03048nas a2200481 4500008004100000022001400041245006500055210006300120260001300183300001000196490000700206520171100213653002201924653000901946653002201955653002001977653002301997653001902020653003402039653004002073653001102113653003802124653001502162653001102177653000902188653001402197653003602211653002402247653001702271653001202288100002402300700002102324700002202345700002202367700002002389700002102409700002002430700001802450700002002468700002402488700001802512856003602530 2010 eng d a1440-184300aCRP gene variation and risk of community-acquired pneumonia.0 aCRP gene variation and risk of communityacquired pneumonia c2010 Jan a160-40 v153 a
BACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.
METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires.
RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.
CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.
10aAfrican Americans10aAged10aAged, 80 and over10aBody Mass Index10aC-Reactive Protein10aCohort Studies10aCommunity-Acquired Infections10aEuropean Continental Ancestry Group10aFemale10aGenetic Predisposition to Disease10aHaplotypes10aHumans10aMale10aPneumonia10aPolymorphism, Single Nucleotide10aProspective Studies10aRisk Factors10aSmoking1 aMukamal, Kenneth, J1 aPai, Jennifer, K1 aO'Meara, Ellen, S1 aTracy, Russell, P1 aPsaty, Bruce, M1 aKuller, Lewis, H1 aNewman, Anne, B1 aYende, Sachin1 aCurhan, Gary, C1 aSiscovick, David, S1 aRimm, Eric, B uhttps://chs-nhlbi.org/node/114706326nas a2201873 4500008004100000022001400041245007300055210006900128260001300197300001100210490000700221520118400228653001901412653001501431653001501446653000901461653001101470653002001481653003401501653003101535653001101566653001101577653002801588653002001616653001701636100001901653700002201672700002301694700002701717700002001744700002201764700001801786700001601804700001601820700002101836700002601857700001201883700002001895700002001915700001801935700002001953700002001973700002301993700001902016700002202035700002102057700002702078700001802105700001702123700002502140700002902165700002402194700001802218700002202236700001902258700002402277700002202301700002202323700002402345700002502369700001902394700002102413700002302434700002602457700002202483700002602505700002002531700002002551700002302571700001902594700002102613700002002634700002502654700001902679700001802698700002202716700002302738700002302761700002002784700002102804700002102825700002402846700001802870700002202888700002202910700001802932700001802950700002302968700002202991700002103013700001603034700002203050700001803072700002103090700001703111700001903128700001603147700001903163700001903182700002003201700002003221700002203241700002203263700002403285700002103309700002603330700002803356700001903384700001903403700002103422700002503443700002303468700002203491700001803513700002203531700001803553700001803571700002003589700002203609700001903631700002103650700002003671700001703691700001903708700002203727700001903749700002503768700002003793700002403813700002403837700001703861700002003878700001803898700002003916700002403936700002103960700001403981700002403995700002304019700001804042700002204060700002004082700002404102700002304126700002004149700002504169700001604194700002004210700002104230700002804251700002604279700001904305700001704324700002304341700001304364700001804377700002104395856003604416 2010 eng d a1546-171800aNew loci associated with kidney function and chronic kidney disease.0 aNew loci associated with kidney function and chronic kidney dise c2010 May a376-840 v423 aChronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
