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

TitleGenetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease.
Publication TypeJournal Article
Year of Publication2015
AuthorsZhang X, Zhang W, Saraf SL, Nouraie M, Han J, Gowhari M, Hassan J, Miasnikova G, Sergueeva A, Nekhai S, Kittles R, Machado RF, Garcia JGN, Gladwin MT, Steinberg MH, Sebastiani P, McClain DA, Gordeuk VR
JournalHum Genet
Volume134
Issue8
Pagination895-904
Date Published2015 Aug
ISSN Number1432-1203
KeywordsAdolescent, Adult, African Americans, Aged, Aged, 80 and over, Alleles, Anemia, Sickle Cell, Apolipoprotein B-100, Cholesterol, Cohort Studies, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Hemoglobins, Humans, Male, Middle Aged, Overweight, Polymorphism, Single Nucleotide, Triglycerides
Abstract

<p>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.</p>

DOI10.1007/s00439-015-1572-3
Alternate JournalHum. Genet.
PubMed ID26025476
PubMed Central IDPMC4607040
Grant ListUL1 TR000430 / TR / NCATS NIH HHS / United States
R01HL079912-04 / HL / NHLBI NIH HHS / United States
R01 HL111656 / HL / NHLBI NIH HHS / United States
R01 HL125005 / HL / NHLBI NIH HHS / United States
G12 MD007597 / MD / NIMHD NIH HHS / United States
P50HL118006 / HL / NHLBI NIH HHS / United States
P50 HL118006 / HL / NHLBI NIH HHS / United States
1P30HL107253 / HL / NHLBI NIH HHS / United States
R25 HL003679 / HL / NHLBI NIH HHS / United States
R01 HL079912 / HL / NHLBI NIH HHS / United States
R01HL111656 / HL / NHLBI NIH HHS / United States
KL2TR000048 / TR / NCATS NIH HHS / United States
2 R25-HL03679-08 / HL / NHLBI NIH HHS / United States
K23HL098454 / HL / NHLBI NIH HHS / United States