Carbonnel; Verena Katzke; Heiner Boeing; Manuela M. Bergmann; Antonia Trichopoulou; Anna Karakatsani; Georgia Martimianaki; Domenico Palli; Giovanna Tagliabue; Salvatore Panico; Rosario Tumino; Carlotta Sacerdote; Guri Skeie; Susana Merino; Catalina Bonet; Miguel Rodríguez-Barranco; Leire Gil; Maria Dolores Chirlaque; Eva Ardanaz; Robin Myte; Johan Hultdin; Aurora Perez-Cornago; Dagfinn Aune; Konstantinos K. Tsilidis; Demetrius Albanes; John A. Baron; Sonja I. Berndt; Stéphane Bézieau; Hermann Brenner; Peter T. Campbell; Graham Casey; Andrew T. Chan; Jenny Chang-Claude; Stephen J. Chanock; Michelle Cotterchio; Steven Gallinger; Stephen B. Gruber; Robert W. Haile; Jochen Hampe; Michael Hoffmeister; John L. Hopper; Li Hsu; Jeroen R. Huyghe; Mark A. Jenkins; Amit D. Joshi; Ellen Kampman; Susanna C. Larsson; Loic Le Marchand; Christopher I. Li; Li Li; Annika Lindblom; Noralane M. Lindor; Vicente Martín; Victor Moreno; Polly A. Newcomb; Kenneth Offit; Shuji Ogino; Patrick S. Parfrey; Paul D.P. Pharoah; Gad Rennert; Lori C. Sakoda; Clemens Schafmayer; Stephanie L. Schmit; Robert E. Schoen; Martha L. Slattery; Stephen N. Thibodeau; Cornelia M. Ulrich; Franzel J.B. Van Duijnhoven; Korbinian Weigl; Stephanie J. Weinstein; Emily White; Alicja Wolk; Michael O. Woods; Anna H. Wu; Xuehong Zhang; Pietro Ferrari; Gabriele Anton; Annette Peters; Ulrike Peters; Marc J. Gunter; Karl Heinz Wagner; Heinz Freisling

doi:10.1186/s12916-020-01703-w

Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses

Nazlisadat Seyed Khoei, Mazda Jenab, Neil Murphy, Barbara L. Banbury, Robert Carreras-Torres, Vivian Viallon, Tilman Kühn, Bas Bueno-De-Mesquita, Krasimira Aleksandrova, Amanda J. Cross, Elisabete Weiderpass, Magdalena Stepien, Andrew Bulmer, Anne Tjønneland, Marie Christine Boutron-Ruault, Gianluca Severi, Franck Carbonnel, Verena Katzke, Heiner Boeing, Manuela M. BergmannAntonia Trichopoulou, Anna Karakatsani, Georgia Martimianaki, Domenico Palli, Giovanna Tagliabue, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Guri Skeie, Susana Merino, Catalina Bonet, Miguel Rodríguez-Barranco, Leire Gil, Maria Dolores Chirlaque, Eva Ardanaz, Robin Myte, Johan Hultdin, Aurora Perez-Cornago, Dagfinn Aune, Konstantinos K. Tsilidis, Demetrius Albanes, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, Hermann Brenner, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Michelle Cotterchio, Steven Gallinger, Stephen B. Gruber, Robert W. Haile, Jochen Hampe, Michael Hoffmeister, John L. Hopper, Li Hsu, Jeroen R. Huyghe, Mark A. Jenkins, Amit D. Joshi, Ellen Kampman, Susanna C. Larsson, Loic Le Marchand, Christopher I. Li, Li Li, Annika Lindblom, Noralane M. Lindor, Vicente Martín, Victor Moreno, Polly A. Newcomb, Kenneth Offit, Shuji Ogino, Patrick S. Parfrey, Paul D.P. Pharoah, Gad Rennert, Lori C. Sakoda, Clemens Schafmayer, Stephanie L. Schmit, Robert E. Schoen, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Franzel J.B. Van Duijnhoven, Korbinian Weigl, Stephanie J. Weinstein, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Xuehong Zhang, Pietro Ferrari, Gabriele Anton, Annette Peters, Ulrike Peters, Marc J. Gunter, Karl Heinz Wagner, Heinz Freisling

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

Original language	English (US)
Article number	229
Journal	BMC Medicine
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12916-020-01703-w
State	Published - Sep 3 2020
Externally published	Yes

Keywords

Anti-oxidants
Bilirubin
Cancer
Colorectal cancer
Mendelian randomization analysis

ASJC Scopus subject areas

General Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/s12916-020-01703-w

Cite this

Seyed Khoei, N., Jenab, M., Murphy, N., Banbury, B. L., Carreras-Torres, R., Viallon, V., Kühn, T., Bueno-De-Mesquita, B., Aleksandrova, K., Cross, A. J., Weiderpass, E., Stepien, M., Bulmer, A., Tjønneland, A., Boutron-Ruault, M. C., Severi, G., Carbonnel, F., Katzke, V., Boeing, H., ... Freisling, H. (2020). Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses. BMC Medicine, 18(1), Article 229. https://doi.org/10.1186/s12916-020-01703-w