10aCohort Studies10aCreatinine10aCystatin C10aDiet10aEurope10aGenetic Markers10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aModels, Genetic10aRisk Factors1 aKöttgen, Anna1 aPattaro, Cristian1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aGlazer, Nicole, L1 aParsa, Afshin1 aGao, Xiaoyi1 aYang, Qiong1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aLi, Man1 aSchmidt, Helena1 aTanaka, Toshiko1 aIsaacs, Aaron1 aKetkar, Shamika1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aDehghan, Abbas1 aTeumer, Alexander1 aParé, Guillaume1 aAtkinson, Elizabeth, J1 aZeller, Tanja1 aLohman, Kurt1 aCornelis, Marilyn, C1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aTönjes, Anke1 aHayward, Caroline1 aAspelund, Thor1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aRampersaud, Evadnie1 aMitchell, Braxton, D1 aArking, Dan, E1 aBoerwinkle, Eric1 aStruchalin, Maksim1 aCavalieri, Margherita1 aSingleton, Andrew1 aGiallauria, Francesco1 aMetter, Jeffrey1 ade Boer, Ian, H1 aHaritunians, Talin1 aLumley, Thomas1 aSiscovick, David1 aPsaty, Bruce, M1 aZillikens, Carola, M1 aOostra, Ben, A1 aFeitosa, Mary1 aProvince, Michael1 ade Andrade, Mariza1 aTurner, Stephen, T1 aSchillert, Arne1 aZiegler, Andreas1 aWild, Philipp, S1 aSchnabel, Renate, B1 aWilde, Sandra1 aMunzel, Thomas, F1 aLeak, Tennille, S1 aIllig, Thomas1 aKlopp, Norman1 aMeisinger, Christa1 aWichmann, H-Erich1 aKoenig, Wolfgang1 aZgaga, Lina1 aZemunik, Tatijana1 aKolcic, Ivana1 aMinelli, Cosetta1 aHu, Frank, B1 aJohansson, Asa1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aSchreiber, Stefan1 aAulchenko, Yurii, S1 aFelix, Janine, F1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aHofman, Albert1 aImboden, Medea1 aNitsch, Dorothea1 aBrandstätter, Anita1 aKollerits, Barbara1 aKedenko, Lyudmyla1 aMägi, Reedik1 aStumvoll, Michael1 aKovacs, Peter1 aBoban, Mladen1 aCampbell, Susan1 aEndlich, Karlhans1 aVölzke, Henry1 aKroemer, Heyo, K1 aNauck, Matthias1 aVölker, Uwe1 aPolasek, Ozren1 aVitart, Veronique1 aBadola, Sunita1 aParker, Alexander, N1 aRidker, Paul, M1 aKardia, Sharon, L R1 aBlankenberg, Stefan1 aLiu, Yongmei1 aCurhan, Gary, C1 aFranke, Andre1 aRochat, Thierry1 aPaulweber, Bernhard1 aProkopenko, Inga1 aWang, Wei1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aShlipak, Michael, G1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKrämer, Bernhard, K1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aWitteman, Jacqueline, C1 aPramstaller, Peter, P1 aRettig, Rainer1 aHastie, Nick1 aChasman, Daniel, I1 aKao, W H1 aHeid, Iris, M1 aFox, Caroline, S uhttps://chs-nhlbi.org/node/118307422nas a2202413 4500008004100000022001400041245009100055210006900146260000900215300001300224490000600237520076400243653002201007653000901029653001201038653001401050653002901064653002701093653001801120653004001138653001101178653002201189653003001211653003401241653003101275653001101306653001101317653002801328653000901356653001601365653003401381653001401415100002201429700001901451700002201470700001901492700002301511700002701534700002001561700002001581700001801601700001901619700001201638700001601650700002001666700001601686700002501702700002401727700002601751700001901777700001801796700001801814700002101832700002601853700002301879700002001902700001201922700002301934700002201957700001801979700002001997700002702017700001702044700002502061700001902086700001802105700001902123700002202142700002702164700002102191700002102212700002202233700001602255700002202271700001802293700001902311700002102330700002002351700001902371700002302390