08133nas a2201957 4500008004100000022001400041245012800055210006900183260001600252300001100268490000800279520256000287653000902847653002002856653001602876653002102892653002102913653003002934653001102964653002002975653001102995653004103006653005103047653000903098653001603107653003603123653004203159653001703201100002403218700001803242700003103260700002303291700002503314700001503339700001803354700002003372700002303392700002103415700002103436700001803457700002203475700001503497700002803512700002103540700001703561700002203578700001403600700001803614700001903632700002203651700001903673700001503692700001703707700002003724700002603744700002103770700002203791700002503813700002103838700003103859700002203890700002403912700002503936700002103961700002303982700002404005700001904029700002304048700002304071700002104094700002504115700002004140700001904160700001804179700002104197700001404218700001904232700002604251700002404277700002004301700001504321700002004336700003404356700002104390700002304411700002604434700002204460700002604482700001804508700001904526700001904545700002204564700002204586700002304608700002004631700002004651700002104671700002104692700002304713700002104736700002004757700002404777700002104801700002304822700002004845700002204865700001904887700001904906700003704925700002104962700002104983700002205004700002305026700002205049700002405071700002105095700002505116700002005141700002405161700001805185700001805203700002105221700002905242700001905271700002105290700002305311700002005334700002305354700001905377700001805396700001705414700001505431700001905446700002205465700002305487700001505510700002105525700002605546700002305572700002205595700001805617700001805635700002505653700002005678700002105698700002205719700002105741700002405762700002405786700001905810700002505829700002405854700002705878700002105905700001805926700001905944700002105963700002005984700002406004700002406028700001906052710002306071710002106094710002406115856003606139 2015 eng d a1474-547X00aHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.0 aHMGcoenzyme A reductase inhibition type 2 diabetes and bodyweigh c2015 Jan 24 a351-610 v3853 a
BACKGROUND: Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
METHODS: We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
FINDINGS: Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05-0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18-0·43), waist circumference (0·32 cm, 0·16-0·47), plasma insulin concentration (1·62%, 0·53-2·72), and plasma glucose concentration (0·23%, 0·02-0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00-1·05); the rs12916-T allele association was consistent (1·06, 1·03-1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18-1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10-0·38 in all trials; 0·33 kg, 95% CI 0·24-0·42 in placebo or standard care controlled trials and -0·15 kg, 95% CI -0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9-6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06-1·18 in all trials; 1·11, 95% CI 1·03-1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04-1·22 in intensive-dose vs moderate dose trials).
INTERPRETATION: The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
FUNDING: The funding sources are cited at the end of the paper.
10aAged10aBody Mass Index10aBody Weight10aCholesterol, HDL10aCholesterol, LDL10aDiabetes Mellitus, Type 210aFemale10aGenetic Testing10aHumans10aHydroxymethylglutaryl CoA Reductases10aHydroxymethylglutaryl-CoA Reductase Inhibitors10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRandomized Controlled Trials as Topic10aRisk Factors1 aSwerdlow, Daniel, I1 aPreiss, David1 aKuchenbaecker, Karoline, B1 aHolmes, Michael, V1 aEngmann, Jorgen, E L1 aShah, Tina1 aSofat, Reecha1 aStender, Stefan1 aJohnson, Paul, C D1 aScott, Robert, A1 aLeusink, Maarten1 aVerweij, Niek1 aSharp, Stephen, J1 aGuo, Yiran1 aGiambartolomei, Claudia1 aChung, Christina1 aPeasey, Anne1 aAmuzu, Antoinette1 aLi, KaWah1 aPalmen, Jutta1 aHoward, Philip1 aCooper, Jackie, A1 aDrenos, Fotios1 aLi, Yun, R1 aLowe, Gordon1 aGallacher, John1 aStewart, Marlene, C W1 aTzoulaki, Ioanna1 aBuxbaum, Sarah, G1 avan der A, Daphne, L1 aForouhi, Nita, G1 aOnland-Moret, Charlotte, N1 aSchouw, Yvonne, T1 