ABCMdb

PMID: 15262185

Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ
Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin.
Atherosclerosis. 2004 Aug;175(2):287-93., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCG5 p.Gln604Glu To investigate the interactions between common polymorphisms in ABCG5/G8 and CYP7A1 and statin response, we examined the relationships between five non-synonymous polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and a promoter variant in CYP7A1 (A-204C) in 337 hypercholesterolemic patients treated with atorvastatin 10 mg. Login to comment 4 ABCG8 p.Asp19His Combination analysis of these polymorphisms explained a greater percentage of LDL cholesterol response variation (8.5% difference across subgroups) than did single polymorphism analysis (4.2% in CYP7A1 and 3.0% in ABCG8 D19H). Login to comment 26 ABCG8 p.Asp19His Very recently, we reported that the ABCG8 D19H polymorphism was significantly and independently associated with a greater LDL cholesterol reduction after atorvastatin treatment [15], which raises the possibility that this variant is associated with a gain of function of the ABCG8 protein. Login to comment 27 ABCG8 p.Asp19His Very recently, we reported that the ABCG8 D19H polymorphism was significantly and independently associated with a greater LDL cholesterol reduction after atorvastatin treatment [15], which raises the possibility that this variant is associated with a gain of function of the ABCG8 protein. Login to comment 43 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys The set of polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and CYP7A1 (A-204C) was examined in 337 subjects from the atorvastatin (10 mg per day) arm. The means (±S.D.) of age and BMI were 58 ± 11 years old and 27.0 ± 3.0 kg/m2, respectively [15]. Login to comment 44 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys The set of polymorphisms in ABCG5/G8 (Q604E, D19H, Y54C, T400K, and A632V) and CYP7A1 (A-204C) was examined in 337 subjects from the atorvastatin (10 mg per day) arm. The means (&#b1;S.D.) of age and BMI were 58 &#b1; 11 years old and 27.0 &#b1; 3.0 kg/m2, respectively [15]. Login to comment 53 ABCG8 p.Asp19His ABCG8 p.Asp19His The interaction between two genotypes was tested using two-way ANOVA and repeated measures of ANOVA for K.Kajinamietal./Atherosclerosis175(2004)287-293289 Table 1 Associations between ABCG8 D19H/CYP7A1 A-204C and the LDL-lowering response to atorvastatin* ABCG8 D19H All subjects CYP7A1 P-values among CYP7A1 genotype† Unadjusted Adjusted AA AC CC Additive Dominant Recessive Whole subjects DD 36.7 ± 10.1 36.6, 35.5-37.6 (293) 38.2, 36.2-40.2 (84) 36.6, 35.1-38.1 (142) 34.5, 32.3-36.8 (67) 0.078 0.078 0.054 DH + HH 38.9 ± 8.0 39.6, 36.9-42.4 (44) 42.7, 38.2-47.2 (16) 38.4, 34.7-42.2 (23) 34.7, 26.6-42.8 (5) 0.049 0.043 0.065 P-values among ABCG8 genotype 0.171 0.043 0.048 0.404 0.901 - - - All Adjusted - - 38.9, 37.1-40.7 (100) 36.9, 35.4-38.3 (165) 34.5, 32.4-36.7 (72) 0.010 0.014 0.013 Unadjusted 37.0 ± 9.8 (337) - 39.2 ± 8.9 37.0 ± 9.7 33.7 ± 10.7 0.001 0.006 0.001 Men DD 36.0 ± 10.7 35.8, 34.3-37.2 (173) 37.8, 35.2-40.4 (54) 35.7, 33.7-37.8 (83) 32.9, 29.8-36.1 (36) 0.089 0.084 0.063 DH + HH 37.3 ± 7.7 38.9, 35.4-42.5 (29) 41.9, 35.2-48.6 (8) 38.7, 34.2-43.3 (17) 33.0, 23.5-42.5 (4) 0.096 0.433 0.029 P-values among ABCG8 genotype 0.544 0.109 0.241 0.288 0.974 - - - All Adjusted - - 38.4, 36.0-40.7 (62) 36.3, 34.4-38.1 (100) 32.8, 29.8-35.8 (40) 0.020 0.039 0.015 Unadjusted 36.2 ± 10.3 (202) - 38.7 ± 9.2 36.5 ± 10.6 31.8 ± 10.1 0.004 0.022 0.002 Women