700002002413700002202433700002202455700001902477700002402496700002502520700002102545700002002566700002602586700002002612700001702632700001902649700001902668700002302687700002302710700002002733700002502753700002302778700002102801700001802822700002002840700002202860700001802882700002202900700001802922700002102940700002402961700001602985700001903001700001903020700002003039700002003059700002203079700002003101700001903121700001903140700002203159700001903181700001803200700002103218700002003239700002003259700001703279700001903296700001803315700002203333700001803355700001903373700002803392700002603420700002403446700001903470700001703489700002203506700002203528700001903550700002203569700001903591700002003610700001903630700002203649700002203671700002003693700001903713700001603732700002303748700002303771700002503794700001803819700001403837700002403851700001703875700002103892700002403913700001703937700001703954700001903971700001903990700001904009700001904028700002404047700002004071700002104091700001804112700002104130700001904151700001904170700002904189700002404218700002104242700002404263700002304287700001804310700002204328700002004350700002404370700002304394700002004417700002404437700001704461700002004478700001604498700002004514700002104534700001804555700002604573700001904599700002104618700003004639700002204669700001704691700001804708700002104726700001804747700002304765700002304788700002004811700002104831710002604852710002004878710002004898710005404918856003604972 2012 eng d a1553-740400aGenome-wide association and functional follow-up reveals new loci for kidney function.0 aGenomewide association and functional followup reveals new loci c2012 ae10025840 v83 aChronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
10aAfrican Americans10aAged10aAnimals10aCaspase 910aCyclin-Dependent Kinases10aDEAD-box RNA Helicases10aDNA Helicases10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGene Knockdown Techniques10aGenome-Wide Association Study10aGlomerular Filtration Rate10aHumans10aKidney10aKidney Failure, Chronic10aMale10aMiddle Aged10aPhosphoric Diester Hydrolases10aZebrafish1 aPattaro, Cristian1 aKöttgen, Anna1 aTeumer, Alexander1 aGarnaas, Maija1 aBöger, Carsten, A1 aFuchsberger, Christian1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aTaliun, Daniel1 aLi, Man1 aGao, Xiaoyi1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aO'Seaghdha, Conall, M1 aGlazer, Nicole1 aIsaacs, Aaron1 aLiu, Ching-Ti1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aJohnson, Andrew, D1 aGierman, Hinco, J1 aFeitosa, Mary1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aChouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aCavalieri, Margherita1 aRao, Madhumathi1 aHu, Frank, B1 aDemirkan, Ayse1 aOostra, Ben, A1 ade Andrade, Mariza1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aKolcic, Ivana1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aEndlich, Karlhans1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aKetkar, Shamika1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aGiulianini, Franco1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMetzger, Marie1 aMitchell, Paul1 aCiullo, Marina1 aKim, Stuart, K1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aSiscovick, David, S1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline, C M1 aHayward, Caroline1 aRidker, Paul1 aParsa, Afshin1 aBochud, Murielle1 aHeid, Iris, M1 aGoessling, Wolfram1 aChasman, Daniel, I1 aKao, Linda, W H1 aFox, Caroline, S1 aCARDIoGRAM consortium1 aICBP Consortium1 aCARe Consortium1 aWellcome Trust Case Control Consortium 2 (WTCCC2) uhttps://chs-nhlbi.org/node/137707440nas a2202173 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2013 eng d a1533-345000aCommon variants in Mendelian kidney disease genes and their association with renal function.0 aCommon variants in Mendelian kidney disease genes and their asso c2013 Dec a2105-170 v243 aMany common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