aSchnabel, Renate, B1 aHubacek, Jaroslav, A1 aKubinova, Ruzena1 aBaceviciene, Migle1 aTamosiunas, Abdonas1 aPajak, Andrzej1 aTopor-Madry, Roman1 aStepaniak, Urszula1 aMalyutina, Sofia1 aBaldassarre, Damiano1 aSennblad, Bengt1 aTremoli, Elena1 ade Faire, Ulf1 aVeglia, Fabrizio1 aFord, Ian1 aJukema, Wouter1 aWestendorp, Rudi, G J1 ade Borst, Gert, Jan1 ade Jong, Pim, A1 aAlgra, Ale1 aSpiering, Wilko1 avan der Zee, Anke, H Maitland1 aKlungel, Olaf, H1 ade Boer, Anthonius1 aDoevendans, Pieter, A1 aEaton, Charles, B1 aRobinson, Jennifer, G1 aDuggan, David1 aKjekshus, John1 aDowns, John, R1 aGotto, Antonio, M1 aKeech, Anthony, C1 aMarchioli, Roberto1 aTognoni, Gianni1 aSever, Peter, S1 aPoulter, Neil, R1 aWaters, David, D1 aPedersen, Terje, R1 aAmarenco, Pierre1 aNakamura, Haruo1 aMcMurray, John, J V1 aLewsey, James, D1 aChasman, Daniel, I1 aRidker, Paul, M1 aMaggioni, Aldo, P1 aTavazzi, Luigi1 aRay, Kausik, K1 aSeshasai, Sreenivasa, Rao Kondap1 aManson, JoAnn, E1 aPrice, Jackie, F1 aWhincup, Peter, H1 aMorris, Richard, W1 aLawlor, Debbie, A1 aSmith, George Davey1 aBen-Shlomo, Yoav1 aSchreiner, Pamela, J1 aFornage, Myriam1 aSiscovick, David, S1 aCushman, Mary1 aKumari, Meena1 aWareham, Nick, J1 aVerschuren, W, M Monique1 aRedline, Susan1 aPatel, Sanjay, R1 aWhittaker, John, C1 aHamsten, Anders1 aDelaney, Joseph, A1 aDale, Caroline1 aGaunt, Tom, R1 aWong, Andrew1 aKuh, Diana1 aHardy, Rebecca1 aKathiresan, Sekar1 aCastillo, Berta, A1 aHarst, Pim1 aBrunner, Eric, J1 aTybjaerg-Hansen, Anne1 aMarmot, Michael, G1 aKrauss, Ronald, M1 aTsai, Michael1 aCoresh, Josef1 aHoogeveen, Ronald, C1 aPsaty, Bruce, M1 aLange, Leslie, A1 aHakonarson, Hakon1 aDudbridge, Frank1 aHumphries, Steve, E1 aTalmud, Philippa, J1 aKivimaki, Mika1 aTimpson, Nicholas, J1 aLangenberg, Claudia1 aAsselbergs, Folkert, W1 aVoevoda, Mikhail1 aBobak, Martin1 aPikhart, Hynek1 aWilson, James, G1 aReiner, Alex, P1 aKeating, Brendan, J1 aHingorani, Aroon, D1 aSattar, Naveed1 aDIAGRAM Consortium1 aMAGIC Consortium1 aInterAct Consortium uhttps://chs-nhlbi.org/node/686303683nas a2200757 4500008004100000022001400041245011200055210006900167260000900236300000700245490000700252520150800259100002401767700002201791700002101813700001601834700001601850700002701866700002501893700002101918700002201939700001601961700001901977700001701996700002402013700001802037700002302055700001802078700002802096700002302124700002602147700002002173700002202193700002302215700002002238700002302258700002302281700002002304700003102324700001802355700001802373700002702391700002002418700002402438700001802462700002202480700002202502700001802524700002102542700002102563700002002584700001902604700002802623700002002651700002402671700002202695700002102717700001902738700001802757700002002775700001902795700002702814700002402841700002402865856003602889 2017 eng d a1756-038100aDiscovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals.0 aDiscovery and replication of SNPSNP interactions for quantitativ c2017 a250 v103 aBACKGROUND: The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).
RESULTS: Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.
CONCLUSIONS: These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.
1 aHolzinger, Emily, R1 aVerma, Shefali, S1 aMoore, Carrie, B1 aHall, Molly1 aDe, Rishika1 aGilbert-Diamond, Diane1 aLanktree, Matthew, B1 aPankratz, Nathan1 aAmuzu, Antoinette1 aBurt, Amber1 aDale, Caroline1 aDudek, Scott1 aFurlong, Clement, E1 aGaunt, Tom, R1 aKim, Daniel, Seung1 aRiess, Helene1 aSivapalaratnam, Suthesh1 aTragante, Vinicius1 avan Iperen, Erik, P A1 aBrautbar, Ariel1 aCarrell, David, S1 aCrosslin, David, R1 aJarvik, Gail, P1 aKuivaniemi, Helena1 aKullo, Iftikhar, J1 aLarson, Eric, B1 aRasmussen-Torvik, Laura, J1 aTromp, Gerard1 aBaumert, Jens1 aCruickshanks, Karen, J1 aFarrall, Martin1 aHingorani, Aroon, D1 aHovingh, G, K1 aKleber, Marcus, E1 aKlein, Barbara, E1 aKlein, Ronald1 aKoenig, Wolfgang1 aLange, Leslie, A1 aMӓrz, Winfried1 aNorth, Kari, E1 aOnland-Moret, Charlotte1 aReiner, Alex, P1 aTalmud, Philippa, J1 aSchouw, Yvonne, T1 aWilson, James, G1 aKivimaki, Mika1 aKumari, Meena1 aMoore, Jason, H1 aDrenos, Fotios1 aAsselbergs, Folkert, W1 aKeating, Brendan, J1 aRitchie, Marylyn, D uhttps://chs-nhlbi.org/node/7566