title: Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Prevalence of type 2 diabetes.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Besseling
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.affiliation: Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
authors.affiliation: Department of Vascular Medicine, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: G Kees
authors.initials: GK
authors.lastname: Hovingh
mesh_terms: D000328:Adult; D008078:Cholesterol, LDL / Q000378:metabolism; D015986:Confounding Factors, Epidemiologic; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000453:epidemiology; D005260:Female; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands / Q000453:epidemiology; D015995:Prevalence; D011973:Receptors, LDL / Q000235:genetics; D012042:Registries
chemical_list: D008078:Cholesterol, LDL; D011973:Receptors, LDL