DD 37.6 ± 9.0 37.6, 36.1-39.2 (120) 38.5, 35.3-40.1 (30) 37.9, 35.6-40.1 (59) 36.4, 33.3-39.5 (31) 0.644 0.562 0.372 DH + HH 41.9 ± 8.0 41.6, 37.1-46.0 (15) 44.8, 38.7-50.9 (8) 37.1, 30.1-44.2 (6) 42.8, 25.6-59.9 (1) 0.188 0.077 0.915 P-values among ABCG8 genotype 0.083 0.101 0.049 0.826 0.539 - - - All Adjusted - - 39.8, 37.0-42.6 (38) 37.8, 35.7-39.9 (65) 36.6, 33.6-39.7 (32) 0.312 0.161 0.294 Unadjusted 38.1 ± 9.0 (135) - 40.1 ± 8.3 37.9 ± 8.0 36.1 ± 11.1 0.179 0.108 0.154 P-values in testing genotype interaction between ABCG8 and CYP7A1 were 0.585, 0.669, and 0.532 in whole subjects, when additive, dominant, and recessive models for CYP7A1 genotype were used, respectively. Login to comment 54 ABCG8 p.Asp19His ABCG8 p.Asp19His The interaction between two genotypes was tested using two-way ANOVA and repeated measures of ANOVA for Table 1 Associations between ABCG8 D19H/CYP7A1 A-204C and the LDL-lowering response to atorvastatin* ABCG8 D19H All subjects CYP7A1 P-values among CYP7A1 genotypeߤ Unadjusted Adjusted AA AC CC Additive Dominant Recessive Whole subjects DD 36.7 &#b1; 10.1 36.6, 35.5-37.6 (293) 38.2, 36.2-40.2 (84) 36.6, 35.1-38.1 (142) 34.5, 32.3-36.8 (67) 0.078 0.078 0.054 DH + HH 38.9 &#b1; 8.0 39.6, 36.9-42.4 (44) 42.7, 38.2-47.2 (16) 38.4, 34.7-42.2 (23) 34.7, 26.6-42.8 (5) 0.049 0.043 0.065 P-values among ABCG8 genotype 0.171 0.043 0.048 0.404 0.901 - - - All Adjusted - - 38.9, 37.1-40.7 (100) 36.9, 35.4-38.3 (165) 34.5, 32.4-36.7 (72) 0.010 0.014 0.013 Unadjusted 37.0 &#b1; 9.8 (337) - 39.2 &#b1; 8.9 37.0 &#b1; 9.7 33.7 &#b1; 10.7 0.001 0.006 0.001 Men DD 36.0 &#b1; 10.7 35.8, 34.3-37.2 (173) 37.8, 35.2-40.4 (54) 35.7, 33.7-37.8 (83) 32.9, 29.8-36.1 (36) 0.089 0.084 0.063 DH + HH 37.3 &#b1; 7.7 38.9, 35.4-42.5 (29) 41.9, 35.2-48.6 (8) 38.7, 34.2-43.3 (17) 33.0, 23.5-42.5 (4) 0.096 0.433 0.029 P-values among ABCG8 genotype 0.544 0.109 0.241 0.288 0.974 - - - All Adjusted - - 38.4, 36.0-40.7 (62) 36.3, 34.4-38.1 (100) 32.8, 29.8-35.8 (40) 0.020 0.039 0.015 Unadjusted 36.2 &#b1; 10.3 (202) - 38.7 &#b1; 9.2 36.5 &#b1; 10.6 31.8 &#b1; 10.1 0.004 0.022 0.002 Women DD 37.6 &#b1; 9.0 37.6, 36.1-39.2 (120) 38.5, 35.3-40.1 (30) 37.9, 35.6-40.1 (59) 36.4, 33.3-39.5 (31) 0.644 0.562 0.372 DH + HH 41.9 &#b1; 8.0 41.6, 37.1-46.0 (15) 44.8, 38.7-50.9 (8) 37.1, 30.1-44.2 (6) 42.8, 25.6-59.9 (1) 0.188 0.077 0.915 P-values among ABCG8 genotype 0.083 0.101 0.049 0.826 0.539 - - - All Adjusted - - 39.8, 37.0-42.6 (38) 37.8, 35.7-39.9 (65) 36.6, 33.6-39.7 (32) 0.312 0.161 0.294 Unadjusted 38.1 &#b1; 9.0 (135) - 40.1 &#b1; 8.3 37.9 &#b1; 8.0 36.1 &#b1; 11.1 0.179 0.108 0.154 P-values in testing genotype interaction between ABCG8 and CYP7A1 were 0.585, 0.669, and 0.532 in whole subjects, when additive, dominant, and recessive models for CYP7A1 genotype were used, respectively. Login to comment 62 ABCG8 p.Asp19His Interaction between the ABCG8 D19H and CYP7A1 A-204C polymorphisms The mean percent reductions of LDL cholesterol according to genotype combination are shown in Tables 1-3. Login to comment 63 ABCG8 p.Asp19His ABCG8 p.Asp19His After adjustment for age and pretreatment LDL cholesterol levels, the D19H variant allele was significantly associated with a greater reduction of LDL cholesterol after atorvastatin treatment, as compared to wild type allele homozygotes (39.6% versus 36.6%, P = 0.043) (Table 1). Login to comment 64 ABCG8 p.Asp19His After adjustment for age and pretreatment LDL cholesterol levels, the D19H variant allele was significantly associated with a greater reduction of LDL cholesterol after atorvastatin treatment, as compared