ABCMdb

PMID: 18522623

Rudkowska I, Jones PJ
Polymorphisms in ABCG5/G8 transporters linked to hypercholesterolemia and gallstone disease.
Nutr Rev. 2008 Jun;66(6):343-8., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Met429Val Various polymorphisms (A632V, T400K, D19H, M429V, and C54Y) in the ABCG8 and ABCG5 (Q604E) gene have been found to be associated with several facets of cholesterol metabolism, including baseline cholesterol level, cholesterol kinetics, individual responsiveness of plasma cholesterol to dietary and pharmaceutical interventions for hypercholesterolemia, and increased risk of gallstones. Login to comment 10 ABCG5 p.Gln604Glu The heterogeneity of the effect of dietary changes on plasma lipid concentrations among individuals is well known.5 Plasma lipids in certain persons are relatively unresponsive to dietary interventions, whereas others have enhanced sensitivity.5 For example, Weggemans et al.6 demonstrated that carriers of the ABCG5 Q604E Affiliations: I Rudkowska is with the School of Dietetics and Human Nutrition, Faculty of Agricultural and Environmental Sciences, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada. Login to comment 16 ABCG5 p.Gln604Glu However, the response to diets either low or high in cholesterol on plasma TC and plasma low-density lipoprotein cholesterol (LDL-C) concentrations were shown not to be related to this genotype.Contrary to these results, Herron et al.7 found that a shift from a low- to a high-dietary-cholesterol diet in individuals with the ABCG5 Q604E mutant allele was associated with a greater increase in plasma LDL-C compared to subjects who were heterozygous or who carried only the wild-type allele. Login to comment 17 ABCG5 p.Gln604Glu Other studies8-10 failed to observe associations between the ABCG5 Q604E polymorphism and plasma lipid concentrations following dietary or drug intervention. Login to comment 18 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu In addition, no differences in plasma TC and LDL-C were found in yet another study, which investigated associations of blood lipids in genotypes of healthy children with the polymorphisms ABCG5 Q604E and ABCG8 A640V.11 Since 55% of the children studied had at least one mutation in ABCG5 Q604E or ABCG8 A640V, a subanalysis was performed separating subjects according to their dietary cholesterol and saturated fat intakes. Login to comment 19 ABCG5 p.Gln604Glu In this subanalysis, the researchers found that the presence of the mutant alleles was associated with higher plasma TC, LDL-C, and apolipoprotein B, but only in children with low cholesterol intake for ABCG8 A640V and low saturated fat intake for ABCG5 Q604E.11 These findings led to speculation that a gene-nutrient interaction could explain the individual variations in plasma lipid in response to changes in cholesterol and fat intake. Login to comment 21 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Hubacek et al.12 reported that none of the polymorphisms examined, including ABCG5 Q604E, ABCG8 D19H and A632V, were related to plasma lipid levels or changes in plasma lipid levels in subjects after "evolutionary" dietary changes from a traditional high-fat Eastern European diet to a lower-fat diet based on nutritional advice. Login to comment 22 ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys Yet, when a subanalysis of male participants was performed, the ABCG8 T400K wild-type allele carriers exhibited a greater decrease in plasma TC and LDL-C than mutant allele carriers.12 This same study also demonstrated that subjects with the ABCG8 C54Y Tyr54 genotype had greater plasma TC and LDL-C reduction than theABCG8 C54Y Cys54 genotype, but only in female subjects.12 Therefore, the investigators concluded that ABCG8 T400K and ABCG5 C54Y genotypes influence plasma TC in a gender-specific manner following dietary intervention.12 Overall, the various studies reviewed above suggest that different ABC transporter gene polymorphisms influence plasma lipids in relation to dietary treatment; however, no single, common,ABC transporter gene polymorphism has been identified across existing studies. Login to comment 25 ABCG8 p.Asp19His Gylling et al.9 found that carriers of a D19H mutation of the ABCG8 gene had low cholesterol absorption efficiency together with high cholesterol synthesis markers leading to suppressed plasma TC and LDL-C. Login to comment 26 ABCG8 p.Asp19His Similarly, Berge et al.8 found that a D19H polymorphism of the ABCG8 gene was associated with lower cholesterol absorption markers; however, no changes in blood lipid concentrations were observed. Login to comment 27 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys In addition, these investigators also observed that carriers of the T400K and A632V polymorphisms in the ABCG8 gene exhibited higher cholesterol synthesis and higher plasma TC, respectively.8 Gylling et al.9 failed to show an association between cholesterol kinetics and T400K and A632V polymorphisms in the ABCG8 gene, but found that carriers of the mutant Q604E allele of the ABCG5 gene had high cholesterol absorption and thus had higher characteristics of the insulin resistance syndrome. Login to comment 28 ABCG5 p.Gln604Glu In accordance, Santosa et al.14 found that women with the Q604E mutation in the ABCG5 gene had greater reductions in cholesterol absorption, along with higher increases in cholesterol synthesis, in contrast to wild-type allele carriers after a weight loss intervention.Additionally,among female subjects, heterozygous ABCG8 C54Y carriers had smaller decreases in cholesterol synthesis compared to homozygous allele carriers.14 These data correspond with evidence from the study mentioned above12 in which the Nutrition Reviews® Vol. 66():343-348344 Cys54 allele carriers possessed lower TC and LDL-C reductions. Login to comment 29 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Met429Val ABCG8 p.Met429Val ROLE OF RACE-RELATED DIFFERENCES IN ABC GENOTYPES Miwa et al.,15 studying a Japanese population, concluded that carriers of a novel ABCG8 M429V allele or a specific haplotype (wild-type allele of Q604E ABCG5, and wild-type allele of C54Y, wild-type allele of T400K, mutant allele of M429V in the ABCG8 