A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1.
A cautionary tale: the non-causal association between type 2 diabetes risk SNP, rs7756992, and levels of non-coding RNA, CDKAL1-v1.
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DOI：
10.1007/s00125-015-3508-9
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发表时间：
2015-04
期刊：
影响因子：
8.2
通讯作者：
Harries, Lorna W.
中科院分区：
文献类型：
--
作者：
Locke, Jonathan M.;Wei, Fan-Yan;Tomizawa, Kazuhito;Weedon, Michael N.;Harries, Lorna W.
关键词：
CDKAL 1基因的内含子单核苷酸多态性（SNPs）与2型糖尿病的发病风险相关。最近有报道称，从日本个体中提取的全血中发现了风险等位基因与非编码RNA CDKAL 1-v1水平较低之间的强相关性。我们试图在两个独立的队列中复制这种关联：一个使用来自英国白色居民个体的全血，另一个使用人类胰岛的集合，这是一种更相关的组织类型，可以研究糖尿病的病因。使用从人全血（n = 70）和人胰岛（n = 48）提取的RNA通过实时PCR测量CDKAL 1-v1的水平。然后确定相对于基因型的表达。在一个简单的线性回归模型中，CDKAL 1-v1的表达与全血和胰岛中的2型糖尿病相关SNP rs7756992相关。然而，在考虑rs 9366357基因型的多元回归模型中，这些关联被消除或大幅减少：一种中度连锁的SNP，解释了CDKAL 1-v1水平的大量变异，但与2型糖尿病的风险没有强相关性。与以前的研究结果相反，我们提供的证据反对CDKAL 1-v1表达失调在介导CDKAL 1内含子SNP与2型糖尿病易感性之间的关联中的作用。这项研究的结果说明了在从疾病风险基因型和非编码RNA表达之间的关联中推断因果关系时应如何谨慎。本文的在线版本（doi：10.1007/s 00125 -015-3508-9）包含同行评审但未经编辑的补充材料，可供授权用户使用。
Intronic single nucleotide polymorphisms (SNPs) in the CDKAL1 gene are associated with risk of developing type 2 diabetes. A strong correlation between risk alleles and lower levels of the non-coding RNA, CDKAL1-v1, has recently been reported in whole blood extracted from Japanese individuals. We sought to replicate this association in two independent cohorts: one using whole blood from white UK-resident individuals, and one using a collection of human pancreatic islets, a more relevant tissue type to study with respect to the aetiology of diabetes. Levels of CDKAL1-v1 were measured by real-time PCR using RNA extracted from human whole blood (n = 70) and human pancreatic islets (n = 48). Expression with respect to genotype was then determined. In a simple linear regression model, expression of CDKAL1-v1 was associated with the lead type 2 diabetes-associated SNP, rs7756992, in whole blood and islets. However, these associations were abolished or substantially reduced in multiple regression models taking into account rs9366357 genotype: a moderately linked SNP explaining a much larger amount of the variation in CDKAL1-v1 levels, but not strongly associated with risk of type 2 diabetes. Contrary to previous findings, we provide evidence against a role for dysregulated expression of CDKAL1-v1 in mediating the association between intronic SNPs in CDKAL1 and susceptibility to type 2 diabetes. The results of this study illustrate how caution should be exercised when inferring causality from an association between disease-risk genotype and non-coding RNA expression. The online version of this article (doi:10.1007/s00125-015-3508-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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影响因子：
30.8
作者：
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium;Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium;South Asian Type 2 Diabetes (SAT2D) Consortium;Mexican American Type 2 Diabetes (MAT2D) Consortium;Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium;Mahajan A;Go MJ;Zhang W;Below JE;Gaulton KJ;Ferreira T;Horikoshi M;Johnson AD;Ng MC;Prokopenko I;Saleheen D;Wang X;Zeggini E;Abecasis GR;Adair LS;Almgren P;Atalay M;Aung T;Baldassarre D;Balkau B;Bao Y;Barnett AH;Barroso I;Basit A;Been LF;Beilby J;Bell GI;Benediktsson R;Bergman RN;Boehm BO;Boerwinkle E;Bonnycastle LL;Burtt N;Cai Q;Campbell H;Carey J;Cauchi S;Caulfield M;Chan JC;Chang LC;Chang TJ;Chang YC;Charpentier G;Chen CH;Chen H;Chen YT;Chia KS;Chidambaram M;Chines PS;Cho NH;Cho YM;Chuang LM;Collins FS;Cornelis MC;Couper DJ;Crenshaw AT;van Dam RM;Danesh J;Das D;de Faire U;Dedoussis G;Deloukas