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Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease

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Abstract

Environmental variations have strong influences in the etiology of type 2 diabetes mellitus. In this study, we investigated the genetic basis of diabetes in patients with sickle cell disease (SCD), a Mendelian disorder accompanied by distinct physiological conditions of hypoxia and hyperactive erythropoiesis. Compared to the general African American population, the prevalence of diabetes as assessed in two SCD cohorts of 856 adults was low, but it markedly increased with older age and overweight. Meta-analyses of over 5 million single-nucleotide polymorphisms (SNPs) in the two SCD cohorts identified a SNP, rs59014890, the C allele of which associated with diabetes risk at P = 3.2 × 10−8 and, surprisingly, associated with decreased APOB expression in peripheral blood mononuclear cells (PBMCs). The risk allele of the APOB polymorphism was associated with overweight in 181 SCD adolescents, with diabetes risk in 592 overweight, non-SCD African Americans ≥45 years of age, and with elevated plasma lipid concentrations in general populations. In addition, lower expression level of APOB in PBMCs was associated with higher values for percent hemoglobin A1C and serum total cholesterol and triglyceride concentrations in patients with Chuvash polycythemia, a congenital disease with elevated hypoxic responses and increased erythropoiesis at normoxia. Our study reveals a novel, environment-specific genetic polymorphism that may affect key metabolic pathways contributing to diabetes in SCD.

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Acknowledgments

This work is supported in part by grants R01 HL079912-04, 2 R25-HL03679-08, and 1P30HL107253 (V.R.G.); KL2TR000048 (S.L.S); P50HL118006 (M.N.); R01HL111656 and K23HL098454 (R.F.M.).

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Xu Zhang, Santosh L. Saraf, Michel Gowhari, Johara Hassan & Victor R. Gordeuk

  2. Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    Wei Zhang

  3. Center for Sickle Cell Disease, Howard University, Washington, DC, USA

    Mehdi Nouraie & Sergei Nekhai

  4. Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA

    Jin Han

  5. Chuvash Republic Clinical Hospital 1, Cheboksary, Russia

    Galina Miasnikova

  6. Cheboksary Children’s Hospital, Cheboksary, Russia

    Adelina Sergueeva

  7. College of Medicine, University of Arizona, Tucson, AZ, USA

    Rick Kittles & Joe G. N. Garcia

  8. Department of Medicine, Pulmonary and Critical Care Medicine, University of Illinois at Chicago, Chicago, IL, USA

    Roberto F. Machado

  9. Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA

    Mark T. Gladwin

  10. Department of Medicine, Boston University School of Medicine, Boston, MA, USA

    Martin H. Steinberg

  11. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA

    Paola Sebastiani

  12. Department of Internal Medicine, Wake Forest University School of Medicine and VA Medical Center, Winston Salem, NC, USA

    Donald A. McClain

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  1. Xu Zhang
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  2. Wei Zhang
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  3. Santosh L. Saraf
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  4. Mehdi Nouraie
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  5. Jin Han
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  7. Johara Hassan
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  8. Galina Miasnikova
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  9. Adelina Sergueeva
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  11. Rick Kittles
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  12. Roberto F. Machado
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  13. Joe G. N. Garcia
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  14. Mark T. Gladwin
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  15. Martin H. Steinberg
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  16. Paola Sebastiani
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  17. Donald A. McClain
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  18. Victor R. Gordeuk
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Correspondence to Xu Zhang or Victor R. Gordeuk.

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Zhang, X., Zhang, W., Saraf, S.L. et al. Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease. Hum Genet 134, 895–904 (2015). https://doi.org/10.1007/s00439-015-1572-3

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