Letter | Published:

Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer

Nature Genetics volume 41, pages 986990 (2009) | Download Citation

Abstract

We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 × 10−8; multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12–1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. Cancer statistics, 2008. CA Cancer J. Clin. 58, 71–96 (2008).

  2. 2.

    , , & GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5, IARCPress, Lyon (2004).

  3. 3.

    , & Cancer of the pancreas. in Cancer Epidemiology and Prevention (ed. Schottenfeld, D. & Fraumeni, J.J.) (Oxford Univ. Press, New York, 2006).

  4. 4.

    et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J. Natl. Cancer Inst. 89, 442–446 (1997).

  5. 5.

    Case records of the Massachusetts General Hospital. N. Engl. J. Med. 286, 1353–1359 (1972).

  6. 6.

    et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res. 64, 2634–2638 (2004).

  7. 7.

    et al. The American Cancer Society Cancer Prevention Study II Nutrition Cohort: rationale, study design, and baseline characteristics. Cancer 94, 2490–2501 (2002).

  8. 8.

    The ATBC Cancer Prevention Study Group. The alpha-tocopherol, beta-carotene lung cancer prevention study: design, methods, participant characteristics, and compliance. Ann. Epidemiol. 4, 1–10 (1994).

  9. 9.

    et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 5, 1113–1124 (2002).

  10. 10.

    et al. Single nucleotide polymorphisms in inflammation-related genes and mortality in a community-based cohort in Washington County, Maryland. Am. J. Epidemiol. 167, 807–813 (2008).

  11. 11.

    et al. Circulating insulin-like growth factor binding protein-1 and the risk of pancreatic cancer. Cancer Res. 67, 7923–7928 (2007).

  12. 12.

    et al. Postmenopausal levels of sex hormones and risk of breast carcinoma in situ: results of a prospective study. Int. J. Cancer 114, 323–327 (2005).

  13. 13.

    et al. Methods for etiologic and early marker investigations in the PLCO trial. Mutat. Res. 592, 147–154 (2005).

  14. 14.

    et al. Joint effect of cigarette smoking and alcohol consumption on mortality. Prev. Med. 45, 313–319 (2007).

  15. 15.

    et al. The Shanghai Women's Health Study: rationale, study design, and baseline characteristics. Am. J. Epidemiol. 162, 1123–1131 (2005).

  16. 16.

    et al. Implementation of the Women's Health Initiative study design. Ann. Epidemiol. 13, S5–S17 (2003).

  17. 17.

    , , , & Baseline characteristics of participants in the Women's Health Study. J. Womens Health Gend. Based Med. 9, 19–27 (2000).

  18. 18.

    et al. Polymorphisms in DNA repair genes, smoking, and pancreatic adenocarcinoma risk. Cancer Res. 68, 4928–4935 (2008).

  19. 19.

    , & Allergies are associated with reduced pancreas cancer risk: A population-based case-control study in Ontario, Canada. Int. J. Cancer 121, 2241–2245 (2007).

  20. 20.

    et al. Detecting pathway-based gene-gene and gene-environment interactions in pancreatic cancer. Cancer Epidemiol. Biomarkers Prev. 17, 1470–1479 (2008).

  21. 21.

    et al. Risk factors for pancreatic cancer: case-control study. Am. J. Gastroenterol. 102, 2696–2707 (2007).

  22. 22.

    et al. Allergies, variants in IL-4 and IL-4R alpha genes, and risk of pancreatic cancer. Cancer Detect. Prev. 31, 345–351 (2007).

  23. 23.

    Etiology of pancreatic cancer, with a hypothesis concerning the role of N-nitroso compounds and excess gastric acidity. J. Natl. Cancer Inst. 95, 948–960 (2003).

  24. 24.

    , , & Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat. Genet. 38, 209–213 (2006).

  25. 25.

    Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  26. 26.

    , & A relationship between cancer of stomach and the ABO blood groups. BMJ 1, 799–801 (1953).

  27. 27.

    The ABO and Lewis blood-group system. Immunochemistry, genetics and relation to human disease. N. Engl. J. Med. 280, 994–1006 (1969).

