ABCMdb

PMID: 24657701

Stender S, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A
The ABCG5/8 cholesterol transporter and myocardial infarction versus gallstone disease.
J Am Coll Cardiol. 2014 May 27;63(20):2121-8. doi: 10.1016/j.jacc.2013.12.055. Epub 2014 Mar 19., [PubMed]

Sentences

No. Mutations Sentence Comment

22 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys We genotyped all common nonsynonymous variants (minor allelefrequency >5%) inABCG5/ 8 (ABCG8D19H, Y54C, T400K, A632V; ABCG5 Q604E) and a functional intronic variant (ABCG8 IVS3&#fe;981) in 2 prospective studies of the Danish general population, CGPS (Copenhagen General Population Study) and CCHS (Copenhagen City Heart Study), and in a case-control study, CIHDS (Copenhagen Ischemic Heart Disease Study), totaling 60,239 participants, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Login to comment 40 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys From the 5 genotypes that were individually associated with reductions in LDL cholesterol levels, we generated combined, weighted genotype scores based on the percentage reductions in LDL cholesterol compared to the reference genotype: ABCG8 D19H, DD &#bc; 0, DH &#bc; 2.7, HH &#bc; 5.8; IVS3&#fe;981 T>C, CC &#bc; 0, TC &#bc; 2.5, TT &#bc; 4.5; Y54C, YY &#bc; 0, YC &#bc; 0.2, CC &#bc; 1.1; T400K, TT &#bc; 0, TK &#bc; 0.9, KK &#bc; 2.9; A632V, VV &#bc; 0, AV &#bc; 0.9, AA &#bc; 1.1. Login to comment 45 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys In analyses stratified on ABCG8 D19H, a weighted genotype score without D19H was constructed (i.e., including IVS3&#fe;981, Y54C, T400K, and A632V). Login to comment 51 ABCG8 p.Asp19His ABCG8 p.Asp19His To test whether the associations were independent of ABCG8 D19H, a known gain-of-function variant strongly associated with increased risk of gallstones, analyses were also stratified on D19H genotype (9,11,12). Login to comment 56 ABCG5 p.Arg50Cys ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG5 R50C and ABCG8 D19H were in almost complete linkage disequilibrium in Abbreviations and Acronyms ABC = adenosine triphosphate-binding cassette transporter CI = confidence interval LDL = low-density lipoprotein MI = myocardial infarction OR = odds ratio the CCHS (D` &#bc; 0.98; r2 &#bc; 0.94), as previously described (11), and therefore only D19H was genotyped in the CGPS and the CIHDS studies (Online Fig. 1). Login to comment 60 ABCG5 p.Gln604Glu For all genotypes except ABCG5 Q604E, there were stepwise decreases in total and LDL cholesterol levels as a function of genotypes from 0.8% (0.04 mmol/l) to 4.1% (0.24 mmol/l) for total cholesterol and 1.1% (0.04 mmol/l) to 5.8% (0.19 mmol/l) for LDL cholesterol, in homozygotes versus noncarriers (p for trend: 0.08 to 1 10-28 ). Login to comment 78 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys For the individual genotypes, ORs for MI ranged from 0.83 (95% CI: 0.76 to 0.92) for IVS3&#fe;981 TT to 1.07 (95% CI: 0.91 to 1.25) for T400K KK versus noncarriers, while ORs for gallstone disease ranged from 3.82 (95% CI: 2.66 to 5.49) for D19H HH to 1.11 (95% CI: 0.99 to 1.23) for Y54C CC versus noncarriers (Online Fig. 3). Login to comment 83 ABCG8 p.Asp19His Stratification on ABCG8 D19H genotype. Login to comment 84 ABCG8 p.Asp19His As previously shown in this cohort (9), the H-allele of D19H was a strong risk factor for symptomatic gallstone disease, with stepwise increased ORs of up to 3.82 (95% CI: 2.66 to 5.49) for HH versus DD-homozygotes (p for trend: 7 10-56 ) (Online Fig. 3). Login to comment 85 ABCG8 p.Asp19His Therefore, to assess whether the other ABCG5/8 variants were independently associated with LDL cholesterol, and with risk of MI and/or symptomatic gallstones, we tested this on a D19H DD wild-type background (Fig. 6). Login to comment 86 ABCG8 p.Asp19His Among ABCG8 D19H DD-homozygotes (n &#bc; 52,769, or 88% of the population), a genotype score constructed from the remaining LDL-lowering variants was associated with stepwise decreases in LDL cholesterol of up to 4.1% (0.14 mmol/l) for individuals with a genotype score of 6.0 versus <2.0 (p for trend: 5 10-22 ) (Fig. 6). Login to comment 87 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys The corresponding multifactorially adjusted ORs for MI and symptomatic gallstone disease were 0.88 (95% CI: 0.80 to 0.98), and 1.74 (95% CI: 1.48 to 2.05), respectively (p for trend Figure 2 Lipid and Lipoprotein Levels as a Function of ABCG5/8 Genotypes, Individually and Combined The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test. Login to comment 90 ABCG8 p.Asp19His The power to detect associations was naturally low