ABCMdb

PMID: 14703505

Kajinami K, Brousseau ME, Nartsupha C, Ordovas JM, Schaefer EJ
ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin.
J Lipid Res. 2004 Apr;45(4):653-6. Epub 2004 Jan 1., [PubMed]

Sentences

No. Mutations Sentence Comment

2 ABCG5 p.Gln604Glu To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. Login to comment 6 ABCG8 p.Asp19His These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy.-Kajinami, K., M. E. Brousseau, C. Nartsupha, J. M. Ordovas, and E. J. Schaefer. Login to comment 37 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys In the present study, five prevalent DNA polymorphisms, one in ABCG5 (Q604E) and four in ABCG8 (D19H, Y54C, T400K, and A632V), were studied using a PCR-restriction length polymorphism method. Login to comment 38 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys For the D19H polymorphism, a 131 bp fragment, including a G to C substitution site at codon 19 of the ABCG8 gene, was amplified using an oligonucleotide primer set (5Ј-GCTGGGTCTAAGAGAGCTGC-3Ј and 5Ј-CTTCCCATTGCT- CACTCACC-3Ј) with 35 cycles of amplification (95ЊC for 30 s, 60ЊC for 30 s, and 72ЊC for 30 s). Login to comment 39 ABCG8 p.Asp19His For the D19H polymorphism, a 131 bp fragment, including a G to C substitution site at codon 19 of the ABCG8 gene, was amplified using an oligonucleotide primer set (5-GCTGGGTCTAAGAGAGCTGC-3 and 5-CTTCCCATTGCT- CACTCACC-3) with 35 cycles of amplification (95 C for 30 s, 60 C for 30 s, and 72 C for 30 s). Login to comment 50 ABCG8 p.Asp19His Lipid and lipoprotein concentrations before and after atorvastatin treatment according to D19H polymorphism of ABCG8 gene All Subjects DD DH/HHa P No. Login to comment 51 ABCG8 p.Asp19His Lipid and lipoprotein concentrations before and after atorvastatin treatment according to D19H polymorphism of ABCG8 gene All Subjects DD DH/HHa P No. of subjects 338 294 44 Age (years) 58 11 58 11 56 11 0.306 BMI (kg/m2) 27.0 3.0 27.0 3.0 26.8 2.6 0.685 Baseline (mg/dl) TC 272 26 273 25 264 28 0.030 LDLC 188 22 189 22 184 22 0.161 HDLC 50 11 50 11 47 9 0.088 TG 172 71 173 71 168 66 0.666 Treatment (mg/dl) TC 199 26 200 26 190 22 0.012 LDLC 118 19 119 19 112 18 0.028 HDLC 53 12 54 12 51 11 0.102 TG 137 58 137 59 136 57 0.957 % Change (adjusted) TC 27 8b 26.6 (25.7, 27.5) 28.8 (26.4, 31.2) 0.092 LDLC 37 10b 36.2 (35.4, 37.6) 39.7 (36.9, 42.4) 0.036 HDLC 8 13b 7.7 ( 6.3, 9.1) 6.9 ( 3.2, 10.6) 0.696 TG 17 30b 17.3 (14.0, 20.6) 16.2 (7.7, 24.7) 0.811 ABCG8, ATP binding cassette transporter G8; BMI, body mass index; TC, total cholesterol; LDLC, LDL cholesterol; HDLC, HDL cholesterol; TG, triglyceride. Login to comment 58 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys RESULTS Genotype, allele, haplotype frequencies, linkage disequilibrium Genotype distributions (wild-type allele homozygote, variant heterozygote, variant homozygote) in each polymorphism were as follows; Q604E (212, 112, 14), D19H (294, 43, 1), Y54C (138, 146, 54), T400K (196, 130, 12), and A632V (225, 96, 17). Login to comment 60 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys Allele frequencies (wild-type, variant) were Q604E (0.79, 0.21), D19H (0.93, 0.07), Y54C (0.62, 0.38), T400K (0.77, 0.23), and A632V (0.81, 0.19). Login to comment 63 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys Significant linkage disequilibrium was found in 5 out of 10 pairs of five polymorphisms: Q604E/D19H (D` ϭ 0.6503, P ?d; 0.0001), Q604E/Y54C (-0.3461, 0.0244), D19H/Y54C (-0.9986, 0.0003), Y54C/T400K (-0.4957, 0.0003), and T400K/A632V (-0.5484, 0.0456). Login to comment 64 ABCG8 p.Asp19His Effects of genotype on lipid levels Among the five examined polymorphisms, only