to wild type allele homozygotes (39.6% versus 36.6%, P = 0.043) (Table 1). Login to comment 66 ABCG8 p.Asp19His In contrast, the CYP7A1 A-204C variant allele has diminishing effects on LDL cholesterol response, regardless of ABCG8 D19H genotype. Login to comment 67 ABCG8 p.Asp19His ABCG8 p.Asp19His Direct interaction between these two polymorphisms tested by two-way ANOVA failed to reach statistical significance due to small number of homozygotes for the CYP7A1 A-204C variant allele who also carried the ABCG8 D19H variant allele (n = 5). Login to comment 68 ABCG8 p.Asp19His ABCG8 p.Asp19His As for mean percent increase of HDL cholesterol from baseline value, no significant differences were observed across CYP7A1 A-204C genotypes (7.9, 6.6, and 9.4% in wild type allele homozygotes, variant allele heterozygotes, and homozygotes, respectively), and ABCG8 D19H genotypes (7.6 and 7.3% increase in wild type allele homozygotes and variant allele carriers, respectively). Login to comment 69 ABCG8 p.Asp19His As for mean percent increase of HDL cholesterol from baseline value, no significant differences were observed across CYP7A1 A-204C genotypes (7.9, 6.6, and 9.4% in wild type allele homozygotes, variant allele heterozygotes, and homozygotes, respectively), and ABCG8 D19H genotypes (7.6 and 7.3% increase in wild type allele homozygotes and variant allele carriers, respectively). Login to comment 72 ABCG8 p.Asp19His In addition, the differences in LDL cholesterol reduction across these four groups, as defined by two polymorphism analyses (8.5%), were more than two-fold greater than those observed across the groups defined by single polymorphism analysis (4.2% in CYP7A1 A-204C and 3.0% in ABCG8 D19H). Login to comment 73 ABCG8 p.Asp19His In addition, the differences in LDL cholesterol reduction across these four groups, as defined by two polymorphism analyses (8.5%), were more than two-fold greater than those observed across the groups defined by single polymorphism analysis (4.2% in CYP7A1 A-204C and 3.0% in ABCG8 D19H). Login to comment 74 ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys Table 2 Associations between ABCG8 Y54C/CYP7A1 A-204C and the LDL-lowering response to atorvastatin * ABCG8 Y54C All subjects CYP7A1 P-values among CYP7A1 genotype ߤ Unadjusted Adjusted AA AC CC Additive Dominant Recessive YY 36.3 &#b1; 10.0 36.3, 34.7-37.8 (138) 37.5, 34.4-40.6 (34) 36.4, 34.4-38.8 (79) 34.1, 30.5-37.7 (25) 0.311 0.358 0.155 YC 36.9 &#b1; 9.7 37.0, 35.4-38.5 (145) 38.7, 36.2-41.3 (50) 36.4, 34.1-38.8 (58) 35.4, 32.5-38.4 (37) 0.215 0.088 0.278 CC 38.9 &#b1; 9.7 38.7, 36.2-41.2 (54) 42.4, 37.9-46.9 (16) 39.1, 35.7-42.5 (28) 31.9, 26.1-37.6 (10) 0.014 0.048 0.008 P-values among ABCG8 genotype ߤ Additive 0.247 0.253 0.168 0.362 0.614 - - - Dominant 0.286 0.240 0.226 0.534 0.750 - - - P-value in testing genotype interaction between ABCG8 and CYP7A1 using two-way ANOVA were 0.439 when additive model of both genotypes are used; 0.709 when a dominant model of ABCG8 and a recessive model of CYP7A1 were used, and 0.073 when a recessive model for each genotype was used. Login to comment 76 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys K.Kajinamietal./Atherosclerosis175(2004)287-293291 Table 3 Associations between ABCG5 Q604E, ABCG8 T400K, ABCG8 A632V/CYP7A1 A-204C and the LDL-lowering response to atorvastatin* ABCG5/G8 All subjects CYP7A1 P-values among CYP7A1 genotype† Unadjusted Adjusted AA AC CC Additive Dominant Recessive ABCG5 Q604E QQ 36.9 ± 10.1 37.0, 35.7-38.2 (212) 39.4, 37.0-41.8 (57) 36.6, 34.8-38.4 (104) 35.0, 32.4-37.5 (51) 