Genetic variants in CETP increase risk of intracerebral hemorrhage.
ABSTRACT: In observational epidemiologic studies, higher plasma high-density lipoprotein cholesterol (HDL-C) has been associated with increased risk of intracerebral hemorrhage (ICH). DNA sequence variants that decrease cholesteryl ester transfer protein (CETP) gene activity increase plasma HDL-C; as such, medicines that inhibit CETP and raise HDL-C are in clinical development. Here, we test the hypothesis that CETP DNA sequence variants associated with higher HDL-C also increase risk for ICH.We performed 2 candidate-gene analyses of CETP. First, we tested individual CETP variants in a discovery cohort of 1,149 ICH cases and 1,238 controls from 3 studies, followed by replication in 1,625 cases and 1,845 controls from 5 studies. Second, we constructed a genetic risk score comprised of 7 independent variants at the CETP locus and tested this score for association with HDL-C as well as ICH risk.Twelve variants within CETP demonstrated nominal association with ICH, with the strongest association at the rs173539 locus (odds ratio [OR]?=?1.25, standard error [SE]?=?0.06, p?=?6.0?×?10-4 ) with no heterogeneity across studies (I2 ?=?0%). This association was replicated in patients of European ancestry (p?=?0.03). A genetic score of CETP variants found to increase HDL-C by ?2.85mg/dl in the Global Lipids Genetics Consortium was strongly associated with ICH risk (OR?=?1.86, SE?=?0.13, p?=?1.39?×?10-6 ).Genetic variants in CETP associated with increased HDL-C raise the risk of ICH. Given ongoing therapeutic development in CETP inhibition and other HDL-raising strategies, further exploration of potential adverse cerebrovascular outcomes may be warranted. Ann Neurol 2016;80:730-740.
Project description:BACKGROUND:To investigate the association of systemic, serum lipids and genetic variants in the high-density lipoprotein (HDL) metabolic pathway with polypoidal choroidal vasculopathy (PCV) in China. METHODS:The case-control study was included 150 controls and 66 cases with PCV. Serum levels of total cholesterol (TC), low-density lipoprotein (LDL), HDL, triglycerides (TG), apolipoprotein A1 (APOA1), apolipoprotein B (APOB) together with systemic risk factors including gender, hyperlipidemia, diabetes mellitus (DM), hypertension, coronary artery disease (CAD) and asthma were identified. All subjects were genotyped for four single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway: rs10468017 of hepatic lipase (LIPC), rs12678919 of lipoprotein lipase (LPL), rs3764261 and rs173539 of cholesterol ester transfer protein (CETP) with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Student's t-tests, chi-square tests, anova and logistic regression were used to evaluate associations. RESULTS:Hyperlipidemia was a risk factor (odds ratio (OR) = 1.19, P = 0.001) for PCV. HDL, LDL and APOB levels were associated with PCV (OR = 0.001, P = 0.004; OR = 0.099, P = 0.010; OR = 0.839, P = 0.018). Higher level of TC was potently associated with increased risk of PCV (OR = 109.8, P = 0.000). LIPC rs10468017 was a risk factor for PCV (OR = 11.68, P = 0.000). CETP rs3764261 conferred a decreased risk for PCV (OR = 0.08, P = 0.000). No associations of LPL rs12678919 or CETP rs173539 with PCV were found. Mean level of HDL increased with T allele of the CETP gene (p = 0.026): 1.24 mmol/L (±0.31) for the GG genotype and 1.66 mmol/L (±0.54) for the TT genotype. Additionally, T allele was associated with the following increase in APOA1: 136.78 mg/dl (±20.53) for the CC genotype and 149.57 mg/dl (±22.67) for the TT genotype of LIPC and 137.91 mg/dl (±20.36) for the GG genotype and 162.67 mg/dl (±22.50) for the TT genotype of CETP gene. CONCLUSION:Our study suggested that the significant association was found between hyperlipidemia, the serum levels of TC, HDL, LDL and APOB and PCV. The result of present study also showed that the association of LIPC rs10468017 and CETP rs3764261 with PCV.
