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

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9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)895-904
Number of pages10
JournalHuman genetics
Volume134
Issue number8
DOIs
StatePublished - Aug 23 2015

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Zhang, X., Zhang, W., Saraf, S. L., Nouraie, M., Han, J., Gowhari, M., Hassan, J., Miasnikova, G., Sergueeva, A., Nekhai, S., Kittles, R., Machado, R. F., Garcia, J. G. N., Gladwin, M. T., Steinberg, M. H., Sebastiani, P., McClain, D. A., & Gordeuk, V. R. (2015). Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease. Human genetics, 134(8), 895-904. https://doi.org/10.1007/s00439-015-1572-3