gene), were associated with higher cholesterol absorption efficiency, as well as lower cholesterol synthesis rates. Login to comment 30 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys These findings in the Japanese group are not without exception; no difference was observed in lipid profiles in relation to common polymorphisms studied previously [ABCG8 (A632V, T400K, D19H, and C54Y) and ABCG5 (Q604E)],6,7,11,12 which might be explained by the fact that carriers of ABCG8 D19H and A632A polymorphisms are rare in the Japanese population compared to Western populations. Login to comment 31 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Met429Val Also, polymorphisms of Q604E and T400K alleles may not be as important in the regulation of non-cholesterol-sterol levels in the Japanese population.15 In a more recent trial, no detection of this SNP (ABCG8 M429V allele) was recorded in either the Caucasian or the African-American population studied, thereby potentially demonstrating a race-specific polymorphism.16 In general, these studies demonstrate the benefits of using an intermediate phenotype, such as cholesterol absorption and synthesis, to determine the link between SNPs and blood lipids in relation to a dietary treatment. Login to comment 35 ABCG8 p.Asp19His Kaijnami et al.10 found that the carriers of the ABCG8 D19H mutant allele had a greater plasma LDL-C reduction after atorvastatin treatment, relative to the wild-type allele. Login to comment 36 ABCG8 p.Asp19His It was previously reported that carriers of the ABCG8 D19H mutant allele exhibit an upregulated cholesterol synthesis,8,9 which might account for the superior efficiency of statin therapy in these subjects. Login to comment 38 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys Other ABCG5 and G8 polymorphisms (Q604E, C54Y, T400K, and A632V) and CYP7A1 in hypercholesterolemic patients had no apparent association with responsiveness to statin treatment. Login to comment 39 ABCG8 p.Thr400Lys ABC GENE POLYMORPHISMS AND PLANT STEROL ABSORPTION Plat et al.17 found that cholesterol-standardized serum campesterol and sitosterol concentrations, as well as changes in serum campesterol and sitosterol concentrations after plant stanol consumption, were associated with the ABCG8 T400K genotype. Login to comment 40 ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys Reductions in serum campesterol and sitosterol levels in subjects with a mutated allele of ABCG8 T400K were greater compared with reductions in subjects with the wild-type allele.17 These investigators hypothesized that their findings indicate the functionality of the ABCG5 and G8 heterodimer is reduced in the wild-type allele, resulting in decreased transport of plant sterols from enterocytes back into the gut lumen, or from hepatocytes into bile, thereby increasing serum concentrations of plant sterols.17 Given that the wild-type ABCG8 T400K allele is present in about 70% of the population,17 it should be relatively straightforward to verify these findings in future plant sterol/stanol studies. Login to comment 41 ABCG5 p.Gln604Glu In addition, carriers of the mutant allele ABCG5 Q604E, compared to wild type, were found to have higher baseline plasma LDL-C. Login to comment 47 ABCG5 p.Gln604Glu ABCG8 p.Asp19His Knowing this, it may be of interest to first determine if a relationship exists between cholesterol in the blood and cholesterol gallstones.Acalovschi et al.18 found that circulatory TC and triglyceride levels in gallstone patients were higher in carriers of the wild-type allele of the ABCG5 Q604E and ABCG8 D19H compared with mutant allele carriers. Login to comment 50 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His Presence of gallstones was strongly linked to the D19H mutant allele of the ABCG8 gene.22 Furthermore, Buch et al.23 performed a whole genome scan association between individuals with gallstones and controls, adjusting for BMI, gender, and age. The presence of the D19H mutant allele of the ABCG8 gene was associated with cholesterol gallstones, suggesting that the mutated allele might confer a more efficient transport of cholesterol into bile, in turn causing cholesterol hypersaturation and promoting the formation of cholesterol gallstones.23 Therefore, plasma TC levels would be lower in subjects with mutant allele, corresponding to the study by Acalovschi et al.18 Support for this finding has also been observed in German and Chilean populations.23 Consistency across various studies argues strongly for a role for the D19H allele of the ABCG8 gene in the development of gallstone disease. Login to comment 51 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys On the other hand, Wang et al.24 investigated a possible association between three polymorphisms, including C54Y, T400K alleles of ABCG8, and Q604E of ABCG5 gene, and gallstone formation in a Chinese population. Login to comment 52 ABCG8 p.Asp19His As mentioned previously, D19H and A632V mutation alleles are rarely found in Asian populations, so they were not informative in this population. Login to comment 53 ABCG8 p.Thr400Lys Wang et al.24 found that only male carriers of the mutant allele of ABCG8 T400K had an elevated risk for gallstone disease compared to males with the common genotype. Login to comment 55 ABCG8 p.Asp19His ABCG8 p.Thr400Lys Overall, these studies on ABC gene polymorphisms and gallstone disease associations demonstrate that the mutant allele of D19H and T400K of ABCG8 might help to predict gallstone disease risk within a given individual. Login to comment 61 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Thr400Lys Overall, these studies identify a variety of polymorphisms in ABCG8 (A632V, T400K, D19H, and C54Y) and in ABCG5 (Q604E) that have been linked with baseline cholesterol levels, cholesterol absorption, or responsiveness to dietary intervention.3-12,15-17 In addition, genetic variations in the ABCG8 gene (D19H and T400K) may increase the risk of gallstone disease in certain populations.22-24 Table 1 summarizes potential SNPs and the effects of the mutant allele on baseline blood lipid concentrations, cholesterol kinetics, responsiveness to interventions, and gallstone disease risk. Login to comment