ABCMdb

PMID: 20529992

Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C, Holdt LM, Leichtle A, Greiser KH, Huster D, Linsel-Nitschke P, Schafer A, Braund PS, Tiret L, Stark K, Raaz-Schrauder D, Fiedler GM, Wilfert W, Beutner F, Gielen S, Grosshennig A, Konig IR, Lichtner P, Heid IM, Kluttig A, El Mokhtari NE, Rubin D, Ekici AB, Reis A, Garlichs CD, Hall AS, Matthes G, Wittekind C, Hengstenberg C, Cambien F, Schreiber S, Werdan K, Meitinger T, Loeffler M, Samani NJ, Erdmann J, Wichmann HE, Schunkert H, Thiery J
Genetic regulation of serum phytosterol levels and risk of coronary artery disease.
Circ Cardiovasc Genet. 2010 Aug;3(4):331-9. Epub 2010 Jun 7., [PubMed]

Sentences

No. Mutations Sentence Comment

48 ABCG8 p.Asp19His ABCG8 p.Thr400Lys These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment 49 ABCG8 p.Asp19His ABCG8 p.Thr400Lys These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment 55 ABCG8 p.Asp19His ABCG8 p.Thr400Lys These included SNP rs4245791, which had initially violated quality criteria (call rate and Hardy-Weinberg equilibrium) on the 500K Array Set due to misgenotyping, and the 2 coding SNPs rs11887534 (D19H) and rs4148217 (T400K) not present on the 500K Array Set with known associations with serum phytosterol levels.9 SNPs were genotyped using the Sequenom assay. Login to comment 75 ABCG8 p.Asp19His online-only Data Supplement Table VIII) revealed that rs41360247 was in close linkage disequilibrium (r2 ϭ0.93) with coding SNP rs11887534 (D19H), which has been associated with phytosterol levels in previous studies and is known to affect protein structure.9 In addition, SNP rs4952688 was identified by fine mapping as a proxy for rs4245791 (r2 ϭ0.89) with the lowest P values of association of all SNPs used for fine mapping. Login to comment 76 ABCG8 p.Asp19His ABCG8 p.Asp19His Haplotype analyses of the ABCG8 locus indicated that the effects of rs11887534 (D19H) and rs4952688 on phytosterol level SNPs were additive (online-only Data Supplement Figure II and online-only Data Supplement Tables IX and X). Login to comment 77 ABCG8 p.Asp19His Haplotype analyses of the ABCG8 locus indicated that the effects of rs11887534 (D19H) and rs4952688 on phytosterol level SNPs were additive (online-only Data Supplement Figure II and online-only Data Supplement Tables IX and X). Login to comment 78 ABCG8 p.Asp19His To test this hypothesis, we determined mRNA levels of these genes in 57 patient samples of normal human liver tissue and observed significantly reduced mRNA expression levels of these 2 genes in association with the T allele of rs4952688 (Figure 3) but not with rs41360247 or rs11887534 (D19H). Login to comment 79 ABCG8 p.Asp19His ABCG8 p.Asp19His 334 Circ Cardiovasc Genet August 2010 online-only Data Supplement Table VIII) revealed that rs41360247 was in close linkage disequilibrium (r2 ϭ0.93) with coding SNP rs11887534 (D19H), which has been associated with phytosterol levels in previous studies and is known to affect protein structure.9 In addition, SNP rs4952688 was identified by fine mapping as a proxy for rs4245791 (r2 ϭ0.89) with the lowest P values of association of all SNPs used for fine mapping. Login to comment 80 ABCG8 p.Asp19His Haplotype analyses of the ABCG8 locus indicated that the effects of rs11887534 (D19H) and rs4952688 on phytosterol level SNPs were additive (online-only Data Supplement Figure II and online-only Data Supplement Tables IX and X). Login to comment 82 ABCG8 p.Asp19His To test this hypothesis, we determined mRNA levels of these genes in 57 patient samples of normal human liver tissue and observed significantly reduced mRNA expression levels of these 2 genes in association with the T allele of rs4952688 (Figure 3) but not with rs41360247 or rs11887534 (D19H). Login to comment 88 ABCG8 p.Asp19His SNP rs41360247 was in strong linkage disequilibrium with rs11887534 (D19H) (r2 ϭ0.93). Login to comment 89 ABCG8 p.Asp19His SNP rs41360247 was in strong linkage disequilibrium with rs11887534 (D19H) (r2 afd;0.93). Login to comment 92 ABCG8 p.Asp19His SNP rs41360247 was in strong linkage disequilibrium with rs11887534 (D19H) (r2 ϭ0.93). Login to comment 108 ABCG8 p.Asp19His ABCG8 is a plausible candidate