10aDatabases, Genetic10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Variation10aGenome-Wide Association Study10aHumans10aKidney10aMendelian Randomization Analysis10aPhenotype10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic1 aParsa, Afshin1 aFuchsberger, Christian1 aKöttgen, Anna1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 ade Andrade, Mariza1 aChasman, Daniel, I1 aTeumer, Alexander1 aEndlich, Karlhans1 aOlden, Matthias1 aChen, Ming-Huei1 aTin, Adrienne1 aKim, Young, J1 aTaliun, Daniel1 aLi, Man1 aFeitosa, Mary1 aGorski, Mathias1 aYang, Qiong1 aHundertmark, Claudia1 aFoster, Meredith, C1 aGlazer, Nicole1 aIsaacs, Aaron1 aRao, Madhumathi1 aSmith, Albert, V1 aO'Connell, Jeffrey, R1 aStruchalin, Maksim1 aTanaka, Toshiko1 aLi, Guo1 aHwang, Shih-Jen1 aAtkinson, Elizabeth, J1 aLohman, Kurt1 aCornelis, Marilyn, C1 aJohansson, Asa1 aTönjes, Anke1 aDehghan, Abbas1 aCouraki, Vincent1 aHolliday, Elizabeth, G1 aSorice, Rossella1 aKutalik, Zoltán1 aLehtimäki, Terho1 aEsko, Tõnu1 aDeshmukh, Harshal1 aUlivi, Sheila1 aChu, Audrey, Y1 aMurgia, Federico1 aTrompet, Stella1 aImboden, Medea1 aKollerits, Barbara1 aPistis, Giorgio1 aHarris, Tamara, B1 aLauner, Lenore, J1 aAspelund, Thor1 aEiriksdottir, Gudny1 aMitchell, Braxton, D1 aBoerwinkle, Eric1 aSchmidt, Helena1 aHofer, Edith1 aHu, Frank1 aDemirkan, Ayse1 aOostra, Ben, A1 aTurner, Stephen, T1 aDing, Jingzhong1 aAndrews, Jeanette, S1 aFreedman, Barry, I1 aGiulianini, Franco1 aKoenig, Wolfgang1 aIllig, Thomas1 aDöring, Angela1 aWichmann, H-Erich1 aZgaga, Lina1 aZemunik, Tatijana1 aBoban, Mladen1 aMinelli, Cosetta1 aWheeler, Heather, E1 aIgl, Wilmar1 aZaboli, Ghazal1 aWild, Sarah, H1 aWright, Alan, F1 aCampbell, Harry1 aEllinghaus, David1 aNöthlings, Ute1 aJacobs, Gunnar1 aBiffar, Reiner1 aErnst, Florian1 aHomuth, Georg1 aKroemer, Heyo, K1 aNauck, Matthias1 aStracke, Sylvia1 aVölker, Uwe1 aVölzke, Henry1 aKovacs, Peter1 aStumvoll, Michael1 aMägi, Reedik1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aAulchenko, Yurii, S1 aPolasek, Ozren1 aHastie, Nick1 aVitart, Veronique1 aHelmer, Catherine1 aWang, Jie, Jin1 aStengel, Bénédicte1 aRuggiero, Daniela1 aBergmann, Sven1 aKähönen, Mika1 aViikari, Jorma1 aNikopensius, Tiit1 aProvince, Michael1 aColhoun, Helen1 aDoney, Alex1 aRobino, Antonietta1 aKrämer, Bernhard, K1 aPortas, Laura1 aFord, Ian1 aBuckley, Brendan, M1 aAdam, Martin1 aThun, Gian-Andri1 aPaulweber, Bernhard1 aHaun, Margot1 aSala, Cinzia1 aMitchell, Paul1 aCiullo, Marina1 aVollenweider, Peter1 aRaitakari, Olli1 aMetspalu, Andres1 aPalmer, Colin1 aGasparini, Paolo1 aPirastu, Mario1 aJukema, Wouter1 aProbst-Hensch, Nicole, M1 aKronenberg, Florian1 aToniolo, Daniela1 aGudnason, Vilmundur1 aShuldiner, Alan, R1 aCoresh, Josef1 aSchmidt, Reinhold1 aFerrucci, Luigi1 aDuijn, Cornelia, M1 aBorecki, Ingrid1 aKardia, Sharon, L R1 aLiu, Yongmei1 aCurhan, Gary, C1 aRudan, Igor1 aGyllensten, Ulf1 aWilson, James, F1 aFranke, Andre1 aPramstaller, Peter, P1 aRettig, Rainer1 aProkopenko, Inga1 aWitteman, Jacqueline1 aHayward, Caroline1 aRidker, Paul, M1 aBochud, Murielle1 aHeid, Iris, M1 aSiscovick, David, S1 aFox, Caroline, S1 aKao, Linda1 