title: Genetic polymorphism of APOB is associated with diabetes mellitus in sickle cell disease.
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.
authors.affiliation: Comprehensive Sickle Cell Center, Section of Hematology/Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA, xuzhangchicago@gmail.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Santosh L
authors.initials: SL
authors.lastname: Saraf
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.forename: Jin
authors.initials: J
authors.lastname: Han
authors.forename: Michel
authors.initials: M
authors.lastname: Gowhari
authors.forename: Johara
authors.initials: J
authors.lastname: Hassan
authors.forename: Galina
authors.initials: G
authors.lastname: Miasnikova
authors.forename: Adelina
authors.initials: A
authors.lastname: Sergueeva
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
authors.forename: Rick
authors.initials: R
authors.lastname: Kittles
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.forename: Mark T
authors.initials: MT
authors.lastname: Gladwin
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
authors.forename: Victor R
authors.initials: VR
authors.lastname: Gordeuk
mesh_terms: D000293:Adolescent; D000328:Adult; D001741:Black or African American; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics*; D053299:Apolipoprotein B-100 / Q000097:blood / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D050177:Overweight / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood
chemical_list: C569471:APOB protein, human; D053299:Apolipoprotein B-100; D006454:Hemoglobins; D014280:Triglycerides; D002784:Cholesterol