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SLCO1B1 transporter polymorphism is not associated with risk of myopathy in Czech population
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Abstracts / Atherosclerosis 235 (2014) e192–e301
66 - Lipid-lowering therapy EAS-0487. DGAT1 AND DGAT2 POLYMORPHISMS HAD NO EFFECT ON THE LIPID RESPONSES TO NIACIN IN CHINESE PATIENTS WITH DYSLIPIDAEMIA M. Hua, Y. Yanga, C. Ngb, C. Leec, V. Leec, B. Tomlinsonc a
Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong China; b Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong China; c School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong China Objectives: Acyl-CoA: diacylglycerol acyltransferase (DGAT) enzymes, including DGAT1 and DGAT2, catalyze the final step in the biosynthesis of triglycerides. Niacin competitively inhibits DGAT2 in cell lines. We previously showed that niacin significantly reduced hepatic triglyceride content in a DGAT2 rs3060 genotype-dependent manner. Here we examine the effect of common polymorphisms in DGAT1 and DGAT2 on the lipid responses to niacin in two separate studies with the ER niacin/laropiprant combination and ER niacin alone, respectively. Methods: Chinese patients with dyslipidaemia were treated with ER niacin 2g /laropiprant 40mg combination for 8 weeks (n¼130) (the primary study) or with ER niacin 1.5g (the replication study) for at least 4 weeks (n¼68). Fasting lipids were measured at baseline and during the studies. The DGAT1 rs7003945 T>C and DGAT2 rs3060 T>C polymorphisms were genotyped. Results: In the primary study in 130 patients (83 males, meanSD age 55.98.9 years, 79 with background statin or other lipid-lowering treatment), ER niacin/laropiprant treatment significantly increased HDL-C by 23.222.4% and reduced triglycerides and LDL-C by -31.229.5% and -19.325.8%, respectively. Neither DGAT1 rs7003945 T>C nor DGAT2 rs3060 T>C polymorphisms had a significant effect on the triglyceride or HDL-C responses to ER niacin/laropiprant. The DGAT2 rs3060 T>C polymorphism tended to be associated with a reduced LDL-C response (TT: TC: CC ¼ -23.322.6%: -17.929.3%: -5.229.9%, P<0.05 for trend), but this association is likely to be driven by an association between this polymorphism and baseline LDL-C levels in these patients (3.400.84 mmol/L: 3.130.97 mmol/L: 2.26 0.70 mmol/L, P<0.001). In the replication group, the DGAT1 rs7003945 T>C and the DGAT2 rs3060 T>C polymorphisms had no effect on either baseline lipids or the lipid response to ER niacin. Conclusion: The DGAT1 rs7003945 and DGAT2 rs3060 polymorphisms had no significant effects on the lipid responses to niacin in Chinese dyslipidaemic patients. 66 - Lipid-lowering therapy EAS-0489. EFFECT OF NIACIN ON OXIDIZED LOW-DENSITY LIPOPROTEIN LEVELS IN CHINESE PATIENTS WITH DYSLIPIDAEMIA M. HUa, Y. Yanga, S. Yamashitab, D. Masudab, B. Tomlinsona a Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong China; b Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Objectives: In addition to the lipid modifying actions, niacin has certain pleiotropic effects, which may contribute to its anti-atherosclerotic effect. This study examined the effect of extended-release (ER) niacin in combination with laropiprant on plasma levels of oxidized low-density lipoprotein (ox-LDL), a biomarker of oxidative stress, in Hong Kong Chinese patients with dyslipidaemia. Methods: Dyslipidaemic patients were treated with ER niacin 1g/laropiprant 20mg for 4 weeks then ER niacin 2g/laropiprant 40mg for an additional 8 weeks. Concentrations of ox-LDL were assayed with the Mercodia immunoassay before and after 12 weeks treatment. The assay is based on the mouse monoclonal antibody 4E6 which is directed against a conformational epitope in oxidized apolipoprotein B-100 (apoB).