aBöger, Carsten, A uhttps://chs-nhlbi.org/node/628806392nas a2201669 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2014 eng d a1460-208300aFTO genetic variants, dietary intake and body mass index: insights from 177,330 individuals.0 aFTO genetic variants dietary intake and body mass index insights c2014 Dec 20 a6961-720 v233 aFTO is the strongest known genetic susceptibility locus for obesity. Experimental studies in animals suggest the potential roles of FTO in regulating food intake. The interactive relation among FTO variants, dietary intake and body mass index (BMI) is complex and results from previous often small-scale studies in humans are highly inconsistent. We performed large-scale analyses based on data from 177,330 adults (154 439 Whites, 5776 African Americans and 17 115 Asians) from 40 studies to examine: (i) the association between the FTO-rs9939609 variant (or a proxy single-nucleotide polymorphism) and total energy and macronutrient intake and (ii) the interaction between the FTO variant and dietary intake on BMI. The minor allele (A-allele) of the FTO-rs9939609 variant was associated with higher BMI in Whites (effect per allele = 0.34 [0.31, 0.37] kg/m(2), P = 1.9 × 10(-105)), and all participants (0.30 [0.30, 0.35] kg/m(2), P = 3.6 × 10(-107)). The BMI-increasing allele of the FTO variant showed a significant association with higher dietary protein intake (effect per allele = 0.08 [0.06, 0.10] %, P = 2.4 × 10(-16)), and relative weak associations with lower total energy intake (-6.4 [-10.1, -2.6] kcal/day, P = 0.001) and lower dietary carbohydrate intake (-0.07 [-0.11, -0.02] %, P = 0.004). The associations with protein (P = 7.5 × 10(-9)) and total energy (P = 0.002) were attenuated but remained significant after adjustment for BMI. We did not find significant interactions between the FTO variant and dietary intake of total energy, protein, carbohydrate or fat on BMI. Our findings suggest a positive association between the BMI-increasing allele of FTO variant and higher dietary protein intake and offer insight into potential link between FTO, dietary protein intake and adiposity.
10aAdult10aAfrican Americans10aAged10aAlleles10aAsian Continental Ancestry Group10aBody Mass Index10aDietary Carbohydrates10aDietary Fats10aDietary Proteins10aEnergy Intake10aEuropean Continental Ancestry Group10aFemale10aGene Frequency10aHumans10aMale10aMiddle Aged10aObesity10aPolymorphism, Single Nucleotide10aProteins1 aQi, Qibin1 aKilpeläinen, Tuomas, O1 aDowner, Mary, K1 aTanaka, Toshiko1 aSmith, Caren, E1 aSluijs, Ivonne1 aSonestedt, Emily1 aChu, Audrey, Y1 aRenstrom, Frida1 aLin, Xiaochen1 aÄngquist, Lars, H1 aHuang, Jinyan1 aLiu, Zhonghua1 aLi, Yanping1 aAli, Muhammad, Asif1 aXu, Min1 aAhluwalia, Tarunveer, Singh1 aBoer, Jolanda, M A1 aChen, Peng1 aDaimon, Makoto1 aEriksson, Johan1 aPerola, Markus1 aFriedlander, Yechiel1 aGao, Yu-Tang1 aHeppe, Denise, H M1 aHolloway, John, W1 aHouston, Denise, K1 aKanoni, Stavroula1 aKim, Yu-Mi1 aLaaksonen, Maarit, A1 aJääskeläinen, Tiina1 aLee, Nanette, R1 aLehtimäki, Terho1 aLemaitre, Rozenn, N1 aLu, Wei1 aLuben, Robert, N1 aManichaikul, Ani1 aMännistö, Satu1 aMarques-Vidal, Pedro1 aMonda, Keri, L1 aNgwa, Julius, S1 aPerusse, Louis1 avan Rooij, Frank, J A1 aXiang, Yong-Bing1 aWen, Wanqing1 aWojczynski, Mary, K1 aZhu, Jingwen1 aBorecki, Ingrid, B1 aBouchard, Claude1 aCai, Qiuyin1 aCooper, Cyrus1 aDedoussis, George, V1 aDeloukas, Panos1 aFerrucci, Luigi1 aForouhi, Nita, G1 aHansen, Torben1 aChristiansen, Lene1 aHofman, Albert1 aJohansson, Ingegerd1 aJørgensen, Torben1 