Human Genetics

, Volume 134, Issue 8, pp 895–904 | Cite as

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

  • Xu Zhang
  • Wei Zhang
  • Santosh L. Saraf
  • Mehdi Nouraie
  • Jin Han
  • Michel Gowhari
  • Johara Hassan
  • Galina Miasnikova
  • Adelina Sergueeva
  • Sergei Nekhai
  • Rick Kittles
  • Roberto F. Machado
  • Joe G. N. Garcia
  • Mark T. Gladwin
  • Martin H. Steinberg
  • Paola Sebastiani
  • Donald A. McClain
  • Victor R. Gordeuk
Original Investigation

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.

Notes

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.

Supplementary material

439_2015_1572_MOESM1_ESM.xls (147 kb)
Supplementary material 1 (XLS 147 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Xu Zhang
    • 1
  • Wei Zhang
    • 2
  • Santosh L. Saraf
    • 1
  • Mehdi Nouraie
    • 3
  • Jin Han
    • 4
  • Michel Gowhari
    • 1
  • Johara Hassan
    • 1
  • Galina Miasnikova
    • 5
  • Adelina Sergueeva
    • 6
  • Sergei Nekhai
    • 3
  • Rick Kittles
    • 7
  • Roberto F. Machado
    • 8
  • Joe G. N. Garcia
    • 7
  • Mark T. Gladwin
    • 9
  • Martin H. Steinberg
    • 10
  • Paola Sebastiani
    • 11
  • Donald A. McClain
    • 12
  • Victor R. Gordeuk
    • 1
  1. 1.Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of MedicineUniversity of Illinois at ChicagoChicagoUSA
  2. 2.Department of Preventive MedicineNorthwestern University Feinberg School of MedicineChicagoUSA
  3. 3.Center for Sickle Cell DiseaseHoward UniversityWashingtonUSA
  4. 4.Department of Pharmacy Practice, College of PharmacyUniversity of Illinois at ChicagoChicagoUSA
  5. 5.Chuvash Republic Clinical Hospital 1CheboksaryRussia
  6. 6.Cheboksary Children’s HospitalCheboksaryRussia
  7. 7.College of MedicineUniversity of ArizonaTucsonUSA
  8. 8.Department of Medicine, Pulmonary and Critical Care MedicineUniversity of Illinois at ChicagoChicagoUSA
  9. 9.Division of Pulmonary, Allergy, and Critical Care Medicine, Vascular Medicine InstituteUniversity of PittsburghPittsburghUSA
  10. 10.Department of MedicineBoston University School of MedicineBostonUSA
  11. 11.Department of BiostatisticsBoston University School of Public HealthBostonUSA
  12. 12.Department of Internal MedicineWake Forest University School of Medicine and VA Medical CenterWinston SalemUSA

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