Results: In 120 patients (meanSD age 55.98.7 years, 73 males) who completed the study with ox-LDL levels measured, there were significant (P<0.001) increases in high-density lipoprotein cholesterol (HDL-C) (23.322.8%) and decreases in ox-LDL (-25.016.4%), LDL cholesterol (LDLC) (-20.126.1%), triglycerides (-31.629.2%), lipoprotein (a) (-38.619.7%) and apoB (-22.615.1%) levels. The ox-LDL correlated at baseline and, more strongly, after treatment with LDL-C (r¼0.554 and r¼0.784; P<0.001) and apoB (r¼0.637 and r¼0.867; P<0.001). Percentage changes in ox-LDL were significantly correlated to the reductions in LDL-C (r¼0.727, P<0.001) and apoB (r¼0.844, P<0.001) .Baseline ox-LDL level and change in apoB were determinants of changes in ox-LDL, explaining 85.4% of the variance in the percentage changes in ox-LDL. Reductions in ox-LDL remained significant after adjustment for changes in apoB and the ratio of ox-LDL to apoB showed a small but significant reduction from 0.062 to 0.059 U/mg (P¼0.005). Conclusion: Treatment with ER niacin/laropiprant led to a significant improvement in all lipid parameters and ox-LDL levels, but the reduction in ox-LDL levels may be largely dependent on the reduction in apoBcontaining lipoproteins. 66 - Lipid-lowering therapy EAS-0158. SLCO1B1 TRANSPORTER POLYMORPHISM IS NOT ASSOCIATED WITH RISK OF MYOPATHY IN CZECH POPULATION J.A. Hubaceka, D. Dlouhaa, V. Adamkovab, R. Ceskac, M. Vrablikc a DEM, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; b DPC, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; c 3rd Department of Internal Medicine, 1st Faculty of Medicine Charles University Prague, Prague, Czech Republic
Objectives: Statins are the most common drugs used in both primary and secondary cardiovascular disease prevention. SLCO1B1 codes for solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs. In patient using statins is elevated risk of undesirable side effects (USE) - developing of myalgia or myopathy. A significant inter-individual variability in risk of USE is likely to have a strong genetic background. Methods: SLCO1B1 rs4363657 (T/C) polymorphism was successfully analysed in the groups of 624 adult patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) 237 patients with USE (the same treatment); and 2,559 healthy control individuals (post-MONICA study). The polymorphism was analysed using nested PCR-RFLP. Results: Distribution of the individual genotypes in Czech patients with (TT¼62.6%, CT¼32.5%, CC¼5,9%; P for codominat model ¼ 0.23) and without (TT¼59.9%, CT¼34.6%, CC¼5.4%; P for codominat model ¼ 0.04) myopathy was similar to the healthy controls (TT¼64.1%, CT¼32.2%, CC¼3.7%). Conclusion: Results of our study suggest that the rs4363657 variant within the SLCO1B1 gene for OATP1B1 transporter is not strongly associated with statin induced USE (myalgia or myopathy) development in Czech patients with dyslipidemia, treated with common doses of statins. The slight difference between controls and patients on statins but without USE could be caused by the relative low number of examined individuals and needs to be reproduced. This study was supported by project No. NT/11307-5 (IGA MH CR). 66 - Lipid-lowering therapy EAS-0861. SIGNIFICANT DIFFERENCES IN LIPID PROFILE ASSOCIATED WITH MACE BETWEEN HEMODIALYSIS (HD) AND NON-HD PATIENTS: FU-REGISTRY A. Ikea, K. Shiraib, I. Nagataa, M. Sugiharaa, H. Nishikawaa, A. Kawamuraa, K. Moric, K. Sakua a
Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan; Cardiology, Fukuoka Hakujyuji Hospital, Fukuoka, Japan; c Cardiology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