Project description:The heritability of high-density lipoprotein cholesterol (HDL-C) level is estimated at approximately 50%. Recent genome-wide association studies have identified genes involved in regulation of high-density lipoprotein cholesterol (HDL-C) levels. The precise genetic profile determining heritability of HDL-C however are far from complete and there is substantial room for further characterization of genetic profiles influencing blood lipid levels. Here we report an association study comparing the distribution of 139 SNPs from more than 30 genes between groups that represent extreme ends of HDL-C distribution. We genotyped 704 individuals that were selected from Genome Database of Latvian Population. 10 SNPs from CETP gene showed convincing association with low HDL-C levels (rs1800775, rs3764261, rs173539, rs9939224, rs711752, rs708272, rs7203984, rs7205804, rs11076175 and rs9929488) while 34 SNPs from 10 genes were nominally associated (p<0.05) with HDL-C levels. We have also identified haplotypes from CETP with distinct effects on determination of HDL-C levels. Our conclusion: So far the SNPs in CETP gene are identified as the most common genetic factor influencing HDL-C levels in the representative sample from Latvian population.
Project description:Genetic variants ?2/?4 within the APOE gene are established risk factors for lobar intracerebral hemorrhage (ICH). Published preliminary data suggest a potential role for APOE ?4 in risk of nonlobar ICH. We therefore investigated the role of APOE in recurrent nonlobar ICH, and sought to clarify whether effects of APOE on circulating lipids mediate this association.Three hundred sixty-three survivors of nonlobar ICH were followed prospectively for ICH recurrence, with APOE genotype determined at enrollment. All participants had clinical, demographic, and laboratory data captured at time of index ICH and during follow-up. Using a multivariate model, we performed association and interaction analyses of the relationships among APOE genotype, lipid levels, and recurrent nonlobar ICH.We observed 29 nonlobar ICH recurrences among 363 survivors. APOE ?4 was associated with recurrent nonlobar ICH (hazard ratio = 1.31; 95% confidence interval = 1.02-2.69; p = 0.038) after adjustment for age/sex/ethnicity and cardiovascular risk factors. Increasing low-density lipoprotein (LDL) levels were associated with decreased risk of recurrent nonlobar ICH (p = 0.027), as were decreasing HDL levels (p = 0.046). LDL levels modified the association of APOE ?4 with recurrent nonlobar ICH (mediation p < 0.05). No associations were identified between APOE ?2 and recurrent nonlobar ICH.APOE ?4 is associated with recurrent ICH in nonlobar brain regions, providing further evidence for its causal role in ICH unrelated to cerebral amyloid angiopathy. LDL levels modulated this effect, suggesting that circulating lipid levels may mediate a portion of the role of APOE ?4 in nonlobar ICH.
Project description:BACKGROUND:Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport by exchanging cholesteryl esters for triglycerides between high-density lipoprotein and low-density lipoprotein particles, effectively decreasing high-density lipoprotein cholesterol levels. Variants within a large haplotype block upstream of CETP (rs247616, rs173539) have been shown to be significantly associated with reduced expression; however, the underlying mechanism has not been identified. METHODS:We analyzed the linkage structure of our top candidate single-nucleotide polymorphism (SNP), rs247616, and assessed each SNP of the haplotype block for potential interactions with transcription factor binding sites. We then used a reporter gene assay to assess the effect of three SNPs (rs247616, rs173539, and rs1723150) on expression in vitro. RESULTS:Several variants in the upstream haplotype, including rs247616, rs173539, and rs1723150, disrupt or generate transcription factor binding sites. In reporter gene assays, rs247616 and rs173539 were found to significantly affected expression in HepG2 cells, whereas rs17231506 had no effect. rs247616 decreased expression by 1.7-fold (P<0.0001), whereas rs173539 increased expression by 2.2-fold (P=0.0006). CONCLUSION:SNPs rs247616 and rs173539 are in high linkage disequilibrium (R=0.96, D'=1.00) and have the potential to regulate CETP expression. Although opposing effects suggest that regulation of CETP expression could vary between tissues, the minor allele of rs247616 and SNPs in high linkage with it were found to be associated with reduced expression across all tissues.
