ABCMdb

PMID: 21285406

Benn M, Tybjaerg-Hansen A, Stender S, Frikke-Schmidt R, Nordestgaard BG
Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study.
J Natl Cancer Inst. 2011 Mar 16;103(6):508-19. Epub 2011 Feb 1., 2011-03-16 [PubMed]

Sentences

No. Mutations Sentence Comment

17 ABCG8 p.Asp19His Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Login to comment 55 ABCG8 p.Asp19His Genotype Analyses We used a Prism 7900HT Sequence Detection System (Applied Biosystems, Inc, Foster City, CA) to genotype four coding single-nucleotide polymorphisms in three genes: PCSK9 R46L (rs11591147) (24), ABCG8 D19H (rs11887534) (25), and APOE R112C (rs429358) and R158C (rs7412) (26). Login to comment 59 ABCG8 p.Asp19His Forward (F) and reverse (R) primer sequences and VIC- and 6-FAM-labeled probe sequences, all in the 5' to 3' direction, were as follows (the variant is underlined in the probe sequences): PCSK9 R46L (rs11591147), F = GACGAGGACGGCGACTAC, R = CC GTGCTCGGGTGCTT, VIC = TGCTAGCCTTGCGTTC, 6-FAM = CTAGCCTTGCTTTC; ABCG8 D19H (rs11887534), F = AGAGGGCTGCCGAAAGG, R = CGACTTCCCATTG CTCACTCA, VIC = ACTCCCCAGGATACCT, 6-FAM = CT CCCCAGCATACCT; APOE R112C (rs429358), F = GGAAC TGGAGGAACAACTGACC,R=ACCTCGCCGCGGTACTG, VIC = ATGGAGGACGTGTGC, 6-FAM = TGGAGGACG TGCGC; and APOE R158C (rs7412), F = TCCGCGATGCC GATGAC, R = CCCCGGCCTGGTACAC, VIC = CAGGCG CTTCTGC, 6-FAM = CAGGCACTTCTGC. Login to comment 99 ABCG8 p.Asp19His Compared with the corresponding noncarriers, PCSK9 R46L homozygotes had a 20% reduction (95% CI = 1% to 39% reduction) in plasma LDL cholesterol levels (Ptrend across genotypes < .001) and ABCG8 D19H homozygotes had a 5% reduction (95% CI = 1% to 8% reduction) (Ptrend across genotypes < .001). Login to comment 101 ABCG8 p.Asp19His Sixty percent of PCSK9 R46L homozygotes, 24% of ABCG8 D19H homozygotes, and 66% of APOE ε22 genotype carriers had a plasma LDL cholesterol level below 100 mg/dL, corresponding to the lowest ATP group. Login to comment 102 ABCG8 p.Asp19His PCSK9 R46L, ABCG8 D19H, and APOE ε genotypes contributed 0.4%, 0.1%, and 5.9%, respectively, to the total variation in plasma LDL cholesterol (P < .001; Table 2). Login to comment 105 ABCG8 p.Asp19His However, the observed risk of cancer as a function of genotype in the CCHS and CGPS combined did not differ statistically significantly from 1.0 for the ABCG8 D19H genotype (Ptrend = .78) or the APOE genotype (Ptrend = .96) (Figure 3, right panel). Login to comment 120 ABCG8 p.Asp19His F statistics was 131 for PCSK9 R46L genotype, 23 for ABCG8 D19H genotype, 844 for APOE genotypes, and 474 for all genotypes combined (Table 2). Login to comment 141 ABCG8 p.Asp19His Table 2.Studies summary of the causal effect of reduced low-density lipoprotein (LDL) cholesterol on increased risk of cancer* Model F R2 , % Relative risk† (95% CI) of cancer for a 50% reduction in LDL cholesterol level P‡ P§ Observational estimate - - 1.10 (1.01 to 1.21) .003 - Instrumental variable estimate All genotypes combined 474 6.5 0.96 (0.87 to 1.05) .31 .03 PCSK9 R46L 131 0.4 1.33 (0.59 to 2.97) .30 .42 ABCG8 D19H 23 0.1 2.28 (0.43 to 12.11) .73 .23 APOE genotype 844 5.9 0.92 (0.75 to 1.10) .39 .02 * F statistics (evaluation of strength of instrument) and R2 (contribution of genotype to variation in LDL cholesterol levels in percent) are from the first-stage regression analysis. Login to comment 183 ABCG8 p.Asp19His ABCG8 p.Asp19His Homozygosity for the ABCG8 D19H variant is associated with an increased risk of biliary tract cancer (25), probably due to an increased concentration of cholesterol in the gall bladder; however, the magnitude of this problem in this study is likely to be limited because of the low frequency of ABCG8 D19H homozygotes (ie, 0.4% = 252/62 786; Figure 3) in the study population. Login to comment