03077nas a2200529 4500008004100000022001400041245010500055210006900160260001600229300001300245490000700258520157300265653001001838653001201848653001101860653001101871653000901882653001601891653003601907653003101943100002601974700001602000700002202016700002202038700001902060700002102079700002002100700001702120700002002137700002302157700001902180700002802199700002202227700002102249700002402270700002202294700002002316700001802336700002402354700002802378700001902406700002502425700002102450700001902471710002102490856003602511 2010 eng d a1460-208300aCommon variants in the calcium-sensing receptor gene are associated with total serum calcium levels.0 aCommon variants in the calciumsensing receptor gene are associat c2010 Nov 01 a4296-3030 v193 a
Serum calcium levels are tightly regulated. We performed genome-wide association studies (GWAS) in population-based studies participating in the CHARGE Consortium to uncover common genetic variations associated with total serum calcium levels. GWAS of serum calcium concentrations was performed in 20 611 individuals of European ancestry for ∼2.5 million genotyped and imputed single-nucleotide polymorphisms (SNPs). The SNP with the lowest P-value was rs17251221 (P = 2.4 * 10(-22), minor allele frequency 14%) in the calcium-sensing receptor gene (CASR). This lead SNP was associated with higher serum calcium levels [0.06 mg/dl (0.015 mmol/l) per copy of the minor G allele] and accounted for 0.54% of the variance in serum calcium concentrations. The identification of variation in CASR that influences serum calcium concentration confirms the results of earlier candidate gene studies. The G allele of rs17251221 was also associated with higher serum magnesium levels (P = 1.2 * 10(-3)), lower serum phosphate levels (P = 2.8 * 10(-7)) and lower bone mineral density at the lumbar spine (P = 0.038), but not the femoral neck. No additional genomic loci contained SNPs associated at genome-wide significance (P < 5 * 10(-8)). These associations resemble clinical characteristics of patients with familial hypocalciuric hypercalcemia, an autosomal-dominant disease arising from rare inactivating mutations in the CASR gene. We conclude that common genetic variation in the CASR gene is associated with similar but milder features in the general population.
10aAdult10aCalcium10aFemale10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptors, Calcium-Sensing1 aO'Seaghdha, Conall, M1 aYang, Qiong1 aGlazer, Nicole, L1 aLeak, Tennille, S1 aDehghan, Abbas1 aSmith, Albert, V1 aKao, Linda, W H1 aLohman, Kurt1 aHwang, Shih-Jen1 aJohnson, Andrew, D1 aHofman, Albert1 aUitterlinden, André, G1 aChen, Yii-Der Ida1 aBrown, Edward, M1 aSiscovick, David, S1 aHarris, Tamara, B1 aPsaty, Bruce, M1 aCoresh, Josef1 aGudnason, Vilmundur1 aWitteman, Jacqueline, C1 aLiu, Yong, Mei1 aKestenbaum, Bryan, R1 aFox, Caroline, S1 aKöttgen, Anna1 aGEFOS Consortium uhttps://chs-nhlbi.org/node/122403845nas a2200817 4500008004100000022001400041245008400055210006900139260001300208300001300221490000600234520156700240653004101807653001001848653000901858653002001867653001501887653004001902653001101942653002201953653003201975653001102007653002002018653002802038653000902066653001602075653003602091653003802127653001502165100002302180700002002203700001202223700002502235700001902260700001602279700002202295700001602317700002602333700002102359700002202380700001702402700001402419700002002433700001802453700002302471700001702494700002402511700001902535700001202554700002402566700001502590700002002605700001902625700002602644700002402670700001902694700002502713700002502738700002502763700002102788700002102809700001902830700002402849700002202873700002202895700001802917700002102935700001302956710002202969856003602991 2011 eng d a1553-740400aAssociation of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.0 aAssociation of eGFRRelated Loci Identified by GWAS with Incident c2011 Sep ae10022920 v73 aFamily studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
