MRC/Wits Developmental Pathways for Health Research Unit, Department of Pediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa; DST-NRF Centre of Excellence in Mathematical and Statistical Sciences (CoE-MaSS), University of the Witwatersrand, Johannesburg, South Africa.
School of Mathematical and Statistical Sciences, North West University, Potchefstroom, North West Province 2520, South Africa.
Diabetes Res Clin Pract. 2018 Oct;144:279-285. doi: 10.1016/j.diabres.2018.09.012. Epub 2018 Sep 15.
To determine the longitudinal association of the loss-of-function (LOF) PCSK9 variants (C679X and A443T), proxies of PCSK9 inhibitor drugs, with LDL-C, fasting glucose and glycated hemoglobin.
We conducted a five year, longitudinal study, nested within the Prospective Urban and Rural Epidemiology study, among 737 apparently healthy, male and female black South Africans of the North West province. Genotyping of the C679X and A443T PCSK9 variants was achieved using Taqman assays from Applied Biosystems. Generalized estimating equations were used to determine longitudinal association of the A443T and C679X PCSK9 variants with LDL-C, fasting glucose and glycated hemoglobin.
C679X and A443T variant carriers were associated with significant reductions in LDL-C of -0.98(-1.29, -0.67) mmol/L; p < 0.001) and -0.39(-0.57, -0.20) mmol/L; p < 0.001) respectively, compared to the non-carriers. Only C679X variant was independently associated with reductions in fasting glucose of -0.37 (-0.61, -0.13) mmol/L; p = 0.002) compared to non-carriers. However, the association of the selected variants with glycated hemoglobin were not significant. C679X and A443T carriers were associated with -0.07 (-0.23, 0.09) %; p = 0.400), 0.05 (-0.13, 0.22) %; p = 0.599) of glycated haemoglobin respectively.
Our results indicated that carriers of A443T and C679X variants exhibit sustained low LDL-C levels over 5 years and have varied effects on T2D biomarkers compared to non-carriers.
确定功能丧失（LOF）PCSK9 变异（C679X 和 A443T），即 PCSK9 抑制剂药物的替代物，与 LDL-C、空腹血糖和糖化血红蛋白的纵向关联。
我们在西北省的 737 名明显健康的男性和女性南非黑人中进行了一项为期 5 年的纵向研究，该研究嵌套在前瞻性城乡流行病学研究中。使用来自 Applied Biosystems 的 Taqman 测定法对 C679X 和 A443T PCSK9 变体进行基因分型。使用广义估计方程确定 A443T 和 C679X PCSK9 变体与 LDL-C、空腹血糖和糖化血红蛋白的纵向关联。
与非携带者相比，C679X 和 A443T 变异携带者的 LDL-C 分别显著降低 -0.98(-1.29，-0.67)mmol/L;p<0.001)和-0.39(-0.57，-0.20)mmol/L;p<0.001)。只有 C679X 变异与空腹血糖的降低独立相关，降低了 -0.37(-0.61，-0.13)mmol/L;p=0.002)与非携带者相比。然而，所选变异与糖化血红蛋白的关联并不显著。C679X 和 A443T 携带者的糖化血红蛋白分别降低-0.07(-0.23，0.09)%;p=0.400)、0.05(-0.13，0.22)%;p=0.599)。
我们的结果表明，与非携带者相比，A443T 和 C679X 变异携带者在 5 年内持续表现出低 LDL-C 水平，并对 T2D 生物标志物产生不同的影响。