Seyed Khoei, N, Jenab, M, Murphy, N, Banbury, BL, Carreras-Torres, R, Viallon, V, Kühn, T, Bueno-De-Mesquita, B, Aleksandrova, K, Cross, AJ, Weiderpass, E, Stepien, M, Bulmer, A, Tjønneland, A, Boutron-Ruault, MC, Severi, G, Carbonnel, F, Katzke, V, Boeing, H, Bergmann, MM, Trichopoulou, A, Karakatsani, A, Martimianaki, G, Palli, D, Tagliabue, G, Panico, S, Tumino, R, Sacerdote, C, Skeie, G, Merino, S, Bonet, C, Rodríguez-Barranco, M, Gil, L, Chirlaque, MD, Ardanaz, E, Myte, R, Hultdin, J, Perez-Cornago, A, Aune, D, Tsilidis, KK, Albanes, D, Baron, JA, Berndt, SI, Bézieau, S, Brenner, H, Campbell, PT, Casey, G, Chan, AT, Chang-Claude, J, Chanock, SJ, Cotterchio, M, Gallinger, S, Gruber, SB, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, L, Huyghe, JR, Jenkins, MA, Joshi, AD, Kampman, E, Larsson, SC, Le Marchand, L, Li, CI, Li, L, Lindblom, A, Lindor, NM, Martín, V, Moreno, V, Newcomb, PA, Offit, K, Ogino, S, Parfrey, PS, Pharoah, PDP, Rennert, G, Sakoda, LC, Schafmayer, C, Schmit, SL, Schoen, RE, Slattery, ML, Thibodeau, SN, Ulrich, CM, Van Duijnhoven, FJB, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Zhang, X, Ferrari, P, Anton, G, Peters, A, Peters, U, Gunter, MJ, Wagner, KH & Freisling, H 2020, 'Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses', BMC Medicine, vol. 18, no. 1, 229. https://doi.org/10.1186/s12916-020-01703-w

@article{a64386540e8a465d8ccd5f5440ab43b1,

title = "Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses",

abstract = "Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.",

keywords = "Anti-oxidants, Bilirubin, Cancer, Colorectal cancer, Mendelian randomization analysis",

author = "{Seyed Khoei}, Nazlisadat and Mazda Jenab and Neil Murphy and Banbury, {Barbara L.} and Robert Carreras-Torres and Vivian Viallon and Tilman K{\"u}hn and Bas Bueno-De-Mesquita and Krasimira Aleksandrova and Cross, {Amanda J.} and Elisabete Weiderpass and Magdalena Stepien and Andrew Bulmer and Anne Tj{\o}nneland and Boutron-Ruault, {Marie Christine} and Gianluca Severi and Franck Carbonnel and Verena Katzke and Heiner Boeing and Bergmann, {Manuela M.} and Antonia Trichopoulou and Anna Karakatsani and Georgia Martimianaki and Domenico Palli and Giovanna Tagliabue and Salvatore Panico and Rosario Tumino and Carlotta Sacerdote and Guri Skeie and Susana Merino and Catalina Bonet and Miguel Rodr{\'i}guez-Barranco and Leire Gil and Chirlaque, {Maria Dolores} and Eva Ardanaz and Robin Myte and Johan Hultdin and Aurora Perez-Cornago and Dagfinn Aune and Tsilidis, {Konstantinos K.} and Demetrius Albanes and Baron, {John A.} and Berndt, {Sonja I.} and St{\'e}phane B{\'e}zieau and Hermann Brenner and Campbell, {Peter T.} and Graham Casey and Chan, {Andrew T.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Michelle Cotterchio and Steven Gallinger and Gruber, {Stephen B.} and Haile, {Robert W.} and Jochen Hampe and Michael Hoffmeister and Hopper, {John L.} and Li Hsu and Huyghe, {Jeroen R.} and Jenkins, {Mark A.} and Joshi, {Amit D.} and Ellen Kampman and Larsson, {Susanna C.} and {Le Marchand}, Loic and Li, {Christopher I.} and Li Li and Annika Lindblom and Lindor, {Noralane M.} and Vicente Mart{\'i}n and Victor Moreno and Newcomb, {Polly A.} and Kenneth Offit and Shuji Ogino and Parfrey, {Patrick S.} and Pharoah, {Paul D.P.} and Gad Rennert and Sakoda, {Lori C.} and Clemens Schafmayer and Schmit, {Stephanie L.} and Schoen, {Robert E.} and Slattery, {Martha L.} and Thibodeau, {Stephen N.} and Ulrich, {Cornelia M.} and {Van Duijnhoven}, {Franzel J.B.} and Korbinian Weigl and Weinstein, {Stephanie J.} and Emily White and Alicja Wolk and Woods, {Michael O.} and Wu, {Anna H.} and Xuehong Zhang and Pietro Ferrari and Gabriele Anton and Annette Peters and Ulrike Peters and Gunter, {Marc J.} and Wagner, {Karl Heinz} and Heinz Freisling",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = sep,

day = "3",

doi = "10.1186/s12916-020-01703-w",

language = "English (US)",

volume = "18",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Circulating bilirubin levels and risk of colorectal cancer

T2 - Serological and Mendelian randomization analyses

AU - Seyed Khoei, Nazlisadat

AU - Jenab, Mazda

AU - Murphy, Neil

AU - Banbury, Barbara L.

