Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
JAMA. 2015 Mar 10;313(10):1029-36. doi: 10.1001/jama.2015.1206.
Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes.
To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study in all individuals (n = 63,320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014.
Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations.
Prevalence of type 2 diabetes.
The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25,137) vs 2.93% in unaffected relatives (n = 1119/38,183) (P < .001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P < .001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <.001 in both comparisons).
In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.
重要性：家族性高胆固醇血症的特征是外周组织（包括肝脏和胰腺）中胆固醇摄取受损。相比之下，他汀类药物会增加细胞内胆固醇摄取，并与 2 型糖尿病风险增加相关。我们假设跨膜胆固醇转运与 2 型糖尿病的发生有关。
目的：评估 2 型糖尿病患病率与家族性高胆固醇血症之间的关系。
设计、设置和参与者：这是一项在荷兰全国性筛查计划中于 1994 年至 2014 年间接受家族性高胆固醇血症 DNA 检测的所有个体（n=63320）的横断面研究。
暴露：家族性高胆固醇血症突变的有害性和非有害性是基于文献或实验室功能测试的。低密度脂蛋白（LDL）受体突变被认为比载脂蛋白 B 基因（APOB）突变更严重，受体阴性 LDL 受体突变被认为比受体缺陷突变更严重。
主要结局和测量：2 型糖尿病的患病率。
结果：家族性高胆固醇血症患者的 2 型糖尿病患病率为 1.75%（n=440/25137），而非受影响亲属的 2 型糖尿病患病率为 2.93%（n=1119/38183）（P<0.001；比值比[OR]，0.62[95%CI，0.55-0.69]）。使用多变量回归模型确定的家族性高胆固醇血症患者中 2 型糖尿病的调整后患病率为 1.44%（差异，1.49%[95%CI，1.24%-1.71%]）（OR，0.49[95%CI，0.41-0.58]；P<0.001）。APOB 与 LDL 受体基因相比，2 型糖尿病的调整后患病率分别为 1.91%和 1.33%（OR，0.65[95%CI，0.48-0.87]和 OR，0.45[95%CI，0.38-0.54]），受体缺陷与受体阴性突变携带者的患病率分别为 1.44%和 1.12%（OR，0.49[95%CI，0.40-0.60]和 OR，0.38[95%CI，0.29-0.49]）（趋势 P 值均<0.001）。
结论和相关性：在荷兰的一项横断面分析中，家族性高胆固醇血症患者的 2 型糖尿病患病率明显低于无家族史的亲属，且与突变类型有关。如果这一发现在纵向分析中得到证实，那么 LDL 受体介导的跨膜胆固醇转运与 2 型糖尿病之间就有可能存在因果关系。