aKarasawa, Shigeru1 aKhaw, Kay-Tee1 aKim, Mi-Kyung1 aKristiansson, Kati1 aLi, Huaixing1 aLin, Xu1 aLiu, Yongmei1 aLohman, Kurt, K1 aLong, Jirong1 aMikkilä, Vera1 aMozaffarian, Dariush1 aNorth, Kari1 aPedersen, Oluf1 aRaitakari, Olli1 aRissanen, Harri1 aTuomilehto, Jaakko1 aSchouw, Yvonne, T1 aUitterlinden, André, G1 aZillikens, Carola, M1 aFranco, Oscar, H1 aTai, Shyong1 aShu, Xiao, Ou1 aSiscovick, David, S1 aToft, Ulla1 aVerschuren, W, M Monique1 aVollenweider, Peter1 aWareham, Nicholas, J1 aWitteman, Jacqueline, C M1 aZheng, Wei1 aRidker, Paul, M1 aKang, Jae, H1 aLiang, Liming1 aJensen, Majken, K1 aCurhan, Gary, C1 aPasquale, Louis, R1 aHunter, David, J1 aMohlke, Karen, L1 aUusitupa, Matti1 aCupples, Adrienne, L1 aRankinen, Tuomo1 aOrho-Melander, Marju1 aWang, Tao1 aChasman, Daniel, I1 aFranks, Paul, W1 aSørensen, Thorkild, I A1 aHu, Frank, B1 aLoos, Ruth, J F1 aNettleton, Jennifer, A1 aQi, Lu uhttps://chs-nhlbi.org/node/693806988nas a2201993 4500008004100000022001400041245011600055210006900171260001600240520137500256100001201631700001301643700001801656700002201674700002201696700002501718700001801743700002701761700002001788700002801808700001901836700002001855700002101875700001801896700001601914700002801930700001901958700002501977700002302002700002302025700002302048700002502071700001902096700002102115700002102136700002202157700002102179700002302200700001502223700001802238700001902256700002102275700001702296700001702313700001602330700002002346700002802366700001802394700001902412700002002431700001702451700001802468700001802486700002202504700002102526700002102547700002902568700002302597700002202620700001702642700002202659700003202681700002102713700002302734700002102757700003102778700001402809700002202823700001902845700001602864700002102880700002102901700002302922700002302945700002402968700001902992700002103011700002303032700002103055700002003076700002403096700001803120700001703138700002003155700001803175700002003193700002403213700002103237700002103258700002503279700002203304700001603326700002103342700001703363700002203380700002303402700002003425700001803445700002403463700002203487700002203509700001903531700001903550700001703569700002803586700002403614700002303638700002503661700002003686700002403706700002103730700002403751700002203775700002203797700002303819700002203842700001703864700002103881700002103902700001703923700002003940700001803960700002503978700001904003700002104022700001904043700002004062700002104082700002504103700001804128700001904146700002004165700001904185700001904204700002004223700002904243700002004272700001104292700002304303700002004326700001904346700002004365700002604385700002404411700001904435700002104454700002004475700002404495700002104519700002304540700002804563700001804591700002304609700001704632700001904649700002604668700001904694700001904713700001804732700002304750700002104773700002304794700002304817700001904840700001904859710003904878710004104917856003604958 2016 eng d a1533-345000aSOS2 and ACP1 Loci Identified through Large-Scale Exome Chip Analysis Regulate Kidney Development and Function.0 aSOS2 and ACP1 Loci Identified through LargeScale Exome Chip Anal c2016 Dec 053 aGenome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium (nStage1: 111,666; nStage2: 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea (PPM1J, EDEM3, ACP1, SPEG, EYA4, CYP1A1, and ATXN2L; PStage1<3.7×10(-7)), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 (P=5.4×10(-8) by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2-knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.