10aAdaptor Proteins, Signal Transducing10aAdult10aAged10aChronic Disease10aCreatinine10aEuropean Continental Ancestry Group10aFemale10aFollow-Up Studies10aGenetic Association Studies10aHumans10aKidney Diseases10aKidney Failure, Chronic10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aReceptor, Epidermal Growth Factor10aUromodulin1 aBöger, Carsten, A1 aGorski, Mathias1 aLi, Man1 aHoffmann, Michael, M1 aHuang, Chunmei1 aYang, Qiong1 aTeumer, Alexander1 aKrane, Vera1 aO'Seaghdha, Conall, M1 aKutalik, Zoltán1 aWichmann, H-Erich1 aHaak, Thomas1 aBoes, Eva1 aCoassin, Stefan1 aCoresh, Josef1 aKollerits, Barbara1 aHaun, Margot1 aPaulweber, Bernhard1 aKöttgen, Anna1 aLi, Guo1 aShlipak, Michael, G1 aPowe, Neil1 aHwang, Shih-Jen1 aDehghan, Abbas1 aRivadeneira, Fernando1 aUitterlinden, Andre1 aHofman, Albert1 aBeckmann, Jacques, S1 aKrämer, Bernhard, K1 aWitteman, Jacqueline1 aBochud, Murielle1 aSiscovick, David1 aRettig, Rainer1 aKronenberg, Florian1 aWanner, Christoph1 aThadhani, Ravi, I1 aHeid, Iris, M1 aFox, Caroline, S1 aKao, W H1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/133605938nas a2201621 4500008004100000022001400041245004200055210004100097260001300138300001100151490000700162520145500169653003901624653001601663653004001679653001701719653003801736653001101774653002301785653002801808100002301836700002001859700001801879700002001897700001901917700002001936700002701956700002601983700002202009700002202031700001802053700002202071700001202093700002602105700002002131700002302151700002102174700001802195700001902213700002002232700002202252700001802274700001502292700002102307700001702328700002302345700002202368700002302390700001802413700001902431700002002450700002402470700002202494700002202516700002302538700002502561700001902586700002302605700002102628700002002649700002002669700002102689700002502710700001902735700002402754700002002778700002202798700002302820700001902843700002402862700002002886700002002906700002102926700002302947700002002970700002002990700001703010700002303027700002703050700002203077700001903099700001903118700002803137700001803165700001803183700002103201700002503222700002103247700002603268700002103294700002503315700002203340700002403362700002003386700002203406700002103428700001903449700002003468700001903488700002203507700001803529700002003547700002203567700002403589700002403613700002403637700001703661700001903678700001703697700002403714700002103738700001603759700001903775700001803794700001803812700001803830700002003848700001803868700002403886700002103910700002603931700002203957700002503979700002004004700002204024700002604046700002504072700002504097700001604122700001804138700001904156700002504175700002104200700002104221700001604242710002204258856003604280 2011 eng d a1533-345000aCUBN is a gene locus for albuminuria.0 aCUBN is a gene locus for albuminuria c2011 Mar a555-700 v223 aIdentification of genetic risk factors for albuminuria may alter strategies for early prevention of CKD progression, particularly among patients with diabetes. Little is known about the influence of common genetic variants on albuminuria in both general and diabetic populations. We performed a meta-analysis of data from 63,153 individuals of European ancestry with genotype information from genome-wide association studies (CKDGen Consortium) and from a large candidate gene study (CARe Consortium) to identify susceptibility loci for the quantitative trait urinary albumin-to-creatinine ratio (UACR) and the clinical diagnosis microalbuminuria. We identified an association between a missense variant (I2984V) in the CUBN gene, which encodes cubilin, and both UACR (P = 1.1 × 10(-11)) and microalbuminuria (P = 0.001). We observed similar associations among 6981 African Americans in the CARe Consortium. The associations between this variant and both UACR and microalbuminuria were significant in individuals of European ancestry regardless of diabetes status. Finally, this variant associated with a 41% increased risk for the development of persistent microalbuminuria during 20 years of follow-up among 1304 participants with type 1 diabetes in the prospective DCCT/EDIC Study. In summary, we identified a missense CUBN variant that associates with levels of albuminuria in both the general population and in individuals with diabetes.