  28. 28.

    et al. A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet. 4, e1000072 (2008).

  29. 29.

    et al. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 4, e1000118 (2008).

  30. 30.

    et al. Population-based genome-wide association studies reveal six loci influencing plasma levels of liver enzymes. Am. J. Hum. Genet. 83, 520–528 (2008).

  31. 31.

    et al. Cancer-associated alterations of blood group antigen expression in the human pancreas. J. Natl. Cancer Inst. 79, 425–434 (1987).

  32. 32.

    et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425, 846–851 (2003).

  33. 33.

    et al. ABO blood group and the risk of pancreatic cancer. J. Natl. Cancer Inst. 101, 424–431 (2009).

  34. 34.

    , & A note on exact tests of Hardy-Weinberg equilibrium. Am. J. Hum. Genet. 76, 887–893 (2005).

  35. 35.

    , & Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000).

  36. 36.

    et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

  37. 37.

    et al. Multiple loci identified in a genome-wide association study of prostate cancer. Nat. Genet. 40, 310–315 (2008).

  38. 38.

    et al. A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer. Nat. Genet. 39, 870–874 (2007).

  39. 39.

    et al. Population substructure and control selection in genome-wide association studies. PLoS One 3, e2551 (2008).

  40. 40.

    et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

  41. 41.

    , & Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

  42. 42.

    , & Enhanced pedigree error detection. Hum. Hered. 54, 99–110 (2002).

  43. 43.

    , & Genetic model testing and statistical power in population-based association studies of quantitative traits. Genet. Epidemiol. 31, 358–362 (2007).

  44. 44.

    & Quantifying heterogeneity in a meta-analysis. Stat. Med. 21, 1539–1558 (2002).

Download references

Acknowledgements

The authors gratefully acknowledge the energy and contribution of our late colleague, Robert Welch. Additional acknowledgments are found in the Supplementary Note.

Author information

Author notes

    • Laufey Amundadottir
    • , Peter Kraft
    • , Rachael Z Stolzenberg-Solomon
    • , Charles S Fuchs
    • , Stephen J Chanock
    • , Patricia Hartge
    •  & Robert N Hoover

    These authors contributed equally to this work.

Affiliations

  1. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Laufey Amundadottir
    •  & Stephen J Chanock
  2. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Laufey Amundadottir
    • , Rachael Z Stolzenberg-Solomon
    • , Demetrius Albanes
    • , Amy Hutchinson
    • , Kevin B Jacobs
    • , Julie B Mendelsohn
    • , Gilles Thomas
    • , Geoffrey S Tobias
    • , Kai Yu
    • , Stephen J Chanock
    • , Patricia Hartge
    •  & Robert N Hoover
  3. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
    • , Edward L Giovannucci
    • , Susan E Hankinson
    • , David J Hunter
    • , Dominique S Michaud
    •  & Dimitrios Trichopoulos
  4. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
  5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Charles S Fuchs
    •  & Brian M Wolpin
  6. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Charles S Fuchs
    • , Edward L Giovannucci
    • , Susan E Hankinson
    • , David J Hunter
    •  & Brian M Wolpin
  7. Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

    • Gloria M Petersen
    • , William Bamlet
    •  & Mariza de Andrade
  8. Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA.

    • Alan A Arslan
  9. Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA.

    • Alan A Arslan
    •  & Anne Zeleniuch-Jacquotte
  10. New York University Cancer Institute, New York, New York, USA.

    • Alan A Arslan
    •  & Anne Zeleniuch-Jacquotte
  11. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands, and Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.

    • H Bas Bueno-de-Mesquita
  12. Department of Laboratory Medicine/Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, USA.

    • Myron Gross
  13. Prevention and Research Center, Mercy Medical Center, Baltimore, Maryland, USA.

    • Kathy Helzlsouer
  14. Department of Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, USA.

    • Eric J Jacobs
    •  & Alpa V Patel
  15. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • Andrea LaCroix
    • , Charles Kooperberg
    •  & Margaret Mandelson
  16. Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee, USA.