1 aLi, Man1 aLi, Yong1 aWeeks, Olivia1 aMijatovic, Vladan1 aTeumer, Alexander1 aHuffman, Jennifer, E1 aTromp, Gerard1 aFuchsberger, Christian1 aGorski, Mathias1 aLyytikäinen, Leo-Pekka1 aNutile, Teresa1 aSedaghat, Sanaz1 aSorice, Rossella1 aTin, Adrienne1 aYang, Qiong1 aAhluwalia, Tarunveer, S1 aArking, Dan, E1 aBihlmeyer, Nathan, A1 aBöger, Carsten, A1 aCarroll, Robert, J1 aChasman, Daniel, I1 aCornelis, Marilyn, C1 aDehghan, Abbas1 aFaul, Jessica, D1 aFeitosa, Mary, F1 aGambaro, Giovanni1 aGasparini, Paolo1 aGiulianini, Franco1 aHeid, Iris1 aHuang, Jinyan1 aImboden, Medea1 aJackson, Anne, U1 aJeff, Janina1 aJhun, Min, A1 aKatz, Ronit1 aKifley, Annette1 aKilpeläinen, Tuomas, O1 aKumar, Ashish1 aLaakso, Markku1 aLi-Gao, Ruifang1 aLohman, Kurt1 aLu, Yingchang1 aMägi, Reedik1 aMalerba, Giovanni1 aMihailov, Evelin1 aMohlke, Karen, L1 aMook-Kanamori, Dennis, O1 aRobino, Antonietta1 aRuderfer, Douglas1 aSalvi, Erika1 aSchick, Ursula, M1 aSchulz, Christina-Alexandra1 aSmith, Albert, V1 aSmith, Jennifer, A1 aTraglia, Michela1 aYerges-Armstrong, Laura, M1 aZhao, Wei1 aGoodarzi, Mark, O1 aKraja, Aldi, T1 aLiu, Chunyu1 aWessel, Jennifer1 aBoerwinkle, Eric1 aBorecki, Ingrid, B1 aBork-Jensen, Jette1 aBottinger, Erwin, P1 aBraga, Daniele1 aBrandslund, Ivan1 aBrody, Jennifer, A1 aCampbell, Archie1 aCarey, David, J1 aChristensen, Cramer1 aCoresh, Josef1 aCrook, Errol1 aCurhan, Gary, C1 aCusi, Daniele1 ade Boer, Ian, H1 ade Vries, Aiko, P J1 aDenny, Joshua, C1 aDevuyst, Olivier1 aDreisbach, Albert, W1 aEndlich, Karlhans1 aEsko, Tõnu1 aFranco, Oscar, H1 aFulop, Tibor1 aGerhard, Glenn, S1 aGlümer, Charlotte1 aGottesman, Omri1 aGrarup, Niels1 aGudnason, Vilmundur1 aHarris, Tamara, B1 aHayward, Caroline1 aHocking, Lynne1 aHofman, Albert1 aHu, Frank, B1 aHusemoen, Lise, Lotte N1 aJackson, Rebecca, D1 aJørgensen, Torben1 aJørgensen, Marit, E1 aKähönen, Mika1 aKardia, Sharon, L R1 aKönig, Wolfgang1 aKooperberg, Charles1 aKriebel, Jennifer1 aLauner, Lenore, J1 aLauritzen, Torsten1 aLehtimäki, Terho1 aLevy, Daniel1 aLinksted, Pamela1 aLinneberg, Allan1 aLiu, Yongmei1 aLoos, Ruth, J F1 aLupo, Antonio1 aMeisinger, Christine1 aMelander, Olle1 aMetspalu, Andres1 aMitchell, Paul1 aNauck, Matthias1 aNürnberg, Peter1 aOrho-Melander, Marju1 aParsa, Afshin1 aPedersen, Oluf1 aPeters, Annette1 aPeters, Ulrike1 aPolasek, Ozren1 aPorteous, David1 aProbst-Hensch, Nicole, M1 aPsaty, Bruce, M1 aQi, Lu1 aRaitakari, Olli, T1 aReiner, Alex, P1 aRettig, Rainer1 aRidker, Paul, M1 aRivadeneira, Fernando1 aRossouw, Jacques, E1 aSchmidt, Frank1 aSiscovick, David1 aSoranzo, Nicole1 aStrauch, Konstantin1 aToniolo, Daniela1 aTurner, Stephen, T1 aUitterlinden, André, G1 aUlivi, Sheila1 aVelayutham, Dinesh1 aVölker, Uwe1 aVölzke, Henry1 aWaldenberger, Melanie1 aWang, Jie, Jin1 aWeir, David, R1 aWitte, Daniel1 aKuivaniemi, Helena1 aFox, Caroline, S1 aFranceschini, Nora1 aGoessling, Wolfram1 aKöttgen, Anna1 aChu, Audrey, Y1 aCHARGE Glycemic-T2D Working Group,1 aCHARGE Blood Pressure Working Group, uhttps://chs-nhlbi.org/node/7255