10aAfrican Continental Ancestry Group10aAlbuminuria10aEuropean Continental Ancestry Group10aGenetic Loci10aGenetic Predisposition to Disease10aHumans10aMutation, Missense10aReceptors, Cell Surface1 aBöger, Carsten, A1 aChen, Ming-Huei1 aTin, Adrienne1 aOlden, Matthias1 aKöttgen, Anna1 ade Boer, Ian, H1 aFuchsberger, Christian1 aO'Seaghdha, Conall, M1 aPattaro, Cristian1 aTeumer, Alexander1 aLiu, Ching-Ti1 aGlazer, Nicole, L1 aLi, Man1 aO'Connell, Jeffrey, R1 aTanaka, Toshiko1 aPeralta, Carmen, A1 aKutalik, Zoltán1 aLuan, Jian'an1 aZhao, Jing Hua1 aHwang, Shih-Jen1 aAkylbekova, Ermeg1 aKramer, Holly1 aHarst, Pim1 aSmith, Albert, V1 aLohman, Kurt1 ade Andrade, Mariza1 aHayward, Caroline1 aKollerits, Barbara1 aTönjes, Anke1 aAspelund, Thor1 aIngelsson, Erik1 aEiriksdottir, Gudny1 aLauner, Lenore, J1 aHarris, Tamara, B1 aShuldiner, Alan, R1 aMitchell, Braxton, D1 aArking, Dan, E1 aFranceschini, Nora1 aBoerwinkle, Eric1 aEgan, Josephine1 aHernandez, Dena1 aReilly, Muredach1 aTownsend, Raymond, R1 aLumley, Thomas1 aSiscovick, David, S1 aPsaty, Bruce, M1 aKestenbaum, Bryan1 aHaritunians, Talin1 aBergmann, Sven1 aVollenweider, Peter1 aWaeber, Gérard1 aMooser, Vincent1 aWaterworth, Dawn1 aJohnson, Andrew, D1 aFlorez, Jose, C1 aMeigs, James, B1 aLu, Xiaoning1 aTurner, Stephen, T1 aAtkinson, Elizabeth, J1 aLeak, Tennille, S1 aAasarød, Knut1 aSkorpen, Frank1 aSyvänen, Ann-Christine1 aIllig, Thomas1 aBaumert, Jens1 aKoenig, Wolfgang1 aKrämer, Bernhard, K1 aDevuyst, Olivier1 aMychaleckyj, Josyf, C1 aMinelli, Cosetta1 aBakker, Stephan, J L1 aKedenko, Lyudmyla1 aPaulweber, Bernhard1 aCoassin, Stefan1 aEndlich, Karlhans1 aKroemer, Heyo, K1 aBiffar, Reiner1 aStracke, Sylvia1 aVölzke, Henry1 aStumvoll, Michael1 aMägi, Reedik1 aCampbell, Harry1 aVitart, Veronique1 aHastie, Nicholas, D1 aGudnason, Vilmundur1 aKardia, Sharon, L R1 aLiu, Yongmei1 aPolasek, Ozren1 aCurhan, Gary1 aKronenberg, Florian1 aProkopenko, Inga1 aRudan, Igor1 aArnlöv, Johan1 aHallan, Stein1 aNavis, Gerjan1 aParsa, Afshin1 aFerrucci, Luigi1 aCoresh, Josef1 aShlipak, Michael, G1 aBull, Shelley, B1 aPaterson, Nicholas, J1 aWichmann, H-Erich1 aWareham, Nicholas, J1 aLoos, Ruth, J F1 aRotter, Jerome, I1 aPramstaller, Peter, P1 aCupples, Adrienne, L1 aBeckmann, Jacques, S1 aYang, Qiong1 aHeid, Iris, M1 aRettig, Rainer1 aDreisbach, Albert, W1 aBochud, Murielle1 aFox, Caroline, S1 aKao, W, H L1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/127107422nas a2202413 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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 4500008004100000022001400041245009700055210006900152260001300221300001200234490000700246520143200253653002301685653004001708653001901748653002201767653003401789653001101823653001101834653003701845653001401882653003601896653003301932100001801965700002701983700001902010700002602029700002202055700002302077700002302100700002202123700002202145700002002167700002002187700001802207700001802225700001902243700001202262700001802274700002002292700001602312700002502328700002402353700001902377700001802396700002002414700002102434700002602455700002302481700002002504700001202524700002002536