in the smaller subgroup of D19H DH-heterozygotes and HH- homozygotes combined (n &#bc; 7,470, or 12% of the population) (Online Fig. 6). Login to comment 96 ABCG8 p.Asp19His Fourth, it is firmly established that ABCG8 D19H constitutes a risk factor for gallstone disease (12). Login to comment 105 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys Figure 3 Cumulative Incidence of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of Age and ABCG5/8 Genotype Score The genotype score was constructed by summation of weighted low-density lipoprotein cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are by log-rank trend test. Login to comment 122 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys For instance, a common intronic ABCG8 variant was recently used together with Figure 4 Risk of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of ABCG5/8 Genotype Score The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering genotypes of adenosine triphosphate-binding cassette transporter G8 (ABCG8) D19H, IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test, or for trend tests of odds ratios (ORs). Login to comment 133 ABCG8 p.Asp19His The H-allele of ABCG8 D19H is a strong risk factor for gallstone disease, comparable in magnitude towell-known risk factors such as female sex and obesity (7,9,12). Login to comment 134 ABCG8 p.Asp19His The H-allele of D19H increases the transport activity of ABCG5/8 approximately 3-fold in vitro, indicating that the variant likely confers a gain of function that increases cholesterol efflux from the liver into the gallbladder (11). Login to comment 136 ABCG8 p.Asp19His Apart from D19H, other genetic variants in ABCG5/8 have not been consistently associated with risk of gallstones. Login to comment 137 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys Although 3 smaller studies (287 gallstone cases) have reported associations for ABCG5 Q604E and ABCG8 T400K with risk of gallstone disease, the large genome-wide association study (n &#bc; 2,280 cases) that initially identified ABCG8 D19H did not report other risk variants in ABCG5/8 (27-30). Login to comment 138 ABCG5 p.Gln604Glu ABCG8 p.Thr400Lys However, re-evaluating the thorough fine-mapping of variants in the ABCG5/8-region performed in this genome-wide association study revealed that ABCG8 IVS&#fe;981 and T400K, as well as ABCG5 Q604E, were indeed associated with gallstone disease, but that the associations did not reach the stringent requirements for statistical significance and/or replication (30). Login to comment 139 ABCG5 p.Gln604Glu ABCG8 p.Asp19His ABCG8 p.Thr400Lys We found that ABCG8 IVS&#fe;981 and T400K, as well as ABCG5 Q604E, were individually associated with risk of symptomatic gallstone disease independent of D19H genotype. Login to comment 140 ABCG8 p.Asp19His In other words, these data, and the results from the studies mentioned previously (27-30), suggest that D19H is not the only lithogenic variant at the ABCG5/8 locus. Login to comment 141 ABCG8 p.Asp19His By which mechanisms might the non-D19H variants promote the formation of gallstones? Login to comment 142 ABCG8 p.Thr400Lys For ABCG8 IVS3&#fe;981 and T400K, the gallstone risk alleles were also associated with decreased levels of plasma LDL cholesterol. Login to comment 143 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Thr400Lys This resembles the association seen for D19H, suggesting that gain-of-function effects similar to the H-allele of D19H might underlie the associations for IVS3&#fe;981 and T400K. Login to comment 145 ABCG5 p.Gln604Glu ABCG5 p.Gln604Glu ABCG5 Q604E was associated with an increased risk of symptomatic gallstone disease in heterozygotes, but in contrast to the ABCG8 alleles that increased the risk of gallstones in the present study, Q604E did not associate with low LDL cholesterol. Login to comment 156 ABCG8 p.Asp19His However, this has only been shown experimentally for the H-allele of D19H (11). Login to comment 159 ABCG8 p.Asp19His ABCG8 p.Thr400Lys ABCG8 p.Tyr54Cys However, other cohorts with measurements of both LDL cholesterol and plant sterols may be better suited to directly assess the LDL cholesterol Figure 6 Risk of Myocardial Infarction and Symptomatic Gallstone Disease as a Function of ABCG5/8 Genotype Score on a D19H DD Background The genotype score was constructed by summation of weighted low-density lipoprotein (LDL) cholesterol lowering alleles of adenosine triphosphate-binding cassette transporter G8 (ABCG8) IVS3&#fe;981, T400K, Y54C, and A632V. The p values are for trend tests by Cuzick`s extension of a Wilcoxon rank sum test, or for trend tests of odds ratios (ORs). Login to comment