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.

Diabetes in Patients with ß-thalassemia or other Hemoglobinopathies – Analysis from the DPV Database

“…A study from Africa described a low prevalence of diabetes in patients with SCD compared to the general African population. Nevertheless, the prevalence increased with higher BMI and age and patients were primarily affected by T2D, associated with a specific single nucleotide polymorphism (rs59014890) [30]. These 2 publications show that SCD may be related to T2D.…”

“…There are only few case reports addressing patients with Sickle Cell Disease (SCD) and type 1 diabetes (T1D), and the interrelation of both diseases is unclear [26]. A recent study describes a possible relation between SCD and T2D and identified a genetic polymorphism leading to overweight and T2D in patients with SCD [30]. In comparison to patients with ß-thalassemia major, patients with SCD rarely receive transfusions.…”

Utility of the revised cardiac risk index for predicting postsurgical morbidity in Hb SC and Hb Sβ+‐thalassemia sickle cell disease

“…The need for better preoperative assessment and care in compound heterozygous SCD is highlighted by the higher rates of non-SCD related postoperative complications in Hb SC (23%) versus Hb SS (11%) patients observed in the Cooperative Study of Sickle Cell Disease (CSSCD) cohort. 1 Patients with compound heterozygous SCD have higher rates of overweight and diabetes mellitus than Hb SS patients 3 and utilizing presurgical evaluation tools commonly used in the general population may help identify patients at higher risk for postoperative complications. The Revised Cardiac Risk Index (RCRI) is a pre-operative risk assessment tool that predicts the Postsurgical Outcome Morbidity Survey (POMS) score and length of hospitalization in non-SCD patients.…”

Increased iron stores influence glucose metabolism in sickle cell anaemia

“…Past studies suggested low prevalence of diabetes mellitus in sickle cell anaemia (SCA). Our recent studies 1,2 suggest that the prevalence may reflect the general African‐American population. Inflammation, oxidative stress, and iron overload due to blood transfusions may result in pancreatic β‐cell damage and decreased insulin production, promoting diabetes 3 .…”