700002702556700001702583700002502600700001902625700001802644700001902662700002102681700002702702700002102729700002102750700002202771700001602793700002202809700001802831700001902849700002102868700002002889700001902909700002302928700002002951700002202971700002202993700001903015700002403034700002503058700002103083700002003104700001703124700001403141700001903155700001903174700002303193700002003216700002503236700002303261700002303284700002103307700001803328700002003346700002203366700001603388700002203404700001803426700002103444700002403465700001603489700001903505700001903524700002003543700002003563700002203583700002003605700001903625700001903644700001903663700001803682700002103700700002003721700002003741700001703761700001903778700001803797700002203815700001803837700001903855700002803874700002603902700002403928700001903952700001703971700002203988700002204010700001904032700002504051700002204076700001904098700002004117700001904137700002204156700002204178700001904200700001604219700002304235700002504258700001804283700001404301700002404315700001704339700002104356700002404377700001704401700001704418700001904435700001904454700002404473700002004497700002104517700001804538700002104556700001904577700001904596700002904615700002404644700002104668700002404689700002304713700001804736700002204754700002004776700002304796700002004819700002404839700001704863700002004880700001604900700002004916700002104936700001804957700002604975700001905001700002105020700002505041700002205066700002005088700002105108700001805129700002405147700002105171700001505192700002305207856003605230 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/628809406nas a2203037 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2013 eng d a1546-171800aGenome-wide association analyses identify 18 new loci associated with serum urate concentrations.0 aGenomewide association analyses identify 18 new loci associated c2013 Feb a145-540 v453 aElevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.
10aAnalysis of Variance10aEuropean Continental Ancestry Group10aGene Frequency10aGenetic Loci10aGenome-Wide Association Study10aGlucose10aGout10aHumans10aInhibins10aPolymorphism, Single Nucleotide10aSignal Transduction10aUric Acid1 aKöttgen, Anna1 aAlbrecht, Eva1 aTeumer, Alexander1 aVitart, Veronique1 aKrumsiek, Jan1 aHundertmark, Claudia1 aPistis, Giorgio1 aRuggiero, Daniela1 aO'Seaghdha, Conall, M1 aHaller, Toomas1 aYang, Qiong1 aTanaka, Toshiko1 aJohnson, Andrew, D1 aKutalik, Zoltán1 aSmith, Albert, V1 aShi, Julia1 aStruchalin, Maksim1 aMiddelberg, Rita, P S1 aBrown, Morris, J1 aGaffo, Angelo, L1 aPirastu, Nicola1 aLi, Guo1 aHayward, Caroline1 aZemunik, Tatijana1 aHuffman, Jennifer1 aYengo, Loic1 aZhao, Jing Hua1 aDemirkan, Ayse1 aFeitosa, Mary, F1 aLiu, Xuan1 aMalerba, Giovanni1 aLopez, Lorna, M1 aHarst, Pim1 aLi, Xinzhong1 aKleber, Marcus, E1 aHicks, Andrew, A1 aNolte, Ilja, M1 aJohansson, Asa1 aMurgia, Federico1 aWild, Sarah, H1 aBakker, Stephan, J L1 aPeden, John, F1 aDehghan, Abbas1 aSteri, Maristella1 aTenesa, Albert1 aLagou, Vasiliki1 aSalo, Perttu1 aMangino, Massimo1 aRose, Lynda, M1 aLehtimäki, Terho1 aWoodward, Owen, M1 aOkada, Yukinori1 