the D19H variant was significantly associated with pre-and post-treatment lipid levels. Login to comment 66 ABCG8 p.Asp19His In addition, percent reductions of LDLC in carriers of D19H variant were significantly greater than that of noncarriers after adjustment for age and pretreatment LDLC levels, both of which are well-known as major determinants for statin response (Table 1). Login to comment 70 ABCG8 p.Asp19His This analysis revealed that D19H genotype, in addition to age and pretreatment LDLC, was significantly and independently associated with posttreatment LDLC level. Login to comment 71 ABCG8 p.Asp19His D19H genotype was also associated significantly and independently with the absolute and percent reduction of LDLC (data not shown). Login to comment 73 ABCG8 p.Asp19His DISCUSSION The results of our study demonstrated that the ABCG8 D19H variant is significantly and independently associated with a greater LDL-lowering response to atorvastatin, while none of the remaining polymorphisms was associated with the response. Login to comment 77 ABCG8 p.Asp19His Second, a previous study reported that the plasma cholestanol/cholesterol ratio in carriers of the D19H variant was significantly lower than that of noncarriers, while the difference in plasma cholesterol levels failed to reach statistical significance (15). Login to comment 80 ABCG8 p.Asp19His Third, among the five polymorphisms examined, only the D19H variant was significantly associated with statin response. Login to comment 81 ABCG8 p.Asp19His This strongly suggests that the D19H variant itself, or another as yet undefined linked variant, appears to have functional significance. Login to comment 84 ABCG8 p.Asp19His In this regard, it is possible to speculate that the D19H variant may result in conformational changes, which may, ultimately, alter such functions as dimerization or ATP binding. Login to comment 87 ABCG8 p.Asp19His However, we failed to find a specific ABCG5/8 haplotype that was more significantly associated with the response to atorvastatin therapy than D19H variant alone. Login to comment 89 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His Stepwise multiple regression coefficients and adjusted R square values for the posttreatment LDLC level by atorvastatina Variables Coefficient SE P Cumulative Adjusted R Square Pretreatment LDLC 0.363 0.042 Ͻ0.001 0.183 Age -0.282 0.082 0.001 0.204 D19H variant -5.529 2.774 0.047 0.211 a Stepwise multiple regression analysis was performed using seven variables (gender, age, BMI, pretreatment LDLC, pretreatment HDLC, log-transformed pretreatment TG, and D19H genotype). Login to comment 90 ABCG8 p.Asp19His ABCG8 p.Asp19His Male gender and homozygotes for wild-type allele of D19H polymorphism were assigned 1, and female gender and subjects carrying variant allele of D19H polymorphism were assigned 2, respectively. Login to comment 93 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His In the present study, E3/E4 subjects who also carried the D19H variant allele showed similar LDLC reductions (-39 Ϯ 8%) and a lower posttreatment level of LDLC (111 Ϯ 18 mg/dl), when compared with E3/ E3 subjects who also were D19H wild allele homozygotes (-38 Ϯ 10%, 116 Ϯ 20 mg/dl). Login to comment 94 ABCG8 p.Asp19His This finding suggests that the D19H variant allele may compensate for the presence of the apoE4 allele in terms of LDLC lowering. Login to comment 95 ABCG8 p.Asp19His In conclusion, in patients with hypercholesterolemia, the ABCG8 D19H variant is significantly and independently associated with greater LDLC response, but not with total cholesterol response, to atorvastatin therapy. Login to comment