期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 33, 期 7, 页码 1521-1528出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.301505
关键词
genetic variation; high-density lipoprotein cholesterol; lipid metabolism; low-density lipoprotein cholesterol; polygenic traits; triglycerides
资金
- COST action [BM0904]
- Fondation Leducq (Transatlantic Network) [2009-2014]
- The Netherlands Organization for Scientific Research (NWO, Veni grant) [91612122]
- British Medical Research Council
- The Netherlands Organization for Scientific Research [184021007]
- NWO [175.010.2007.006]
- Dutch government's Economic Structure Enhancing Fund
- Ministry of Economic Affairs
- Ministry of Education, Culture and Science
- Ministry for Health, Welfare and Sports
- Northern Netherlands Collaboration of Provinces
- Province of Groningen
- University Medical Center Groningen
- University of Groningen
- Dutch Kidney Foundation
- Dutch Diabetes Research Foundation
- Erasmus Medical Center Ergo Study
- Leiden University Medical Center Longevity Study
- Innovation-Oriented Research Program on Genomics (SenterNovem) [IGE01014, IGE05007]
- Centre for Medical Systems Biology
- National Institute for Healthy Ageing [05040202, 05060810]
- MRC [MC_U120074258] Funding Source: UKRI
- Medical Research Council [MC_U120074258] Funding Source: researchfish
Objective-There are several known monogenic causes of high and low high-density lipoprotein cholesterol (HDL-C) levels, but traditional sequencing studies have had limited success in identifying mutations in the majority of individuals with extreme HDL-C levels. The aim of this study was to assess the power of a targeted high-throughput sequencing strategy to elucidate the genetic basis of extreme HDL-C phenotypes. Approach and Results-We sequenced 195 genes with either established or implicated roles in lipid and lipoprotein metabolism plus 78 lipid-unrelated genes in patients with HDL-C <1st (n=40) or >99th (n=40) percentile values, and the results were compared with those of 498 individuals representative of the Dutch general population and 95 subjects with normal HDL-C (between 40th and 60th percentile values). The extreme HDL cohort carried more rare nonsynonymous variants in the lipid geneset than both the general population (odds ratio, 1.39; P=0.019) and normal HDL-C (odds ratio, 1.43; P=0.040) cohorts. The prevalence of such variants in the lipid-related and lipid-unrelated genesets was similar in the control groups, indicative of equal mutation rates. In the extreme HDL cohort, however, there was enrichment of rare nonsynonymous variants in the lipid versus the control geneset (odds ratio, 2.23; P<0.0001), and 70% of the lipid-related variants altered conserved nucleotides. The lipid geneset comprised 4 nonsense, 10 splice-site, and 8 coding indel variants, whereas the control geneset contained only 1 such variant. In the lipid geneset, 87% and 28% of the patients carried >= 2 and >= 5 rare variants. Conclusions-This study suggests that most extreme HDL-C phenotypes have a polygenic origin.
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