aTin, Adrienne1 aMüller, Christian1 aOldmeadow, Christopher1 aPutku, Margus1 aCzamara, Darina1 aKraft, Peter1 aFrogheri, Laura1 aThun, Gian, Andri1 aGrotevendt, Anne1 aGislason, Gauti, Kjartan1 aHarris, Tamara, B1 aLauner, Lenore, J1 aMcArdle, Patrick1 aShuldiner, Alan, R1 aBoerwinkle, Eric1 aCoresh, Josef1 aSchmidt, Helena1 aSchallert, Michael1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aKubo, Michiaki1 aNakamura, Yusuke1 aTanaka, Toshihiro1 aMunroe, Patricia, B1 aSamani, Nilesh, J1 aJacobs, David, R1 aLiu, Kiang1 aD'Adamo, Pio1 aUlivi, Sheila1 aRotter, Jerome, I1 aPsaty, Bruce, M1 aVollenweider, Peter1 aWaeber, Gérard1 aCampbell, Susan1 aDevuyst, Olivier1 aNavarro, Pau1 aKolcic, Ivana1 aHastie, Nicholas1 aBalkau, Beverley1 aFroguel, Philippe1 aEsko, Tõnu1 aSalumets, Andres1 aKhaw, Kay, Tee1 aLangenberg, Claudia1 aWareham, Nicholas, J1 aIsaacs, Aaron1 aKraja, Aldi1 aZhang, Qunyuan1 aWild, Philipp, S1 aScott, Rodney, J1 aHolliday, Elizabeth, G1 aOrg, Elin1 aViigimaa, Margus1 aBandinelli, Stefania1 aMetter, Jeffrey, E1 aLupo, Antonio1 aTrabetti, Elisabetta1 aSorice, Rossella1 aDöring, Angela1 aLattka, Eva1 aStrauch, Konstantin1 aTheis, Fabian1 aWaldenberger, Melanie1 aWichmann, H-Erich1 aDavies, Gail1 aGow, Alan, J1 aBruinenberg, Marcel1 aStolk, Ronald, P1 aKooner, Jaspal, S1 aZhang, Weihua1 aWinkelmann, Bernhard, R1 aBoehm, Bernhard, O1 aLucae, Susanne1 aPenninx, Brenda, W1 aSmit, Johannes, H1 aCurhan, Gary1 aMudgal, Poorva1 aPlenge, Robert, M1 aPortas, Laura1 aPersico, Ivana1 aKirin, Mirna1 aWilson, James, F1 aLeach, Irene, Mateo1 aGilst, Wiek, H1 aGoel, Anuj1 aOngen, Halit1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aImboden, Medea1 avon Eckardstein, Arnold1 aCucca, Francesco1 aNagaraja, Ramaiah1 aPiras, Maria, Grazia1 aNauck, Matthias1 aSchurmann, Claudia1 aBudde, Kathrin1 aErnst, Florian1 aFarrington, Susan, M1 aTheodoratou, Evropi1 aProkopenko, Inga1 aStumvoll, Michael1 aJula, Antti1 aPerola, Markus1 aSalomaa, Veikko1 aShin, So-Youn1 aSpector, Tim, D1 aSala, Cinzia1 aRidker, Paul, M1 aKähönen, Mika1 aViikari, Jorma1 aHengstenberg, Christian1 aNelson, Christopher, P1 aMeschia, James, F1 aNalls, Michael, A1 aSharma, Pankaj1 aSingleton, Andrew, B1 aKamatani, Naoyuki1 aZeller, Tanja1 aBurnier, Michel1 aAttia, John1 aLaan, Maris1 aKlopp, Norman1 aHillege, Hans, L1 aKloiber, Stefan1 aChoi, Hyon1 aPirastu, Mario1 aTore, Silvia1 aProbst-Hensch, Nicole, M1 aVölzke, Henry1 aGudnason, Vilmundur1 aParsa, Afshin1 aSchmidt, Reinhold1 aWhitfield, John, B1 aFornage, Myriam1 aGasparini, Paolo1 aSiscovick, David, S1 aPolasek, Ozren1 aCampbell, Harry1 aRudan, Igor1 aBouatia-Naji, Nabila1 aMetspalu, Andres1 aLoos, Ruth, J F1 aDuijn, Cornelia, M1 aBorecki, Ingrid, B1 aFerrucci, Luigi1 aGambaro, Giovanni1 aDeary, Ian, J1 aWolffenbuttel, Bruce, H R1 aChambers, John, C1 aMärz, Winfried1 aPramstaller, Peter, P1 aSnieder, Harold1 aGyllensten, Ulf1 aWright, Alan, F1 aNavis, Gerjan1 aWatkins, Hugh1 aWitteman, Jacqueline, C M1 aSanna, Serena1 aSchipf, Sabine1 aDunlop, Malcolm, G1 aTönjes, Anke1 aRipatti, Samuli1 aSoranzo, Nicole1 aToniolo, Daniela1 aChasman, Daniel, I1 aRaitakari, Olli1 