Manjae Kwon1, Soo Min Han2, Do-Il Kim3, Moo-Yong Rhee4, Byoung-Kwon Lee5, Young Keun Ahn6, Byung Ryul Cho7, Jeongtaek Woo8, Seung-Ho Hur9, Jin-Ok Jeong10, Yangsoo Jang11, Sang-Hak Lee12, Ji Hyun Lee13. 1. Yonsei University College of Medicine, Seoul, South Korea. 2. Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, South Korea. 3. Cardiology Division, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, South Korea. 4. Cardiovascular Center, Dongguk University Ilsan Hospital, Goyang, South Korea. 5. Cardiology Division, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea. 6. Heart Center of Chonnam National University Hospital, Gwangju, South Korea. 7. Cardiology Division, Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University College of Medicine, Chunchon, South Korea. 8. Endocrinology Division, Department of Internal Medicine, Kyunghee University School of Medicine, Seoul, South Korea. 9. Cardiology Division, Department of Internal Medicine, Keimyung University Dongsan Medical Center, Daegu, South Korea. 10. Cardiology Division, Department of Internal Medicine, School of Medicine, Chungnam National University, Chungnam National University Hospital, Daejeon, South Korea. 11. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Cardiovascular Research Institute and Cardiovascular Genome Center, Yonsei University, South Korea. 12. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Cardiovascular Research Institute and Cardiovascular Genome Center, Yonsei University, South Korea. Electronic address: shl1106@yuhs.ac. 13. Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, South Korea. Electronic address: jihyni@yuhs.ac.
Abstract
BACKGROUND/ OBJECTIVE: Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FH patients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians. METHODS: We gathered data from 66 mutation-negative and 31 mutation-positive Korean FH patients, as well as from 2274 controls who participated in the Korean Health Examinee (HEXA) shared control study. We genotyped the patients for six GLGC SNPs and four East Asian LDL-C-associated SNPs and compared SNP scores among patient groups and controls. RESULTS: Weighted mean 6- and 4-SNP scores (0.67 [SD = 0.07] and 0.46 [0.11], respectively) were both significantly associated with LDL-C levels in controls (p = 2.1 × 10(-4), R(2) = 0.01 and p = 5.0 × 10(-12), R(2) = 0.02, respectively). Mutation-negative FH patients had higher 6-SNP (0.72 [0.07]) and 4-SNP (0.49 [0.08]) scores than controls (p = 1.8 × 10(-8) and p = 3.6 × 10(-3), respectively). We also observed higher scores in mutation-positive FH patients compared with controls, but the difference did not reach statistical significance. CONCLUSION: The present study demonstrates the utility of SNP score analysis for identifying polygenic FH in Korean patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels.
BACKGROUND/ OBJECTIVE:Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in LDLR, APOB, or PCSK9. Polygenicity is a plausible cause in mutation-negative FHpatients based on LDL cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs) identified by the Global Lipids Genetics Consortium (GLGC). However, there are limited data regarding the polygenic cause of FH in Asians. METHODS: We gathered data from 66 mutation-negative and 31 mutation-positive Korean FHpatients, as well as from 2274 controls who participated in the Korean Health Examinee (HEXA) shared control study. We genotyped the patients for six GLGC SNPs and four East Asian LDL-C-associated SNPs and compared SNP scores among patient groups and controls. RESULTS: Weighted mean 6- and 4-SNP scores (0.67 [SD = 0.07] and 0.46 [0.11], respectively) were both significantly associated with LDL-C levels in controls (p = 2.1 × 10(-4), R(2) = 0.01 and p = 5.0 × 10(-12), R(2) = 0.02, respectively). Mutation-negative FHpatients had higher 6-SNP (0.72 [0.07]) and 4-SNP (0.49 [0.08]) scores than controls (p = 1.8 × 10(-8) and p = 3.6 × 10(-3), respectively). We also observed higher scores in mutation-positive FHpatients compared with controls, but the difference did not reach statistical significance. CONCLUSION: The present study demonstrates the utility of SNP score analysis for identifying polygenic FH in Korean patients by showing that small-effect common SNPs may cumulatively elevate LDL-C levels.