ABCMdb

PMID: 18977479

Koeijvoets KC, van der Net JB, Dallinga-Thie GM, Steyerberg EW, Mensink RP, Kastelein JJ, Sijbrands EJ, Plat J
ABCG8 gene polymorphisms, plasma cholesterol concentrations, and risk of cardiovascular disease in familial hypercholesterolemia.
Atherosclerosis. 2009 Jun;204(2):453-8. Epub 2008 Sep 27., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Therefore, we examined associations between the D19H and T400K polymorphisms in the ABCG8 gene and CVD in a large cohort study of 2012 patients with heterozygous familial hypercholesterolemia (FH). Login to comment 4 ABCG8 p.Asp19His ABCG8 p.Thr400Lys A total of 244 individuals carried one or two alleles of the D19H variant and 568 individuals the T400K variant. Login to comment 6 ABCG8 p.Asp19His In a Cox proportional hazard regression model adjusted for relevant cardiovascular risk factors, the D19H polymorphism was not associated with total CVD risk (p = 0.2), but there was evidence of an association with higher risk of CHD (RR 1.42, CI 1.04-1.95; p = 0.03). Login to comment 7 ABCG8 p.Thr400Lys We observed no relationship between the T400K polymorphism and cardiovascular endpoints (p > 0.1). Login to comment 42 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Since the D19H and T400K polymorphisms in the ABCG8 gene showed the strongest relationship with cholesterol standardized serum plant sterol concentrations [15,16], we decided to evaluate associations with these ABCG8 variants. Login to comment 69 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys This resulted in the selection of two polymorphisms in ABCG8: D19H (substitution of histidine for aspartic acid at amino acid 19 in exon 1) and T400K (substitution of thyrosine for lysine at amino acid 400 in exon 8) that resulted both in lower cholesterol standardized plasma plant sterol concentrations [15,16]. Login to comment 71 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Taqman SNP Genotyping Assay ID for the D19H was C 26135643 10 and for the T400K C 375061 10 (Applied Biosystems). Login to comment 76 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Genotyping was successful in 2053 (95.7%) patients for the T400K polymorphism, and in 2065 (96.3%) patients for the D19H polymorphism. Login to comment 86 ABCG8 p.Asp19His ABCG8 p.Thr400Lys The association between the D19H and T400K polymorphisms in ABCG8 and the occurrence of CVD or CHD was assessed using a Cox proportional hazard regression analysis. Login to comment 98 ABCG8 p.Asp19His For the D19H polymorphism, we observed homozygosity (HH) in seven (0.3%) patients, heterozygosity (DH) in 237 (11.8%) patients, and 1768 (87.9%) patients were homozygous for the wild type allele (DD). Login to comment 99 ABCG8 p.Thr400Lys For the T400K polymorphism, 45 (2.2%) patients were homozygous (KK), 523 (26.0%) patients were heterozygous (TK), and in 1444 (71.8%) patients the homozygous wild type allele (TT) was detected. Login to comment 101 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Using chi-square analyses, ABCG8 genotype distributions were similar between individuals without and with a history of CVD (D19H, p = 0.9; T400K, p = 0.1) 3.2. Login to comment 102 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 genotypes and plasma cholesterol concentrations Plasma cholesterol concentrations according to D19H and T400K genotypes are presented in Table 3. Login to comment 103 ABCG8 p.Asp19His ABCG8 p.Thr400Lys No significant differences in plasma lipid concentrations among D19H and T400K genotypes were found. Login to comment 105 ABCG8 p.Thr400Lys Patients homozygous or heterozygous for the T400K polymorphism had significantly less often hypertension compared to carriers of the wild type alleles (7.0% vs. 9.8%; p = 0.03). Login to comment 109 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys The percentage of D19H and T400K carriers that were Table 2 Genotype and allele distributions for D19H and T400K polymorphisms in ABCG8. Login to comment 110 ABCG8 p.Asp19His ABCG8 p.Thr400Lys D19H T400K Total CVD- CVD+ Total CVD- CVD+ N (%) N (%) N (%) N (%) N (%) N (%) Genotypes Wild type (DD or TT) 1768 (87.9) 1198 (87.8) 570 (88.0) 1444 (71.8) 965 (70.7) 479 (73.9) Heterozygous (DH or TK) 237 (11.8) 161 (11.8) 76 (11.7) 523 (26.0) 372 (27.3) 151 (23.3) Homozygous (HH or KK) 7 (0.3) 5 (0.4) 2 (0.3) 45 (2.2) 27 (2.0) 18 (2.8) Total 2012 (100.0) 1364 (100.0) 648 (100.0) 2012 (100.0) 1364 (100.0) 648 (100.0) Alleles Wild type allele (D or T) 3773 (93.8) 2557 (93.7) 1216 (93.8) 3411 (84.8) 2302 (84.4) 1109 (85.6) Minor allele (H or K) 251 (6.2) 171 (6.3) 80 (6.2) 613 (15.2) 426 (15.6) 187 (14.4) Total 4024 (100.0) 2728 (100.0) 1296 (100.0) 4024 (100.0) 2728 (100.0) 1296 (100.0) CVD+ indicates history of cardiovascular disease, CVD- indicates no cardiovascular disease. Login to comment 111 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Table 3 Plasma cholesterol concentrations according to D19H and T400K genotypes. Login to comment 112 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys Polymorphism Genotype Total cholesterol LDL cholesterol HDL cholesterol Triglycerides D19H DD 9.50 (±1.99) 7.32 (±1.91) 1.22 (±0.36) 1.81 (±1.04) DH/HH 9.50 (±1.92) 7.40 (±1.87) 1.22 (±0.36) 1.75 (1;1.04) T400K TT 9.50 (±2.00) 7.32 (±1.91) 1.21 (±0.34) 1.82 (±1.04) TK/KK 9.51 (±1.94) 7.36 (±1.92) 1.24 (±0.39) 1.78 (±1.07) LDL indicates low-density lipoprotein HDL indicates high-density lipoprotein. Login to comment 121 ABCG8 p.Asp19His ABCG8 p.Thr400Lys As shown in Table 5, we found no evidence for associations of the D19H or T400K polymorphisms with total CVD risk. Login to comment 124 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Although we found no significant relationship between the ABCG8 variants and CVD overall, the effect estimates seemed opposite for the D19H and T400K polymorphisms (Table 5). Login to comment 126 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys The risk genotype for the D19H variant was the DH/HH genotype ("carriers" of the D19H polymorphism) and the risk genotype for the T400K variant was the frequent TT genotype ("non-carriers" of the T400K polymorphism). Login to comment 136 ABCG8 p.Asp19His The D19H polymorphism was associated with increased risk of CHD, but only after adjustment for year of birth, gender, smoking, diabetes, HDL cholesterol, and triglycerides levels in multiple Cox regression analyses (model 2, Table 5). Login to comment 138 ABCG8 p.Thr400Lys We found no significant relationship of the T400K polymorphism with susceptibility of CHD. Login to comment 144 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Model 1 Model 2 Model 3 Polymorphism RR (95% CI) p RR (95% CI) p RR (95% CI) p ABCG8 D19H CVD 1.13 (0.89-1.46) 0.3 1.26 (0.93-1.71) 0.1 1.27 (0.93-1.72) 0.1 CHD 1.27 (0.98-1.64) 0.07 1.42 (1.04-1.95) 0.03 1.42 (1.04-1.95) 0.03 ABCG8 T400K CVD 0.88 (0.73-1.05) 0.2 0.87 (0.70-1.08) 0.2 0.87 (0.69-1.08) 0.2 CHD 0.87 (0.72-1.06) 0.2 0.84 (0.66-1.06) 0.1 0.83 (0.65-1.05) 0.1 RR indicates relative risk, CI indicates confidence interval, CVD indicates cardiovascular disease, CHD indicates coronary heart disease. Login to comment 151 ABCG8 p.Asp19His Discussion In this large cohort study of FH patients with a high-risk of CVD, we found that the D19H polymorphism was not significantly associated with plasma cholesterol levels nor with total CVD risk, but there was evidence of an association with higher risk of CHD. Login to comment 152 ABCG8 p.Thr400Lys We observed no significant association between the T400K polymorphism and plasma cholesterol levels or cardiovascular endpoints. Login to comment 157 ABCG8 p.Asp19His Heterozygous and homozygous carriers of the D19H polymorphism had a slightly higher risk of CHD than carriers of the wild type. Login to comment 159 ABCG8 p.Asp19His Hence, it was speculated that the substitution of histidine for aspartic acid at amino acid 19 increases the transporter function of ABCG8. Login to comment 162 ABCG8 p.Asp19His Data showing the relationship of the D19H polymorphism with plasma cholesterol levels were more contradicting: one study has found an association of the 19H allele with lower plasma total and LDL cholesterol levels [16], whereas other genetic association studies have failed to confirm this relationship [15,19]. Login to comment 163 ABCG8 p.Asp19His Based on the association with lower plasma plant sterol concentrations, we had a priori expected that carriers of the D19H variant would have had a decreased risk of cardiovascular events. Login to comment 168 ABCG8 p.Thr400Lys We found no association between the T400K polymorphism and any cardiovascular event nor with plasma cholesterol concentrations. Login to comment 169 ABCG8 p.Asp19His Previous studies have shown that this polymorphism was associated with lower sitosterol to cholesterol ratios, but these findings were not as consistent as for the D19H variant [15-17]. Login to comment 170 ABCG8 p.Thr400Lys In line with our observations, none of these studies found a significant relationship between the T400K variant and plasma cholesterol levels. Login to comment 190 ABCG8 p.Asp19His ABCG8 p.Thr400Lys In conclusion, in this large, multicenter, cohort study amongst high-risk individuals with FH, we found a modest effect of the ABCG8 D19H gene variant on risk of CHD, but we did not observe a relationship between the ABCG8 T400K polymorphism and cardiovascular endpoints. Login to comment