aKao, Linda, W H1 aCiullo, Marina1 aFox, Caroline, S1 aCaulfield, Mark1 aBochud, Murielle1 aGieger, Christian1 aLifeLines Cohort Study1 aCARDIoGRAM consortium1 aDIAGRAM Consortium1 aICBP Consortium1 aMAGIC Consortium uhttps://chs-nhlbi.org/node/607505590nas a2201609 4500008004100000022001400041245011100055210006900166260000900235300001300244490000600257520112100263653001201384653001901396653001701415653001201432653004001444653003101484653003401515653001601549653001101565653001101576653000901587653003601596100002601632700001801658700001601676700001701692700002001709700002601729700001901755700002301774700002201797700002101819700002101840700001901861700001801880700002401898700001201922700002001934700001801954700002001972700002201992700001702014700002002031700002502051700001902076700002102095700001802116700002502134700002202159700002002181700002202201700002402223700002202247700001902269700002202288700001902310700002002329700002102349700002102370700002402391700002202415700002402437700002002461700001902481700002402500700002202524700002002546700002202566700001802588700001802606700001702624700002102641700001902662700002002681700002202701700002502723700002002748700002502768700002102793700002202814700002402836700002302860700002202883700002302905700001702928700001902945700002202964700002302986700002803009700001503037700002103052700001903073700002003092700002203112700002103134700001903155700002803174700002603202700001703228700002003245700001903265700002303284700001803307700002103325700001803346700002303364700002403387700002103411700002003432700001903452700002203471700002003493700001503513700002003528700002103548700001603569700002103585700001903606700001803625700001903643700002003662700001703682700002203699700002203721700003003743700002003773700002003793700002503813700001903838700002103857700002103878710002403899710002103923856003603944 2013 eng d a1553-740400aMeta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations.0 aMetaanalysis of genomewide association studies identifies six ne c2013 ae10037960 v93 aCalcium is vital to the normal functioning of multiple organ systems and its serum concentration is tightly regulated. Apart from CASR, the genes associated with serum calcium are largely unknown. We conducted a genome-wide association meta-analysis of 39,400 individuals from 17 population-based cohorts and investigated the 14 most strongly associated loci in ≤ 21,679 additional individuals. Seven loci (six new regions) in association with serum calcium were identified and replicated. Rs1570669 near CYP24A1 (P = 9.1E-12), rs10491003 upstream of GATA3 (P = 4.8E-09) and rs7481584 in CARS (P = 1.2E-10) implicate regions involved in Mendelian calcemic disorders: Rs1550532 in DGKD (P = 8.2E-11), also associated with bone density, and rs7336933 near DGKH/KIAA0564 (P = 9.1E-10) are near genes that encode distinct isoforms of diacylglycerol kinase. Rs780094 is in GCKR. We characterized the expression of these genes in gut, kidney, and bone, and demonstrate modulation of gene expression in bone in response to dietary calcium in mice. Our results shed new light on the genetics of calcium homeostasis.