    • Wei Zheng
    •  & Xiao-Ou Shu
  17. Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Christine D Berg
  18. Etiological Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

    • Franco Berrino
  19. MRC Dunn Human Nutrition Unit, University of Cambridge, Cambridge, UK.

    • Sheila Bingham
  20. Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Julie E Buring
  21. Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, Massachusetts, USA.

    • Julie E Buring
  22. Department of Epidemiology & Biostatistics, University of California San Francisco, San Francisco, California, USA.

    • Paige M Bracci
    •  & Elizabeth A Holly
  23. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Federico Canzian
    •  & Rudolf Kaaks
  24. Institut National de la Santé et de la Recherche Médicale (INSERM) and Institut Gustave Roussy, Villejuif, France.

    • Françoise Clavel-Chapelon
  25. The Johns Hopkins Bloomberg School of Public Health, George W. Comstock Center for Public Health Research and Prevention, Hagerstown, Maryland, USA.

    • Sandra Clipp
  26. Cancer Care Ontario and Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.

    • Michelle Cotterchio
  27. International Agency for Research on Cancer, Lyon, France.

    • Eric J Duell
    •  & Mazda Jenab
  28. College of Human Medicine, Michigan State University, East Lansing, Michigan, USA.

    • John W Fox Jr
  29. Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

    • Steven Gallinger
  30. Physicians' Health Study, Divisions of Aging, Cardiovascular Medicine and Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, and Massachusetts Veterans Epidemiology Research and Information Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA.

    • J Michael Gaziano
  31. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Edward L Giovannucci
  32. Departments of Oncology, Pathology and Medicine, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Michael Goggins
  33. Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), Barcelona, Spain.

    • Carlos A González
  34. Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden.

    • Göran Hallmans
  35. Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

    • Manal Hassan
    •  & Donghui Li
  36. Core Genotyping Facility, Advanced Technology Program, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland, USA.

    • Amy Hutchinson
    •  & Kevin B Jacobs
  37. Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine and Center for Clinical and Translational Science, Ohio State University, Columbus, Ohio, USA.

    • Rebecca Jackson
  38. Bioinformed, LLC, Gaithersburg, Maryland, USA.

    • Kevin B Jacobs
  39. Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Alison P Klein
  40. Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, The Sol Goldman Pancreatic Research Center, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.

    • Alison P Klein
  41. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Robert C Kurtz
  42. Epidemiology and Genetics Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Shannon M Lynch
  43. Group Health Center for Health Studies, Seattle, Washington, USA.

    • Margaret Mandelson
  44. Department of Oncology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

    • Robert R McWilliams
  45. Division of Epidemiology, Public Health and Primary Care, Imperial College London, London, UK.

    • Dominique S Michaud
    • , Petra H M Peeters
    •  & Elio Riboli
  46. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Sara H Olson
  47. Department of Cardiology and Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.

    • Kim Overvad
  48. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Petra H M Peeters
  49. Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA.

    • Aleksandar Rajkovic
  50. Yale University School of Public Health, New Haven, Connecticut, USA.

    • Harvey A Risch
    •  & Herbert Yu
  51. Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece.

    • Dimitrios Trichopoulos
  52. Division of Research, Kaiser Permanente, Northern California Region, Oakland, California, USA.

    • Stephen K Van Den Eeden
  53. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Jarmo Virtamo
  54. Department of Social and Preventive Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA.