Project description:To investigate the effect of genetic variants in the high-density lipoprotein (HDL) metabolic pathway and risk factors on neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in China.A total of 742 Chinese subjects, including 221 controls, 230 cases with nAMD, and 291 cases with PCV, were included in the present study. Five single nucleotide polymorphisms (SNPs) from three genes in the HDL metabolic pathway (HDLMP) including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC) and lipoprotein lipase (LPL) were genotyped in all study subjects with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Risk factors including gender, hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease were identified. Chi-square tests or Fisher's exact tests were applied to discover associations between SNPs and risk factors for PCV and nAMD. Gene-gene interactions and gene-environment interactions were evaluated by the multifactor-dimensionality reduction (MDR) method.CETP rs3764261 were significantly associated with an increased risk for PCV (odds ratio (OR) = 1.444, P = 0.0247). LIPC rs1532085 conferred an increased risk for PCV (OR = 1.393, P = 0.0094). We found no association between PCV and LPL rs12678919, LIPC rs10468017 or CETP rs173539. No association was found between five SNPs with nAMD. Regarding risk factors, females were found to have significantly decreased risks for both PCV and nAMD (P = 0.006 and 0.001, respectively). Coronary artery disease (CAD) was a risk factor in PCV patients but played a protective role in nAMD patients. Hyperlipidemia was associated with PCV but not with nAMD. Neither hypertension nor diabetes mellitus was associated with PCV or nAMD. The MDR analysis revealed that a three-locus model with rs12678919, rs1532085, and gender was the best model for nAMD, while a five-locus model consisting of rs10468017, rs3764261, rs1532085, gender, and hyperlipidemia was best for PCV.Our large-sample study suggested that CETP rs3764261 conferred an increased risk for PCV. We also first found the association between rs1532085 and PCV. The result of present study also showed that gender and CAD are associated with PCV and nAMD. Significant association was found between hyperlipidemia and PCV but not nAMD.
Project description:The role of cholesteryl ester transfer protein (CETP) in the metabolism of high-density lipoprotein cholesterol (HDL-C) is well studied but still controversial. More recently, genome-wide association studies and meta-analyses reported the association of a promoter variant (rs3764261) with HDL-C in Caucasians and other ethnic groups. In this study, we have examined the role of genetic variation in the promoter region of CETP with HDL-C, CETP activity, coronary artery disease (CAD), CAD risk factors, and the interaction of genetic factors with environment in a unique diabetic cohort of Asian Indian Sikhs.We genotyped four variants; three tagging single nucleotide polymorphisms from promoter (rs3764261, rs12447924, rs4783961) and one intronic variant (rs708272 Taq1B) on 2431 individuals from the Sikh Diabetes study. Two variants (rs3764261 and rs708272) exhibited a strong association with HDL-C in both normoglycemic controls (?=0.12; P=9.35×10 for rs3764261; ?=0.10, P=0.002 for rs708272) and diabetic cases (?=0.07, P=0.016 for rs3764261; ?=0.08, P=0.005 for rs708272) with increased levels among minor homozygous 'AA' carriers. In addition, the same 'A' allele carriers in rs3764261 showed a significant decrease in systolic blood pressure (?=-0.08, P=0.002) in normoglycemic controls. Haplotype analysis of rs3764261, rs12447924, rs4783961, and rs708272 further revealed a significant association of 'ATAA' haplotype with an increased HDL-C (?=2.71, P=6.38×10) and 'CTAG' haplotype with decreased HDL-C levels (?=-1.78, P=2.5×10). Although there was no direct association of CETP activity and CETP polymorphisms, low CETP activity was associated with an increased risk to CAD (age, BMI, and sex-adjusted odds ratio=2.2; 95% confidence interval: 1.4-3.4; P=0.001) in this study. Our data revealed a strong interaction of rs3764261 and rs708272 for affecting the association between CETP activity and HDL-C levels (P=2.2×10 and P=4.4×10, respectively).Our results, in conjunction with earlier reports confirm low CETP activity to be associated with higher CAD risk. Although there was no direct association of CETP activity with CETP polymorphisms, our findings revealed a significant interaction between CETP variants and CETP activity for affecting HDL-C levels. These results urge a deeper evaluation of the individual genetic variation in the CETP before implementing pharmaceutical intervention of blocking CETP for preventing CAD events.