b
Abstracts / Atherosclerosis 235 (2014) e192–e301
66 - Lipid-lowering therapy EAS-0487. DGAT1 AND DGAT2 POLYMORPHISMS HAD NO EFFECT ON THE LIPID RESPONSES TO NIACIN IN CHINESE PATIENTS WITH DYSLIPIDAEMIA M. Hua, Y. Yanga, C. Ngb, C. Leec, V. Leec, B. Tomlinsonc a
Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong China; b Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong China; c School of Pharmacy, The Chinese University of Hong Kong, Shatin, Hong Kong China Objectives: Acyl-CoA: diacylglycerol acyltransferase (DGAT) enzymes, including DGAT1 and DGAT2, catalyze the final step in the biosynthesis of triglycerides. Niacin competitively inhibits DGAT2 in cell lines. We previously showed that niacin significantly reduced hepatic triglyceride content in a DGAT2 rs3060 genotype-dependent manner. Here we examine the effect of common polymorphisms in DGAT1 and DGAT2 on the lipid responses to niacin in two separate studies with the ER niacin/laropiprant combination and ER niacin alone, respectively. Methods: Chinese patients with dyslipidaemia were treated with ER niacin 2g /laropiprant 40mg combination for 8 weeks (n¼130) (the primary study) or with ER niacin 1.5g (the replication study) for at least 4 weeks (n¼68). Fasting lipids were measured at baseline and during the studies. The DGAT1 rs7003945 T>C and DGAT2 rs3060 T>C polymorphisms were genotyped. Results: In the primary study in 130 patients (83 males, meanSD age 55.98.9 years, 79 with background statin or other lipid-lowering treatment), ER niacin/laropiprant treatment significantly increased HDL-C by 23.222.4% and reduced triglycerides and LDL-C by -31.229.5% and -19.325.8%, respectively. Neither DGAT1 rs7003945 T>C nor DGAT2 rs3060 T>C polymorphisms had a significant effect on the triglyceride or HDL-C responses to ER niacin/laropiprant. The DGAT2 rs3060 T>C polymorphism tended to be associated with a reduced LDL-C response (TT: TC: CC ¼ -23.322.6%: -17.929.3%: -5.229.9%, P<0.05 for trend), but this association is likely to be driven by an association between this polymorphism and baseline LDL-C levels in these patients (3.400.84 mmol/L: 3.130.97 mmol/L: 2.26 0.70 mmol/L, P<0.001). In the replication group, the DGAT1 rs7003945 T>C and the DGAT2 rs3060 T>C polymorphisms had no effect on either baseline lipids or the lipid response to ER niacin. Conclusion: The DGAT1 rs7003945 and DGAT2 rs3060 polymorphisms had no significant effects on the lipid responses to niacin in Chinese dyslipidaemic patients. 66 - Lipid-lowering therapy EAS-0489. EFFECT OF NIACIN ON OXIDIZED LOW-DENSITY LIPOPROTEIN LEVELS IN CHINESE PATIENTS WITH DYSLIPIDAEMIA M. HUa, Y. Yanga, S. Yamashitab, D. Masudab, B. Tomlinsona a Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong China; b Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
Objectives: In addition to the lipid modifying actions, niacin has certain pleiotropic effects, which may contribute to its anti-atherosclerotic effect. This study examined the effect of extended-release (ER) niacin in combination with laropiprant on plasma levels of oxidized low-density lipoprotein (ox-LDL), a biomarker of oxidative stress, in Hong Kong Chinese patients with dyslipidaemia. Methods: Dyslipidaemic patients were treated with ER niacin 1g/laropiprant 20mg for 4 weeks then ER niacin 2g/laropiprant 40mg for an additional 8 weeks. Concentrations of ox-LDL were assayed with the Mercodia immunoassay before and after 12 weeks treatment. The assay is based on the mouse monoclonal antibody 4E6 which is directed against a conformational epitope in oxidized apolipoprotein B-100 (apoB).
