BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
BACKGROUND: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia. METHODS AND RESULTS: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis. CONCLUSIONS: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
Authors: S S Drury; K Theall; M M Gleason; A T Smyke; I De Vivo; J Y Y Wong; N A Fox; C H Zeanah; C A Nelson Journal: Mol Psychiatry Date: 2011-05-17 Impact factor: 15.992
Authors: Alison L Harte; Nancy F da Silva; Michelle A Miller; Francesco P Cappuccio; Ann Kelly; Joseph P O'Hare; Anthony H Barnett; Nasser M Al-Daghri; Omar Al-Attas; Majed Alokail; Shaun Sabico; Gyanendra Tripathi; Srikanth Bellary; Sudhesh Kumar; Philip G McTernan Journal: Exp Diabetes Res Date: 2012-03-01
Authors: Samuel J Ridout; Kathryn K Ridout; Hung-Teh Kao; Linda L Carpenter; Noah S Philip; Audrey R Tyrka; Lawrence H Price Journal: Adv Psychosom Med Date: 2015-03-30
Authors: Margaret A Taub; Matthew P Conomos; Rebecca Keener; Kruthika R Iyer; Joshua S Weinstock; Lisa R Yanek; John Lane; Tyne W Miller-Fleming; Jennifer A Brody; Laura M Raffield; Caitlin P McHugh; Deepti Jain; Stephanie M Gogarten; Cecelia A Laurie; Ali Keramati; Marios Arvanitis; Albert V Smith; Benjamin Heavner; Lucas Barwick; Lewis C Becker; Joshua C Bis; John Blangero; Eugene R Bleecker; Esteban G Burchard; Juan C Celedón; Yen Pei C Chang; Brian Custer; Dawood Darbar; Lisa de Las Fuentes; Dawn L DeMeo; Barry I Freedman; Melanie E Garrett; Mark T Gladwin; Susan R Heckbert; Bertha A Hidalgo; Marguerite R Irvin; Talat Islam; W Craig Johnson; Stefan Kaab; Lenore Launer; Jiwon Lee; Simin Liu; Arden Moscati; Kari E North; Patricia A Peyser; Nicholas Rafaels; Christine Seidman; Daniel E Weeks; Fayun Wen; Marsha M Wheeler; L Keoki Williams; Ivana V Yang; Wei Zhao; Stella Aslibekyan; Paul L Auer; Donald W Bowden; Brian E Cade; Zhanghua Chen; Michael H Cho; L Adrienne Cupples; Joanne E Curran; Michelle Daya; Ranjan Deka; Celeste Eng; Tasha E Fingerlin; Xiuqing Guo; Lifang Hou; Shih-Jen Hwang; Jill M Johnsen; Eimear E Kenny; Albert M Levin; Chunyu Liu; Ryan L Minster; Take Naseri; Mehdi Nouraie; Muagututi'a Sefuiva Reupena; Ester C Sabino; Jennifer A Smith; Nicholas L Smith; Jessica Lasky Su; James G Taylor; Marilyn J Telen; Hemant K Tiwari; Russell P Tracy; Marquitta J White; Yingze Zhang; Kerri L Wiggins; Scott T Weiss; Ramachandran S Vasan; Kent D Taylor; Moritz F Sinner; Edwin K Silverman; M Benjamin Shoemaker; Wayne H-H Sheu; Frank Sciurba; David A Schwartz; Jerome I Rotter; Daniel Roden; Susan Redline; Benjamin A Raby; Bruce M Psaty; Juan M Peralta; Nicholette D Palmer; Sergei Nekhai; Courtney G Montgomery; Braxton D Mitchell; Deborah A Meyers; Stephen T McGarvey; Angel Cy Mak; Ruth Jf Loos; Rajesh Kumar; Charles Kooperberg; Barbara A Konkle; Shannon Kelly; Sharon Lr Kardia; Robert Kaplan; Jiang He; Hongsheng Gui; Frank D Gilliland; Bruce D Gelb; Myriam Fornage; Patrick T Ellinor; Mariza de Andrade; Adolfo Correa; Yii-Der Ida Chen; Eric Boerwinkle; Kathleen C Barnes; Allison E Ashley-Koch; Donna K Arnett; Cathy C Laurie; Goncalo Abecasis; Deborah A Nickerson; James G Wilson; Stephen S Rich; Daniel Levy; Ingo Ruczinski; Abraham Aviv; Thomas W Blackwell; Timothy Thornton; Jeff O'Connell; Nancy J Cox; James A Perry; Mary Armanios; Alexis Battle; Nathan Pankratz; Alexander P Reiner; Rasika A Mathias Journal: Cell Genom Date: 2022-01-13