0.055 0.031 0.080 QE 37.1 ± 9.5 36.9, 35.1-38.6 (111) 37.6, 34.7-40.5 (39) 37.3, 34.8-39.9 (54) 33.9, 29.6-38.2 (18) 0.321 0.646 0.131 EE 36.9 ± 9.3 37.8, 32.9-42.7 (14) 44.3, 35.1-53.4 (4) 36.9, 30.0-43.7 (7) 31.0, 20.5-41.5 (3) 0.159 0.081 0.164 ABCG8 T400K TT 37.3 ± 10.3 37.4, 36.2-38.8 (197) 37.5, 34.4-40.6 (62) 36.4, 34.4-38.4 (92) 34.1, 30.4-37.7 (43) 0.022 0.030 0.019 TK 36.5 ± 8.6 36.2, 34.6-37.9 (128) 38.7, 36.2-41.3 (33) 36.4, 34.1-38.8 (67) 35.4, 32.5-38.4 (28) 0.611 0.726 0.320 KK 35.8 ± 13.5 36.0, 30.7-41.3 (12) 42.4, 37.9-46.9 (5) 39.1, 35.7-42.5 (6) 31.9, 26.1-37.6 (1) 0.157 0.046 0.988 ABCG8 A632V AA 36.5 ± 10.0 36.4, 35.2-37.6 (224) 39.8, 37.4-42.1 (65) 37.4, 35.6-39.3 (116) 34.3, 31.4-37.1 (43) 0.005 0.004 0.020 AV 38.0 ± 9.6 38.3, 36.4-40.2 (97) 36.7, 33.5-39.8 (28) 36.6, 34.4-38.8 (41) 34.9, 31.6-38.3 (28) 0.288 0.794 0.126 VV 36.9 ± 7.3 36.2, 31.7-40.8 (16) 42.4, 34.3-50.5 (7) 30.4, 23.0-37.8 (8) 37.0, 18.9-55.1 (1) 0.697 0.992 0.397 In testing the effects of ABCG5 (Q604E) or ABCG8 (T400K and A632V) genotype on LDL-lowering response, none of P-values reached statistical significance. Login to comment 77 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu P-values in testing genotype interaction between ABCG5 Q604E and CYP7A1 using two-way ANOVA were 0.584 when additive model of both genotypes were used; 0.568 when a dominant model of ABCG5 Q604E and recessive model of CYP7A1 were used, and 0.359 when a recessive model for each genotype was used. Login to comment 78 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys Corresponding values between ABCG8 T400K and CYP7A1 were 0.439, 0.709, and 0.641, and those between ABCG8 A632V and CYP7A1 were 0.267, 0.593, and 0.279, respectively. Login to comment 79 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu P-values in testing genotype interaction between ABCG5 Q604E and CYP7A1 using two-way ANOVA were 0.584 when additive model of both genotypes were used; 0.568 when a dominant model of ABCG5 Q604E and recessive model of CYP7A1 were used, and 0.359 when a recessive model for each genotype was used. Login to comment 80 ABCG8 p.Thr400Lys Corresponding values between ABCG8 T400K and CYP7A1 were 0.439, 0.709, and 0.641, and those between ABCG8 A632V and CYP7A1 were 0.267, 0.593, and 0.279, respectively. Login to comment 92 ABCG8 p.Asp19His Additionally, ABCG8 D19H genotype nearly reached statistical significance (P = 0.075, regression coefficient = 0.092). Login to comment 94 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys Interaction between other ABCG5/G8 polymorphisms and the CYP7A1 A-204C polymorphism Among the remaining four polymorphisms in ABCG5/G8 (Tables 2 and 3), only Y54C showed a potential interaction with the CYP7A1 A-204C polymorphism. Login to comment 95 ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys The difference in LDL cholesterol reduction across the three CYP7A1 genotypes was greater in Y54C mutant allele homozygotes than in Y54C wild type allele homozygotes (10.5% versus 3.4%) (Table 2). Login to comment 96 ABCG8 p.Tyr54Cys Interaction between other ABCG5/G8 polymorphisms and the CYP7A1 A-204C polymorphism Among the remaining four polymorphisms in ABCG5/G8 (Tables 2 and 3), only Y54C showed a potential interaction with the CYP7A1 A-204C polymorphism. Login to comment 97 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys ABCG8 p.Tyr54Cys We again reclassified subjects to test cumulative allele effects, as we had done for the ABCG8 D19H variant. Login to comment 98 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys In this