for affecting the inherited variability of serum phytosterol levels, given that the gene encodes the ABC hemitransporter that carries phytosterols into the bile.1,2,5 Indeed, smaller studies previously reported an association between the coding variant D19H in this gene and serum phytosterols,9 a finding that was confirmed by our data. Login to comment 109 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His D19H also was found to affect the susceptibility for cholesterol gallstone disease.24 It was speculated that the 19H variant may increase the efficiency of sterol excretion into the bile lumen, causing hypersaturation of the bile and subsequently leading to gallstone formation.25 Indeed, there are published data about an association between the D19H variant and serum cholesterol levels.26,27 Moreover, recent genome-wide studies identified an association of LDL cholesterol with proxies to D19H and the other ABCG8 variant rs4245791.22,23 This effect could be confirmed in the present study (online-only Data Supplement Figure VI), albeit the association of D19H (and the other variants we identified) with serum cholesterol levels was only weak, and effects on phytosterols remained highly significant after normalization to cholesterol (Table) or adjustment to LDL cholesterol (online-only Data Supplement Table XVII). Login to comment 110 ABCG8 p.Asp19His ABCG8 is a plausible candidate for affecting the inherited variability of serum phytosterol levels, given that the gene encodes the ABC hemitransporter that carries phytosterols into the bile.1,2,5 Indeed, smaller studies previously reported an association between the coding variant D19H in this gene and serum phytosterols,9 a finding that was confirmed by our data. Login to comment 111 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His D19H also was found to affect the susceptibility for cholesterol gallstone disease.24 It was speculated that the 19H variant may increase the efficiency of sterol excretion into the bile lumen, causing hypersaturation of the bile and subsequently leading to gallstone formation.25 Indeed, there are published data about an association between the D19H variant and serum cholesterol levels.26,27 Moreover, recent genome-wide studies identified an association of LDL cholesterol with proxies to D19H and the other ABCG8 variant rs4245791.22,23 This effect could be confirmed in the present study (online-only Data Supplement Figure VI), albeit the association of D19H (and the other variants we identified) with serum cholesterol levels was only weak, and effects on phytosterols remained highly significant after normalization to cholesterol (Table) or adjustment to LDL cholesterol (online-only Data Supplement Table XVII). Login to comment 113 ABCG8 p.Asp19His ABCG8 is a plausible candidate for affecting the inherited variability of serum phytosterol levels, given that the gene encodes the ABC hemitransporter that carries phytosterols into the bile.1,2,5 Indeed, smaller studies previously reported an association between the coding variant D19H in this gene and serum phytosterols,9 a finding that was confirmed by our data. Login to comment 114 ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His ABCG8 p.Asp19His D19H also was found to affect the susceptibility for cholesterol gallstone disease.24 It was speculated that the 19H variant may increase the efficiency of sterol excretion into the bile lumen, causing hypersaturation of the bile and subsequently leading to gallstone formation.25 Indeed, there are published data about an association between the D19H variant and serum cholesterol levels.26,27 Moreover, recent genome-wide studies identified an association of LDL cholesterol with proxies to D19H and the other ABCG8 variant rs4245791.22,23 This effect could be confirmed in the present study (online-only Data Supplement Figure VI), albeit the association of D19H (and the other variants we identified) with serum cholesterol levels was only weak, and effects on phytosterols remained highly significant after normalization to cholesterol (Table) or adjustment to LDL cholesterol (online-only Data Supplement Table XVII). 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