10aAnimals10aBone and Bones10aBone Density10aCalcium10aEuropean Continental Ancestry Group10aGene Expression Regulation10aGenome-Wide Association Study10aHomeostasis10aHumans10aKidney10aMice10aPolymorphism, Single Nucleotide1 aO'Seaghdha, Conall, M1 aWu, Hongsheng1 aYang, Qiong1 aKapur, Karen1 aGuessous, Idris1 aZuber, Annie, Mercier1 aKöttgen, Anna1 aStoudmann, Candice1 aTeumer, Alexander1 aKutalik, Zoltán1 aMangino, Massimo1 aDehghan, Abbas1 aZhang, Weihua1 aEiriksdottir, Gudny1 aLi, Guo1 aTanaka, Toshiko1 aPortas, Laura1 aLopez, Lorna, M1 aHayward, Caroline1 aLohman, Kurt1 aMatsuda, Koichi1 aPadmanabhan, Sandosh1 aFirsov, Dmitri1 aSorice, Rossella1 aUlivi, Sheila1 aBrockhaus, Catharina1 aKleber, Marcus, E1 aMahajan, Anubha1 aErnst, Florian, D1 aGudnason, Vilmundur1 aLauner, Lenore, J1 aMace, Aurelien1 aBoerwinckle, Eric1 aArking, Dan, E1 aTanikawa, Chizu1 aNakamura, Yusuke1 aBrown, Morris, J1 aGaspoz, Jean-Michel1 aTheler, Jean-Marc1 aSiscovick, David, S1 aPsaty, Bruce, M1 aBergmann, Sven1 aVollenweider, Peter1 aVitart, Veronique1 aWright, Alan, F1 aZemunik, Tatijana1 aBoban, Mladen1 aKolcic, Ivana1 aNavarro, Pau1 aBrown, Edward, M1 aEstrada, Karol1 aDing, Jingzhong1 aHarris, Tamara, B1 aBandinelli, Stefania1 aHernandez, Dena1 aSingleton, Andrew, B1 aGirotto, Giorgia1 aRuggiero, Daniela1 ad'Adamo, Adamo, Pio1 aRobino, Antonietta1 aMeitinger, Thomas1 aMeisinger, Christa1 aDavies, Gail1 aStarr, John, M1 aChambers, John, C1 aBoehm, Bernhard, O1 aWinkelmann, Bernhard, R1 aHuang, Jie1 aMurgia, Federico1 aWild, Sarah, H1 aCampbell, Harry1 aMorris, Andrew, P1 aFranco, Oscar, H1 aHofman, Albert1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aVölker, Uwe1 aHannemann, Anke1 aBiffar, Reiner1 aHoffmann, Wolfgang1 aShin, So-Youn1 aLescuyer, Pierre1 aHenry, Hughes1 aSchurmann, Claudia1 aMunroe, Patricia, B1 aGasparini, Paolo1 aPirastu, Nicola1 aCiullo, Marina1 aGieger, Christian1 aMärz, Winfried1 aLind, Lars1 aSpector, Tim, D1 aSmith, Albert, V1 aRudan, Igor1 aWilson, James, F1 aPolasek, Ozren1 aDeary, Ian, J1 aPirastu, Mario1 aFerrucci, Luigi1 aLiu, Yongmei1 aKestenbaum, Bryan1 aKooner, Jaspal, S1 aWitteman, Jacqueline, C M1 aNauck, Matthias1 aKao, Linda, W H1 aWallaschofski, Henri1 aBonny, Olivier1 aFox, Caroline, S1 aBochud, Murielle1 aSUNLIGHT Consortium1 aGEFOS Consortium uhttps://chs-nhlbi.org/node/629103889nas a2200493 4500008004100000022001400041245013300055210006900188260001300257300001000270490000700280520249200287653000902779653000902788653001502797653002802812653001502840653001502855653001102870653002202881653003102903653001102934653000902945653001602954653003602970653003303006653002003039653001703059653003003076653002403106653001803130100002603148700001803174700001603192700001603208700001703224700001903241700001603260700001803276700002103294700002003315700002403335856003603359 2014 eng d a1523-683800aAssociation of a cystatin C gene variant with cystatin C levels, CKD, and risk of incident cardiovascular disease and mortality.0 aAssociation of a cystatin C gene variant with cystatin C levels c2014 Jan a16-220 v633 aBACKGROUND: Carriers of the T allele of the single-nucleotide polymorphism rs13038305 tend to have lower cystatin C levels and higher cystatin C-based estimated glomerular filtration rate (eGFRcys). Adjusting for this genetic effect on cystatin C concentrations may improve GFR estimation, reclassify cases of chronic kidney disease (CKD), and strengthen risk estimates for cardiovascular disease (CVD) and mortality.