case, the differences in LDL cholesterol reduction across the newly categorized groups were 5.5% in a dominant model for Y54C, and 7.5% in a recessive model, both of which were smaller than those observed for the D19H polymorphism (8.5%, Fig. 1). Login to comment 99 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys Stepwise multiple regression analysis also failed to show any significant association between LDL cholesterol reduction and Y54C genotype in any type of model (data not shown). Login to comment 100 ABCG8 p.Asp19His ABCG8 p.Tyr54Cys In this case, the differences in LDL cholesterol reduction across the newly categorized groups were 5.5% in a dominant model for Y54C, and 7.5% in a recessive model, both of which were smaller than those observed for the D19H polymorphism (8.5%, Fig. 1). Login to comment 101 ABCG8 p.Tyr54Cys Stepwise multiple regression analysis also failed to show any significant association between LDL cholesterol reduction and Y54C genotype in any type of model (data not shown). Login to comment 102 ABCG8 p.Asp19His Our chief observations were that: (1) among five polymorphisms tested in ABCG5/G8, only D19H has the potential to influence the effects of the CYP7A1 A-204C polymorphism (enhancing the drug response), and (2) combination analysis of these two polymorphisms enabled us to identify a subgroup showing a more striking response to treatment, as compared to single locus analysis. Login to comment 104 ABCG8 p.Asp19His Our chief observations were that: (1) among five polymorphisms tested in ABCG5/G8, only D19H has the potential to influence the effects of the CYP7A1 A-204C polymorphism (enhancing the drug response), and (2) combination analysis of these two polymorphisms enabled us to identify a subgroup showing a more striking response to treatment, as compared to single locus analysis. Login to comment 106 ABCG8 p.Asp19His In addition, the fact that the difference in LDL cholesterol reduction between non-carriers and carriers of the ABCG8 D19H variant allele decreased in accordance with the number of CYP7A1 A-204C variant alleles (Table 1) raises the possibility that unaffected promoter activity of CYP7A1 is important for the expression of gain of function variant in ABCG8. Login to comment 107 ABCG8 p.Asp19His In our study subjects, there were no significant differences in pretreatment LDL cholesterol levels among groups defined by CYP7A1 A-204C genotype, those defined by ABCG8 D19H genotype, or those defined by the combination of both genotypes. Login to comment 108 ABCG8 p.Asp19His In addition, the fact that the difference in LDL cholesterol reduction between non-carriers and carriers of the ABCG8 D19H variant allele decreased in accordance with the number of CYP7A1 A-204C variant alleles (Table 1) raises the possibility that unaffected promoter activity of CYP7A1 is important for the expression of gain of function variant in ABCG8. Login to comment 109 ABCG8 p.Asp19His In our study subjects, there were no significant differences in pretreatment LDL cholesterol levels among groups defined by CYP7A1 A-204C genotype, those defined by ABCG8 D19H genotype, or those defined by the combination of both genotypes. Login to comment 113 ABCG8 p.Asp19His As observed in Fig. 1, subjects who are homozygous for both CYP7A1 A-204C variant allele and ABCG8 D19H wild type allele would be expected as poor responder. Login to comment 115 ABCG8 p.Asp19His As observed in Fig. 1, subjects who are homozygous for both CYP7A1 A-204C variant allele and ABCG8 D19H wild type allele would be expected as poor responder. Login to comment