    • Jean Wactawski-Wende

Authors

  1. Search for Laufey Amundadottir in:

  2. Search for Peter Kraft in:

  3. Search for Rachael Z Stolzenberg-Solomon in:

  4. Search for Charles S Fuchs in:

  5. Search for Gloria M Petersen in:

  6. Search for Alan A Arslan in:

  7. Search for H Bas Bueno-de-Mesquita in:

  8. Search for Myron Gross in:

  9. Search for Kathy Helzlsouer in:

  10. Search for Eric J Jacobs in:

  11. Search for Andrea LaCroix in:

  12. Search for Wei Zheng in:

  13. Search for Demetrius Albanes in:

  14. Search for William Bamlet in:

  15. Search for Christine D Berg in:

  16. Search for Franco Berrino in:

  17. Search for Sheila Bingham in:

  18. Search for Julie E Buring in:

  19. Search for Paige M Bracci in:

  20. Search for Federico Canzian in:

  21. Search for Françoise Clavel-Chapelon in:

  22. Search for Sandra Clipp in:

  23. Search for Michelle Cotterchio in:

  24. Search for Mariza de Andrade in:

  25. Search for Eric J Duell in:

  26. Search for John W Fox Jr in:

  27. Search for Steven Gallinger in:

  28. Search for J Michael Gaziano in:

  29. Search for Edward L Giovannucci in:

  30. Search for Michael Goggins in:

  31. Search for Carlos A González in:

  32. Search for Göran Hallmans in:

  33. Search for Susan E Hankinson in:

  34. Search for Manal Hassan in:

  35. Search for Elizabeth A Holly in:

  36. Search for David J Hunter in:

  37. Search for Amy Hutchinson in:

  38. Search for Rebecca Jackson in:

  39. Search for Kevin B Jacobs in:

  40. Search for Mazda Jenab in:

  41. Search for Rudolf Kaaks in:

  42. Search for Alison P Klein in:

  43. Search for Charles Kooperberg in:

  44. Search for Robert C Kurtz in:

  45. Search for Donghui Li in:

  46. Search for Shannon M Lynch in:

  47. Search for Margaret Mandelson in:

  48. Search for Robert R McWilliams in:

  49. Search for Julie B Mendelsohn in:

  50. Search for Dominique S Michaud in:

  51. Search for Sara H Olson in:

  52. Search for Kim Overvad in:

  53. Search for Alpa V Patel in:

  54. Search for Petra H M Peeters in:

  55. Search for Aleksandar Rajkovic in:

  56. Search for Elio Riboli in:

  57. Search for Harvey A Risch in:

  58. Search for Xiao-Ou Shu in:

  59. Search for Gilles Thomas in:

  60. Search for Geoffrey S Tobias in:

  61. Search for Dimitrios Trichopoulos in:

  62. Search for Stephen K Van Den Eeden in:

  63. Search for Jarmo Virtamo in:

  64. Search for Jean Wactawski-Wende in:

  65. Search for Brian M Wolpin in:

  66. Search for Herbert Yu in:

  67. Search for Kai Yu in:

  68. Search for Anne Zeleniuch-Jacquotte in:

  69. Search for Stephen J Chanock in:

  70. Search for Patricia Hartge in:

  71. Search for Robert N Hoover in:

Contributions

L.A., P.K., R.Z.S.-S., C.S.F., G.M.P., K.B.J., S.M.L., J.B.M., G.S.T., S.J.C., P.H. and R.N.H. organized and designed the study. L.A., A.H., K.B.J., G.T. and S.J.C. supervised genotyping of samples. L.A., P.K., R.Z.S.-S., C.S.F., K.B.J., C.K., K.Y., S.J.C., P.H. and R.N.H. contributed to the design and execution of statistical analysis. LA., S.J.C., P.H. and R.N.H. wrote the first draft of the manuscript. R.Z.S.-S., C.S.F., G.M.P., A.A.A., H.B.B.-d.-M., M.G., K.H., E.J.J., A.L., W.Z., D.A., W.B., C.D.B., F.B., S.B., J.E.B., P.M.B., F.C., F.C.-C., S.C., M.C., M.d.A., E.J.D., J.W.F., S.G., J.M.G., E.L.G., M.G., C.A.G., G.H., S.E.H., M.H., E.A.H., D.J.H., R.J., M.J., R.K., A.P.K., C.K., R.C.K., D.L., M.M., R.R.M., D.S.M., S.H.O., K.O., A.V.P., P.H.M.P., A.R., E.R., H.A.R., X.-O.S., D.T., S.K.V.D.E., J.V., J.W.-W., B.M.W., H.Y. and A.Z.-J. conducted the epidemiologic studies and contributed samples to the PanScan GWAS and/or replication. All authors contributed to the writing of the manuscript.

Corresponding author

Correspondence to Stephen J Chanock.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4, Supplementary Tables 1–5 and Supplementary Note

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.429

Further reading