期刊
CIRCULATION
卷 122, 期 5, 页码 470-U66出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.109.912519
关键词
atherosclerosis; genetics; lipoproteins; HDL; PLTP protein; human
资金
- Dutch Diabetes Research Foundation [2001.00012]
- Parke-Davis, the Netherlands
- British Heart Foundation
- Swedish Research Council [09533]
- Swedish Heart and Lung Foundation
- Medical Research Council
- Cancer Research UK [C490/A11021, C8197/A1012]
- Erasmus Medical Center
- Erasmus University Rotterdam
- Netherlands Organization for Health Research and Development
- Research Institute for Diseases in the Elderly
- Netherlands Heart Foundation
- Ministry of Education, Culture, and Science
- Ministry of Health Welfare and Sports
- European Commission
- Municipality of Rotterdam
- Netherlands Organization for Scientific Research [175.010.2005.011, 911.03.012]
- Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO) [050-060-810]
- MRC [G0801566] Funding Source: UKRI
- British Heart Foundation [PG/08/094/26019] Funding Source: researchfish
- Cancer Research UK [11021] Funding Source: researchfish
- Medical Research Council [G0401527, G0801566, MC_U106179471] Funding Source: researchfish
Background-In contrast to clear associations between variants in genes participating in low-density lipoprotein metabolism and cardiovascular disease risk, such associations for high-density lipoprotein (HDL)-related genes are not well supported by recent large studies. We aimed to determine whether genetic variants at the locus encoding phospholipid transfer protein (PLTP), a protein involved in HDL remodeling, underlie altered PLTP activity, HDL particle concentration and size, and cardiovascular disease risk. Methods and Results-We assessed associations between 6 PLTP tagging single nucleotide polymorphisms and PLTP activity in 2 studies (combined n = 384) and identified 2 variants that show reproducible associations with altered plasma PLTP activity. A gene score based on these variants is associated with lower hepatic PLTP transcription (P = 3.2 x 10(-18)) in a third study (n = 957) and with an increased number of HDL particles of smaller size (P = 3.4 x 10(-17)) in a fourth study (n = 3375). In a combination of 5 cardiovascular disease case-control studies (n = 4658 cases and 11 459 controls), a higher gene score was associated with a lower cardiovascular disease risk (per-allele odds ratio, 0.94; 95% confidence interval, 0.90 to 0.98; P = 1.2 x 10(-3); odds ratio for highest versus lowest gene score, 0.69; 95% confidence interval, 0.55 to 0.86; P = 1.0 x 10(-3)). Conclusions-A gene score based on 2 PLTP single nucleotide polymorphisms is associated with lower PLTP transcription and activity, an increased number of HDL particles, smaller HDL size, and decreased risk of cardiovascular disease. These findings indicate that PLTP is a proatherogenic entity and suggest that modulation of specific elements of HDL metabolism may offer cardiovascular benefit. (Circulation. 2010; 122: 470-477.)
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