AU - Carreras-Torres, Robert

AU - Viallon, Vivian

AU - Kühn, Tilman

AU - Bueno-De-Mesquita, Bas

AU - Aleksandrova, Krasimira

AU - Cross, Amanda J.

AU - Weiderpass, Elisabete

AU - Stepien, Magdalena

AU - Bulmer, Andrew

AU - Tjønneland, Anne

AU - Boutron-Ruault, Marie Christine

AU - Severi, Gianluca

AU - Carbonnel, Franck

AU - Katzke, Verena

AU - Boeing, Heiner

AU - Bergmann, Manuela M.

AU - Trichopoulou, Antonia

AU - Karakatsani, Anna

AU - Martimianaki, Georgia

AU - Palli, Domenico

AU - Tagliabue, Giovanna

AU - Panico, Salvatore

AU - Tumino, Rosario

AU - Sacerdote, Carlotta

AU - Skeie, Guri

AU - Merino, Susana

AU - Bonet, Catalina

AU - Rodríguez-Barranco, Miguel

AU - Gil, Leire

AU - Chirlaque, Maria Dolores

AU - Ardanaz, Eva

AU - Myte, Robin

AU - Hultdin, Johan

AU - Perez-Cornago, Aurora

AU - Aune, Dagfinn

AU - Tsilidis, Konstantinos K.

AU - Albanes, Demetrius

AU - Baron, John A.

AU - Berndt, Sonja I.

AU - Bézieau, Stéphane

AU - Brenner, Hermann

AU - Campbell, Peter T.

AU - Casey, Graham

AU - Chan, Andrew T.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Cotterchio, Michelle

AU - Gallinger, Steven

AU - Gruber, Stephen B.

AU - Haile, Robert W.

AU - Hampe, Jochen

AU - Hoffmeister, Michael

AU - Hopper, John L.

AU - Hsu, Li

AU - Huyghe, Jeroen R.

AU - Jenkins, Mark A.

AU - Joshi, Amit D.

AU - Kampman, Ellen

AU - Larsson, Susanna C.

AU - Le Marchand, Loic

AU - Li, Christopher I.

AU - Li, Li

AU - Lindblom, Annika

AU - Lindor, Noralane M.

AU - Martín, Vicente

AU - Moreno, Victor

AU - Newcomb, Polly A.

AU - Offit, Kenneth

AU - Ogino, Shuji

AU - Parfrey, Patrick S.

AU - Pharoah, Paul D.P.

AU - Rennert, Gad

AU - Sakoda, Lori C.

AU - Schafmayer, Clemens

AU - Schmit, Stephanie L.

AU - Schoen, Robert E.

AU - Slattery, Martha L.

AU - Thibodeau, Stephen N.

AU - Ulrich, Cornelia M.

AU - Van Duijnhoven, Franzel J.B.

AU - Weigl, Korbinian

AU - Weinstein, Stephanie J.

AU - White, Emily

AU - Wolk, Alicja

AU - Woods, Michael O.

AU - Wu, Anna H.

AU - Zhang, Xuehong

AU - Ferrari, Pietro

AU - Anton, Gabriele

AU - Peters, Annette

AU - Peters, Ulrike

AU - Gunter, Marc J.

AU - Wagner, Karl Heinz

AU - Freisling, Heinz

PY - 2020/9/3

Y1 - 2020/9/3

N2 - Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

AB - Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10-8) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study. Results: The associations between circulating UCB levels and CRC risk differed by sex (P heterogeneity = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P heterogeneity ≥ 0.2). Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.

KW - Anti-oxidants

KW - Bilirubin

KW - Cancer

KW - Colorectal cancer

KW - Mendelian randomization analysis

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UR - http://www.scopus.com/inward/citedby.url?scp=85090261575&partnerID=8YFLogxK

U2 - 10.1186/s12916-020-01703-w

DO - 10.1186/s12916-020-01703-w

M3 - Article

C2 - 32878631

AN - SCOPUS:85090261575

SN - 1741-7015

VL - 18

JO - BMC Medicine

JF - BMC Medicine

IS - 1

M1 - 229

ER -

Circulating bilirubin levels and risk of colorectal cancer: Serological and Mendelian randomization analyses

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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