Authors: Philip C Haycock; Stephen Burgess; Aayah Nounu; Jie Zheng; George N Okoli; Jack Bowden; Kaitlin Hazel Wade; Nicholas J Timpson; David M Evans; Peter Willeit; Abraham Aviv; Tom R Gaunt; Gibran Hemani; Massimo Mangino; Hayley Patricia Ellis; Kathreena M Kurian; Karen A Pooley; Rosalind A Eeles; Jeffrey E Lee; Shenying Fang; Wei V Chen; Matthew H Law; Lisa M Bowdler; Mark M Iles; Qiong Yang; Bradford B Worrall; Hugh Stephen Markus; Rayjean J Hung; Chris I Amos; Amanda B Spurdle; Deborah J Thompson; Tracy A O'Mara; Brian Wolpin; Laufey Amundadottir; Rachael Stolzenberg-Solomon; Antonia Trichopoulou; N Charlotte Onland-Moret; Eiliv Lund; Eric J Duell; Federico Canzian; Gianluca Severi; Kim Overvad; Marc J Gunter; Rosario Tumino; Ulrika Svenson; Andre van Rij; Annette F Baas; Matthew J Bown; Nilesh J Samani; Femke N G van t'Hof; Gerard Tromp; Gregory T Jones; Helena Kuivaniemi; James R Elmore; Mattias Johansson; James Mckay; Ghislaine Scelo; Robert Carreras-Torres; Valerie Gaborieau; Paul Brennan; Paige M Bracci; Rachel E Neale; Sara H Olson; Steven Gallinger; Donghui Li; Gloria M Petersen; Harvey A Risch; Alison P Klein; Jiali Han; Christian C Abnet; Neal D Freedman; Philip R Taylor; John M Maris; Katja K Aben; Lambertus A Kiemeney; Sita H Vermeulen; John K Wiencke; Kyle M Walsh; Margaret Wrensch; Terri Rice; Clare Turnbull; Kevin Litchfield; Lavinia Paternoster; Marie Standl; Gonçalo R Abecasis; John Paul SanGiovanni; Yong Li; Vladan Mijatovic; Yadav Sapkota; Siew-Kee Low; Krina T Zondervan; Grant W Montgomery; Dale R Nyholt; David A van Heel; Karen Hunt; Dan E Arking; Foram N Ashar; Nona Sotoodehnia; Daniel Woo; Jonathan Rosand; Mary E Comeau; W Mark Brown; Edwin K Silverman; John E Hokanson; Michael H Cho; Jennie Hui; Manuel A Ferreira; Philip J Thompson; Alanna C Morrison; Janine F Felix; Nicholas L Smith; Angela M Christiano; Lynn Petukhova; Regina C Betz; Xing Fan; Xuejun Zhang; Caihong Zhu; Carl D Langefeld; Susan D Thompson; Feijie Wang; Xu Lin; David A Schwartz; Tasha Fingerlin; Jerome I Rotter; Mary Frances Cotch; Richard A Jensen; Matthias Munz; Henrik Dommisch; Arne S Schaefer; Fang Han; Hanna M Ollila; Ryan P Hillary; Omar Albagha; Stuart H Ralston; Chenjie Zeng; Wei Zheng; Xiao-Ou Shu; Andre Reis; Steffen Uebe; Ulrike Hüffmeier; Yoshiya Kawamura; Takeshi Otowa; Tsukasa Sasaki; Martin Lloyd Hibberd; Sonia Davila; Gang Xie; Katherine Siminovitch; Jin-Xin Bei; Yi-Xin Zeng; Asta Försti; Bowang Chen; Stefano Landi; Andre Franke; Annegret Fischer; David Ellinghaus; Carlos Flores; Imre Noth; Shwu-Fan Ma; Jia Nee Foo; Jianjun Liu; Jong-Won Kim; David G Cox; Olivier Delattre; Olivier Mirabeau; Christine F Skibola; Clara S Tang; Merce Garcia-Barcelo; Kai-Ping Chang; Wen-Hui Su; Yu-Sun Chang; Nicholas G Martin; Scott Gordon; Tracey D Wade; Chaeyoung Lee; Michiaki Kubo; Pei-Chieng Cha; Yusuke Nakamura; Daniel Levy; Masayuki Kimura; Shih-Jen Hwang; Steven Hunt; Tim Spector; Nicole Soranzo; Ani W Manichaikul; R Graham Barr; Bratati Kahali; Elizabeth Speliotes; Laura M Yerges-Armstrong; Ching-Yu Cheng; Jost B Jonas; Tien Yin Wong; Isabella Fogh; Kuang Lin; John F Powell; Kenneth Rice; Caroline L Relton; Richard M Martin; George Davey Smith Journal: JAMA Oncol Date: 2017-05-01 Impact factor: 31.777