Low Prevalence of Mutations in Known Loci for Autosomal Dominant Hypercholesterolemia in a Multiethnic Patient Cohort

Background-Autosomal dominant hypercholesterolemia (ADH), characterized by elevated plasma levels of low-density lipoprotein (LDL)-cholesterol, is caused by variants in at least 3 different genes: LDL receptor (LDLR), apolipoprotein B-100, and proprotein convertase subtilisin-like kexin type 9. There is paucity of data about the molecular basis of ADH among ethnic groups other than those of European or Japanese descent. Here, we examined the molecular basis of ADH in a multiethnic patient cohort from lipid clinics in a large, urban US city. Methods and Results-A total of 38 men and 53 women, aged 22 to 76 years, met modified Simon-Broome criteria for ADH and were screened for mutations in the exons and consensus splice sites of LDLR, and in selected exons of apolipoprotein B-100 and proprotein convertase subtilisin-like kexin type 9. Deletions and duplications of LDLR exons were detected with multiplex ligation-dependent probe amplification. Heterozygous variants in LDLR were identified in 30 patients and in apolipoprotein B-100 in 1 patient. The remaining 60 patients (65%) had unexplained ADH. A higher proportion of blacks (77%) than either non-Hispanic whites (57%) or Hispanics (53%) had unexplained ADH. Compared with patients with LDLR variants, those with unexplained ADH had lower levels of LDL-cholesterol (292 +/- 47 mg/dL versus 239 +/- 42 mg/dL, respectively; P<0.0001) and higher levels of high-density lipoprotein cholesterol (45 +/- 12 mg/dL versus 54 +/- 13 mg/dL, respectively; P=0.003). Conclusions-Our findings suggest that additional loci may contribute to ADH, especially in understudied populations such as blacks. (Circ Cardiovasc Genet. 2012;5:666-675.)