02408nas a2200361 4500008004100000022001400041245012300055210006900178260001600247520131200263100002201575700002001597700001701617700002201634700001801656700001801674700002301692700002301715700002501738700001601763700001701779700002301796700002501819700002201844700002201866700002001888700002201908700002201930700001901952700001901971710002001990856003602010 2019 eng d a1473-115000aStatin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study.0 aStatininduced LDL cholesterol response and type 2 diabetes a bid c2019 Dec 053 a
It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, n = 40,914) and DIAGRAM (n = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: -0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.
1 aSmit, Roelof, A J1 aTrompet, Stella1 aLeong, Aaron1 aGoodarzi, Mark, O1 aPostmus, Iris1 aWarren, Helen1 aTheusch, Elizabeth1 aBarnes, Michael, R1 aArsenault, Benoit, J1 aLi, Xiaohui1 aFeng, QiPing1 aChasman, Daniel, I1 aCupples, Adrienne, L1 aHitman, Graham, A1 aKrauss, Ronald, M1 aPsaty, Bruce, M1 aRotter, Jerome, I1 ale Cessie, Saskia1 aStein, Michael1 aJukema, Wouter1 aGIST consortium uhttps://chs-nhlbi.org/node/829202876nas a2200337 4500008004100000022001400041245014800055210006900203260000900272300001100281490000700292520184000299100002002139700001802159700002102177700002102198700002202219700002302241700001602264700002202280700002302302700002202325700002402347700002202371700002002393700002302413700001902436700002502455700002202480856003602502 2021 eng d a1663-981200aThe Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.0 aPharmacogenetics of Statin Therapy on Clinical Events No Evidenc c2021 a6798570 v123 aThe pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with -values <5.0 × 10 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. In stage-1 meta-analysis (eight studies, = 10,769, 4,212 cases), we observed no genome-wide significant results ( < 5.0 × 10). A total of 144 genetic variants were followed-up in the second stage (three studies, = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.
1 aTrompet, Stella1 aPostmus, Iris1 aWarren, Helen, R1 aNoordam, Raymond1 aSmit, Roelof, A J1 aTheusch, Elizabeth1 aLi, Xiaohui1 aArsenault, Benoit1 aChasman, Daniel, I1 aHitman, Graham, A1 aMunroe, Patricia, B1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aCaulfield, Mark, J1 aKrauss, Ron, M1 aCupples, Adrienne, L1 aJukema, Wouter, J uhttps://chs-nhlbi.org/node/8980