The association of vitamin D binding protein levels and genotypes with type 1 diabetes in the black South African population.

BACKGROUND: Vitamin D deficiency and the vitamin D pathway have previously been associated with type 1 diabetes (T1D). The majority of vitamin D is transported through the blood bound to the vitamin D binding protein (VDBP). Two polymorphisms in the VDBP gene (rs4588 and rs7041) result in different VDBP variants and have been associated with T1D, however the results are not consistent. The association of VDBP levels and its polymorphisms with T1D have not been investigated in the black South African population. Therefore, this study aimed to determine whether rs4588, rs7041 or serum VDBP levels were associated with T1D in this population. METHODS: Participants with type 1 diabetes and controls were recruited from the greater Johannesburg area, South Africa. Participants were genotyped for rs4588 and rs7041 using PCR-RFLP and serum VDBP levels were determined by ELISA. RESULTS: There was no difference in VDBP allelic or genotypic frequencies between participants with T1D and controls (rs4588 C allele frequency 0.92 vs. 0.94; p = 0.390 and rs7041 T allele frequency 0.95 vs. 0.95; p = 0.890). In univariate analysis, the rs4588 CC genotype was associated with increased serum VDBP levels, however, this association was lost with multivariate analysis. The VDBP genotypes were not associated with any other study variables. In logistic regression analysis, higher VBDP levels were associated with T1D (OR: (95% CI): 6.58 (1.45-29.9); p = 0.015), and within a linear regression analysis, T1D disease status was found to be associated with 0.044 mg/ml higher VDBP levels (p = 0.028). CONCLUSIONS: These data suggest that serum VDBP levels are positively associated with the presence of T1D in the African population. Whether VDBP lies in the causal pathway or its elevation is an effect of T1D is uncertain and requires further investigation.

Zinc transporter 8 (ZnT8) autoantibody prevalence in black South African participants with type 1 diabetes.

BACKGROUND: Autoantibodies to ß-cell specific antigens are markers of type 1 diabetes. The most recently identified autoantibodies are targeted to the zinc transporter 8 (ZnT8) protein located in the membrane of ß-cell insulin secretory granules. The prevalence of ZnT8 autoantibodies in newly diagnosed participants with type 1 diabetes has been found to range from 33 to 80 %. Due to the lack of data on the immunological aetiology of type 1 diabetes in African populations, this study aimed to determine the prevalence of ZnT8 autoantibodies in black South Africans with type 1 diabetes and whether ZnT8 autoantibody positivity was associated with age at diagnosis and disease duration. METHODS: Participants with type 1 diabetes and controls were recruited from the greater Johannesburg area, South Africa. Positivity for ZnT8, GAD65 and IA2 autoantibodies was determined by ELISA. RESULTS: Participants with type 1 diabetes (n = 183) and controls (n = 49) were matched for age (29.1 ± 9.53 vs. 27.3 ± 7.29, respectively; p = 0.248). The mean age at diagnosis for participants with type 1 diabetes was 20.8 ± 8.46 years. The prevalence of ZnT8 autoantibody positivity was 17.5 % (32 of 183) in participants with type 1 diabetes with a median disease duration of 7.00 [2.00; 11.0] years. ZnT8 autoantibody prevalence in newly diagnosed participants (< 1 year duration) was 27.3 % (6 of 22). Logistic regression analysis found an association between ZnT8 autoantibody positivity and shorter disease duration (OR: 0.9 (0.81-1.00); p = 0.042). In addition, ZnT8 autoantibody positivity was significantly associated with an increased chance of being GAD65 (OR: 3.37 (1.10-10.3)) and IA2 (OR: 8.63 (2.82-26.4)) autoantibody positive. Multiple regression analysis found no association between ZnT8 autoantibody positivity and age at diagnosis. However, the presence of ≥ 2 autoantibodies was associated with a younger age at diagnosis of type 1 diabetes when compared to participants with ≤ 1 autoantibody (B = -5.270; p = 0.002). CONCLUSIONS: The presence of ZnT8 autoantibodies was not related to a younger age at diagnosis in black South African patients with type 1 diabetes. However, the greater the numbers of autoantibodies present in an individual the earlier the age at diagnosis. ZnT8 autoantibodies decline with disease duration in the black South African population.

A Polymorphism in the Gene Encoding the Insulin Receptor Binding Protein ENPP-1 Is Associated with Decreased Glomerular Filtration Rate in an Under-Investigated Indigenous African Population.

INTRODUCTION: The C allele of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP-1) rs1044498 polymorphism has previously been associated with increased binding of ENPP-1 to the insulin receptor (IR), resulting in decreased IR signalling and enhanced insulin resistance. It has also been associated with reduced kidney function in participants with diabetes of predominantly European and Asian descent. The association of this polymorphism with kidney disease in healthy Black South African participants has yet to be ascertained. OBJECTIVE: This study, therefore, aimed to determine whether the K121Q polymorphism is associated with estimated glomerular filtration rate (eGFR) in a Black South African cohort. METHODS: Black South African participants (n = 348) from an existing cohort with known eGFR levels were genotyped for the K121Q polymorphism using PCR-RFLP and assessed for any statistical association between genotype and kidney function. RESULTS: Individuals with the A allele had significantly lower eGFR levels than individuals with the CC genotype (86.52 ± 18.95 vs. 93.29 ± 23.55 mL/min; p = 0.022). The association of the A allele with lower eGFR levels remained after controlling for sex, blood pressure, insulin resistance, age, smoking, thyroid-stimulating hormone, insulin-like growth factor-1, and BMI (R2 = 0.030, p < 0.001). CONCLUSION: The rs1044498 A allele was significantly associated with lower eGFR levels in a cohort of apparently healthy Black South Africans, through an unknown mechanism that was independent of insulin resistance. It is possible that the rs1044498 polymorphism affects kidney function by altering the role of ENPP-1 in endothelial wound healing, podocyte signalling, or oxidative stress. Thus, the presence of this polymorphism may predispose individuals to a greater risk of CKD even in the absence of diabetes.