Results: In 120 patients (meanSD age 55.98.7 years, 73 males) who completed the study with ox-LDL levels measured, there were significant (P<0.001) increases in high-density lipoprotein cholesterol (HDL-C) (23.322.8%) and decreases in ox-LDL (-25.016.4%), LDL cholesterol (LDLC) (-20.126.1%), triglycerides (-31.629.2%), lipoprotein (a) (-38.619.7%) and apoB (-22.615.1%) levels. The ox-LDL correlated at baseline and, more strongly, after treatment with LDL-C (r¼0.554 and r¼0.784; P<0.001) and apoB (r¼0.637 and r¼0.867; P<0.001). Percentage changes in ox-LDL were significantly correlated to the reductions in LDL-C (r¼0.727, P<0.001) and apoB (r¼0.844, P<0.001) .Baseline ox-LDL level and change in apoB were determinants of changes in ox-LDL, explaining 85.4% of the variance in the percentage changes in ox-LDL. Reductions in ox-LDL remained significant after adjustment for changes in apoB and the ratio of ox-LDL to apoB showed a small but significant reduction from 0.062 to 0.059 U/mg (P¼0.005). Conclusion: Treatment with ER niacin/laropiprant led to a significant improvement in all lipid parameters and ox-LDL levels, but the reduction in ox-LDL levels may be largely dependent on the reduction in apoBcontaining lipoproteins. 66 - Lipid-lowering therapy EAS-0158. SLCO1B1 TRANSPORTER POLYMORPHISM IS NOT ASSOCIATED WITH RISK OF MYOPATHY IN CZECH POPULATION J.A. Hubaceka, D. Dlouhaa, V. Adamkovab, R. Ceskac, M. Vrablikc a DEM, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; b DPC, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; c 3rd Department of Internal Medicine, 1st Faculty of Medicine Charles University Prague, Prague, Czech Republic
Objectives: Statins are the most common drugs used in both primary and secondary cardiovascular disease prevention. SLCO1B1 codes for solute carrier organic anion transporter, which has been shown to regulate the hepatic uptake of statins and some other drugs. In patient using statins is elevated risk of undesirable side effects (USE) - developing of myalgia or myopathy. A significant inter-individual variability in risk of USE is likely to have a strong genetic background. Methods: SLCO1B1 rs4363657 (T/C) polymorphism was successfully analysed in the groups of 624 adult patients with dyslipidemia (treated with simvastin or atorvastatin, 10 or 20 mg per day) 237 patients with USE (the same treatment); and 2,559 healthy control individuals (post-MONICA study). The polymorphism was analysed using nested PCR-RFLP. Results: Distribution of the individual genotypes in Czech patients with (TT¼62.6%, CT¼32.5%, CC¼5,9%; P for codominat model ¼ 0.23) and without (TT¼59.9%, CT¼34.6%, CC¼5.4%; P for codominat model ¼ 0.04) myopathy was similar to the healthy controls (TT¼64.1%, CT¼32.2%, CC¼3.7%). Conclusion: Results of our study suggest that the rs4363657 variant within the SLCO1B1 gene for OATP1B1 transporter is not strongly associated with statin induced USE (myalgia or myopathy) development in Czech patients with dyslipidemia, treated with common doses of statins. The slight difference between controls and patients on statins but without USE could be caused by the relative low number of examined individuals and needs to be reproduced. This study was supported by project No. NT/11307-5 (IGA MH CR). 66 - Lipid-lowering therapy EAS-0861. SIGNIFICANT DIFFERENCES IN LIPID PROFILE ASSOCIATED WITH MACE BETWEEN HEMODIALYSIS (HD) AND NON-HD PATIENTS: FU-REGISTRY A. Ikea, K. Shiraib, I. Nagataa, M. Sugiharaa, H. Nishikawaa, A. Kawamuraa, K. Moric, K. Sakua a
Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan; Cardiology, Fukuoka Hakujyuji Hospital, Fukuoka, Japan; c Cardiology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
b