STUDY DESIGN: Observational.
SETTING & POPULATION: 4 population-based cohorts: Atherosclerosis Risk in Communities (ARIC), Cardiovascular Health (CHS), Framingham Heart (FHS), and Health, Aging, and Body Composition (Health ABC) studies.
PREDICTORS: We estimated the association of rs13038305 with eGFRcys and serum creatinine-based eGFR (eGFRcr) and performed longitudinal analyses of the associations of eGFRcys with mortality and cardiovascular events following adjustment for rs13038305.
OUTCOMES: We assessed reclassification by genotype-adjusted eGFRcys across CKD categories: <45, 45-59, 60-89, and ≥ 90 mL/min/1.73 m(2). We compared mortality and CVD outcomes in those reclassified to a worse eGFRcys category with those unaffected. Results were combined using fixed-effect inverse-variance meta-analysis.
RESULTS: In 14,645 participants, each copy of the T allele of rs13038305 (frequency, 21%) was associated with a 6.4% lower cystatin C concentration, 5.5-mL/min/1.73 m(2) higher eGFRcys, and 36% [95% CI, 29%-41%] lower odds of CKD. Associations with CVD (HR, 1.17; 95% CI, 1.14-1.20) and mortality (HR, 1.22; 95% CI, 1.19-1.24) per 10-mL/min/1.73 m(2) lower eGFRcys were similar with or without rs13038305 adjustment. 1,134 (7.7%) participants were reclassified to a worse CKD category following rs13038305 adjustment, and rates of CVD and mortality were higher in individuals who were reclassified. However, the overall net reclassification index was not significant for either outcome, at 0.009 (95% CI, -0.003 to 0.022) for mortality and 0.014 (95% CI, 0.0 to 0.028) for CVD.
LIMITATIONS: rs13038305 explains only a small proportion of cystatin C variation.
CONCLUSIONS: Statistical adjustment can correct a genetic bias in GFR estimates based on cystatin C in carriers of the T allele of rs13038305 and result in changes in disease classification. However, on a population level, the effects on overall reclassification of CKD status are modest.
10aAged10aBias10aBiomarkers10aCardiovascular Diseases10aCreatinine10aCystatin C10aFemale10aGenetic Variation10aGlomerular Filtration Rate10aHumans10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide10aRenal Insufficiency, Chronic10aRisk Assessment10aRisk Factors10aSeverity of Illness Index10aStatistics as Topic10aSurvival Rate1 aO'Seaghdha, Conall, M1 aTin, Adrienne1 aYang, Qiong1 aKatz, Ronit1 aLiu, Yongmei1 aHarris, Tamara1 aAstor, Brad1 aCoresh, Josef1 aFox, Caroline, S1 aKao, Linda, W H1 aShlipak, Michael, G uhttps://chs-nhlbi.org/node/6587