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provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 52, No. 19, 2008 © 2008 by the American College of Cardiology Foundation ISSN 0735-1097/08/$34.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2008.08.012

patients (8) and Mexican patients (9). Paradoxically, a dyslip- EDITORIAL COMMENT idemia haplotype was associated with lower cardiovascular disease risk (10). The USF-1 haplotype has been associated with lower interleukin-6 and C-reactive protein Frequent Detection of levels increasing with age, suggesting that the reduced risk may not involve regulation of genes (11). Familial However, this locus only accounts for some FCH fami- lies, suggesting other factors remain undetected. Other loci Mutations in Familial implicated include lipase (12) and the apoli- Combined * poprotein A1/C3/A4/A5 gene cluster (13,14). Additionally, a large number of chromosomal regions have been impli- cated by linkage in FCH families. Clearly, FCH is geneti- Gail P. Jarvik, MD, PHD,†§ John D. Brunzell, MD,‡ cally heterogeneous. Heterozygous familial hypercholesterolemia (FH) is di- Arno G. Motulsky, MD, SCD†§ agnosed based on high LDL- levels (usually Seattle, Washington Ͼ250 mg/dl) in untreated adults and frequent tendinous . Familial hypercholesterolemia, which is autoso- mal dominant and associated with early vascular disease, can be confirmed by molecular demonstration of a mutant LDL Familial combined hyperlipidemia (FCH) is the most com- mon genetic cause of hyperlipidemia, affecting approxi- receptor (LDLR) gene. However, molecular studies are mately 1% of the population. It was first described in the rarely done clinically, as the results do not influence treat- Seattle Myocardial Infarction Study in 1973 (1). This ment. A defect in the ligand for the LDLR, apoB, is a less condition is characterized by variable lipid phenotypes common cause of FH, as are missense mutations of PCSK9 (increased levels of or cholesterol or both ) (15). FH occurs in about 1 in 500 persons in the population, in the proband and in relatives that may vary within an and accounts for approximately 4% of premature myocardial individual person from time to time. Familial combined infarctions (1). can independently oc- hyperlipidemia contributes to Ն20% of coronary artery cur in FH, causing mixed hyperlipidemia and leading to disease in males under the age of 60 years (2,3). confusion with FCH. Against this background and potential uncertainties See page 1546 about the diagnosis of FCH, Civiera et al. (16) searched for classical FH mutations in FCH using probes for 203 LDLR The diagnosis of FCH is difficult, requiring data from mutations and 4 apoB mutations. Their novel microarray family members who may not be available. Percentile techniques (Lipochip) (17) recognized 88% of 230 different cutoffs, often Ͼ90th or Ͼ95th percentile for cholesterol, LDLR mutations from Spain. Methodology to find rear- low-density lipoprotein (LDL)-cholesterol, or rangements in the LDLR gene was also utilized (18). In all, elevations, are utilized to establish the diagnosis. As lipid 143 unrelated middle-aged men and women with FCH levels vary over time, both a negative and a positive were selected from the clinical records of 2 lipid clinics (16). Ͼ diagnosis can be unreliable. An increase in apolipoprotein B Inclusion required LDL-cholesterol levels of 170 mg/dl Ͼ (apoB) (4,5), together with elevated numbers of small, dense or non–high-density lipoprotein-cholesterol of 220 mg/dl LDL particles, appears to be a more consistent phenotype when triglyceride levels were over 400 mg/dl. At least 1 for FCH than are total cholesterol and triglycerides, whose first-degree relative had to have hyperlipidemia, which was Ͼ levels vary over time (6). defined as total cholesterol and/or triglyceride levels 90th Although originally described as autosomal dominant, more percentile. Functional LDLR mutations were found in 28 recent data indicate a more complex inheritance. Several loci patients (20%). No apoB mutations were detected. Patients with major and minor impacts on risk of FCH, as well as with LDLR mutations had higher levels of cholesterol environmental factors, have been demonstrated. LDL-cholesterol and apoB levels as compared with patients Variants in upstream transcription factor (USF)-1 were without these mutations, and their triglyceride levels were linked in a Finnish FCH cohort (7) and associated in Dutch somewhat higher than in patients without LDLR muta- tions. Diabetes mellitus was found in 26 patients (23%) without LDLR mutations and was absent in all LDLR

*Editorials published in the Journal of the American College of Cardiology reflect the mutation carriers. Considering only nondiabetic patients views of the authors and do not necessarily represent the views of JACC or the with cholesterol levels of Ͼ335 mg/dl and apoB levels of American College of Cardiology. Ͼ185 mg/dl, 48 patients (or 42% of study subjects) had From the Department of Medicine (†Division of Medical Genetics and ‡Division of Metabolism, , and Nutrition) and the §Department of Genome LDLR mutations. The detected LDLR mutations were Sciences, University of Washington Medical Center, Seattle, Washington. likely to be pathogenic, as most of the LDLR abnormalities JACC Vol. 52, No. 19, 2008 Jarvik et al. 1555 November 4, 2008:1554–6 FH Mutations in FCH in this study had been observed in other Spanish FH can be diagnosed by examining very low-density lipoprotein patients (17). composition (21) or with APOE phenotyping by gradient Although it is not surprising that “weaker” mutations in gel electrophoresis (21). Less than 1% of most populations LDLR might result in diagnostic uncertainty in the absence carry such APOE ␧2␧2. In view of the higher risk of of molecular diagnosis, the high frequency of FH mutations Alzheimer’s disease—2 to 3 times higher for ␧4 heterozy- in nondiabetic patients with a presumptive clinical diagnosis gotes and 15 times higher for ␧4␧4 homozygotes (22) of FCH is unexpected. Whereas part of this excess can be compared with non-␧4 genotypes—and the fact that ␧2 and ascribed to selection or referral bias of more complicated ␧4 are separately testable polymorphisms, many physicians patients to a referral center, and to the atypically high LDL request only APOE ␧2 testing or do not inform patients of levels in this cohort, these data indicate potential difficulties their APOE ␧4 status and its predictive significance for with the clinical diagnoses of FH and FCH. Subjects with Alzheimer’s disease. Ideally, before any testing that may LDLR mutations lacked tendon xanthomas, which would disclose ␧4 status, all patients should be advised about have suggested FH but frequently are absent. Furthermore, potential risks for Alzheimer’s disease and offered clinical patients with LDLR mutations in this study had lower lipid genetics consultation. levels than those typical for FH. The lack of persons with isolated elevated triglyceride levels in a family with pre- Reprint requests and correspondence: Dr. Gail P. Jarvik, De- sumptive FCH should suggest the possibility of FH rather partment of Medicine, Division of Medical Genetics, University of than FCH. Washington Medical Center, Box 357720, Seattle, Washington Similar studies on FCH using molecular search for 98195-7720. E-mail: [email protected]. LDLR mutations are strongly suggested. What should be the role of molecular testing for LDLR mutations in FCH? REFERENCES Currently, LDLR molecular studies are rarely done clini- cally, owing to the absence of both the impact on patient 1. Goldstein J, Schrott HG, Hazzard WR, Bierman EL, Motulsky AG. management and the ability to test for affected relatives Hyperlipidemia in coronary heart disease. II. 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