Project description:BACKGROUND:Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. METHODS:We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. RESULTS:The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (?unadjusted=3.179?mg/dl (P value=5.25×10-509), ?adjusted=0.859?mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. CONCLUSIONS:The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.
Project description:Some cholesteryl ester transfer protein (CETP) inhibitors lower low-density lipoprotein cholesterol (LDL-C) levels without reducing cardiovascular events, suggesting that the clinical benefit of lowering LDL-C may depend on how LDL-C is lowered.To estimate the association between changes in levels of LDL-C (and other lipoproteins) and the risk of cardiovascular events related to variants in the CETP gene, both alone and in combination with variants in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.Mendelian randomization analyses evaluating the association between CETP and HMGCR scores, changes in lipid and lipoprotein levels, and the risk of cardiovascular events involving 102?837 participants from 14 cohort or case-control studies conducted in North America or the United Kingdom between 1948 and 2012. The associations with cardiovascular events were externally validated in 189?539 participants from 48 studies conducted between 2011 and 2015.Differences in mean high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein B (apoB) levels in participants with CETP scores at or above vs below the median.Odds ratio (OR) for major cardiovascular events.The primary analysis included 102?837 participants (mean age, 59.9 years; 58% women) who experienced 13?821 major cardiovascular events. The validation analyses included 189?539 participants (mean age, 58.5 years; 39% women) with 62?240 cases of coronary heart disease (CHD). Considered alone, the CETP score was associated with higher levels of HDL-C, lower LDL-C, concordantly lower apoB, and a corresponding lower risk of major vascular events (OR, 0.946 [95% CI, 0.921-0.972]) that was similar in magnitude to the association between the HMGCR score and risk of major cardiovascular events per unit change in levels of LDL-C (and apoB). When combined with the HMGCR score, the CETP score was associated with the same reduction in LDL-C levels but an attenuated reduction in apoB levels and a corresponding attenuated nonsignificant risk of major cardiovascular events (OR, 0.985 [95% CI, 0.955-1.015]). In external validation analyses, a genetic score consisting of variants with naturally occurring discordance between levels of LDL-C and apoB was associated with a similar risk of CHD per unit change in apoB level (OR, 0.782 [95% CI, 0.720-0.845] vs 0.793 [95% CI, 0.774-0.812]; P?=?.79 for difference), but a significantly attenuated risk of CHD per unit change in LDL-C level (OR, 0.916 [95% CI, 0.890-0.943] vs 0.831 [95% CI, 0.816-0.847]; P?<?.001) compared with a genetic score associated with concordant changes in levels of LDL-C and apoB.Combined exposure to variants in the genes that encode the targets of CETP inhibitors and statins was associated with discordant reductions in LDL-C and apoB levels and a corresponding risk of cardiovascular events that was proportional to the attenuated reduction in apoB but significantly less than expected per unit change in LDL-C. The clinical benefit of lowering LDL-C levels may therefore depend on the corresponding reduction in apoB-containing lipoprotein particles.
Project description:Importance:Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective:To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants:This prospective biobank study included 151?217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17?854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures:Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures:Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results:Among the 151?217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P?=?9.4?×?10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18?550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13?759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P?=?.003). Conclusions and Relevance:CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.
Project description:Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain.In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5×10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted.The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not.