P;Dimas AS;Dina C;Doney AS;Donnelly PJ;Dorkhan M;van Duijn C;Dupuis J;Edkins S;Elliott P;Emilsson V;Erbel R;Eriksson JG;Escobedo J;Esko T;Eury E;Florez JC;Fontanillas P;Forouhi NG;Forsen T;Fox C;Fraser RM;Frayling TM;Froguel P;Frossard P;Gao Y;Gertow K;Gieger C;Gigante B;Grallert H;Grant GB;Grrop LC;Groves CJ;Grundberg E;Guiducci C;Hamsten A;Han BG;Hara K;Hassanali N;Hattersley AT;Hayward C;Hedman AK;Herder C;Hofman A;Holmen OL;Hovingh K;Hreidarsson AB;Hu C;Hu FB;Hui J;Humphries SE;Hunt SE;Hunter DJ;Hveem K;Hydrie ZI;Ikegami H;Illig T;Ingelsson E;Islam M;Isomaa B;Jackson AU;Jafar T;James A;Jia W;Jöckel KH;Jonsson A;Jowett JB;Kadowaki T;Kang HM;Kanoni S;Kao WH;Kathiresan S;Kato N;Katulanda P;Keinanen-Kiukaanniemi KM;Kelly AM;Khan H;Khaw KT;Khor CC;Kim HL;Kim S;Kim YJ;Kinnunen L;Klopp N;Kong A;Korpi-Hyövälti E;Kowlessur S;Kraft P;Kravic J;Kristensen MM;Krithika S;Kumar A;Kumate J;Kuusisto J;Kwak SH;Laakso M;Lagou V;Lakka TA;Langenberg C;Langford C;Lawrence R;Leander K;Lee JM;Lee NR;Li M;Li X;Li Y;Liang J;Liju S;Lim WY;Lind L;Lindgren CM;Lindholm E;Liu CT;Liu JJ;Lobbens S;Long J;Loos RJ;Lu W;Luan J;Lyssenko V;Ma RC;Maeda S;Mägi R;Männisto S;Matthews DR;Meigs JB;Melander O;Metspalu A;Meyer J;Mirza G;Mihailov E;Moebus S;Mohan V;Mohlke KL;Morris AD;Mühleisen TW;Müller-Nurasyid M;Musk B;Nakamura J;Nakashima E;Navarro P;Ng PK;Nica AC;Nilsson PM;Njølstad I;Nöthen MM;Ohnaka K;Ong TH;Owen KR;Palmer CN;Pankow JS;Park KS;Parkin M;Pechlivanis S;Pedersen NL;Peltonen L;Perry JR;Peters A;Pinidiyapathirage JM;Platou CG;Potter S;Price JF;Qi L;Radha V;Rallidis L;Rasheed A;Rathman W;Rauramaa R;Raychaudhuri S;Rayner NW;Rees SD;Rehnberg E;Ripatti S;Robertson N;Roden M;Rossin EJ;Rudan I;Rybin D;Saaristo TE;Salomaa V;Saltevo J;Samuel M;Sanghera DK;Saramies J;Scott J;Scott LJ;Scott RA;Segrè AV;Sehmi J;Sennblad B;Shah N;Shah S;Shera AS;Shu XO;Shuldiner AR;Sigurđsson G;Sijbrands E;Silveira A;Sim X;Sivapalaratnam S;Small KS;So WY;Stančáková A;Stefansson K;Steinbach G;Steinthorsdottir V;Stirrups K;Strawbridge RJ;Stringham HM;Sun Q;Suo C;Syvänen AC;Takayanagi R;Takeuchi F;Tay WT;Teslovich TM;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tikkanen E;Trakalo J;Tremoli E;Trip MD;Tsai FJ;Tuomi T;Tuomilehto J;Uitterlinden AG;Valladares-Salgado A;Vedantam S;Veglia F;Voight BF;Wang C;Wareham NJ;Wennauer R;Wickremasinghe AR;Wilsgaard T;Wilson JF;Wiltshire S;Winckler W;Wong TY;Wood AR;Wu JY;Wu Y;Yamamoto K;Yamauchi T;Yang M;Yengo L;Yokota M;Young R;Zabaneh D;Zhang F;Zhang R;Zheng W;Zimmet PZ;Altshuler D;Bowden DW;Cho YS;Cox NJ;Cruz M;Hanis CL;Kooner J;Lee JY;Seielstad M;Teo YY;Boehnke M;Parra EJ;Chambers JC;Tai ES;McCarthy MI;Morris AP
通讯作者：
Morris AP
影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
9.8
作者：
Popadin, Konstantin;Gutierrez-Arcelus, Maria;Antonarakis, Stylianos E.
通讯作者：
Antonarakis, Stylianos E.
影响因子：
7
作者：
Nica AC;Ongen H;Irminger JC;Bosco D;Berney T;Antonarakis SE;Halban PA;Dermitzakis ET
通讯作者：
Dermitzakis ET
2型糖尿病易感性变异对定量血糖特征的影响揭示了机械异质性。
影响因子：
7.7
作者：
Dimas AS;Lagou V;Barker A;Knowles JW;Mägi R;Hivert MF;Benazzo A;Rybin D;Jackson AU;Stringham HM;Song C;Fischer-Rosinsky A;Boesgaard TW;Grarup N;Abbasi FA;Assimes TL;Hao K;Yang X;Lecoeur C;Barroso I;Bonnycastle LL;Böttcher Y;Bumpstead S;Chines PS;Erdos MR;Graessler J;Kovacs P;Morken MA;Narisu N;Payne F;Stancakova A;Swift AJ;Tönjes A;Bornstein SR;Cauchi S;Froguel P;Meyre D;Schwarz PE;Häring HU;Smith U;Boehnke M;Bergman RN;Collins FS;Mohlke KL;Tuomilehto J;Quertemous T;Lind L;Hansen T;Pedersen O;Walker M;Pfeiffer AF;Spranger J;Stumvoll M;Meigs JB;Wareham NJ;Kuusisto J;Laakso M;Langenberg C;Dupuis J;Watanabe RM;Florez JC;Ingelsson E;McCarthy MI;Prokopenko I;MAGIC Investigators
通讯作者：
MAGIC Investigators