Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets

被引：47

作者：

Khetan, Shubham ^{[1
,2
]}

Kursawe, Romy ^{[1
]}

Youn, Ahrim ^{[1
]}

Lawlor, Nathan ^{[1
]}

Jillette, Alexandria ^{[1
]}

Marquez, Eladio J. ^{[1
]}

Ucar, Duygu ^{[1
,2
,3
]}

Stitzel, Michael L. ^{[1
,2
,3
]}

机构：

[1] Jackson Lab Genom Med, Farmington, CT 06032 USA

[2] Univ Connecticut, Dept Genet & Genome Sci, Farmington, CT 06030 USA

[3] Univ Connecticut, Inst Syst Genom, Farmington, CT 06030 USA

来源：

DIABETES | 2018年 / 67卷 / 11期

关键词：

GENOME-WIDE ASSOCIATION; PANCREATIC BETA-CELLS; HISTONE MODIFICATIONS; TRANSCRIPTION FACTORS; READ ALIGNMENT; EXPRESSION; PACKAGE; BINDING; ARCHITECTURE; MECHANISMS;

D O I：

10.2337/db18-0393

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants and their target genes and whether they lead to gain or loss of function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2,949 SNPs associated with in vivo cis-regulatory element use (i.e., chromatin accessibility quantitative trait loci [caQTL]). Among the caQTLs tested (n = 13) using luciferase reporter assays in MIN6 beta-cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.

引用

页码：2466 / 2477

页数：12

共 55 条

[41] A Type 2 Diabetes-Associated Functional Regulatory Variant in a Pancreatic Islet Enhancer at the ADCY5 Locus [J].

Roman, Tamara S. ;

Cannon, Maren E. ;

Vadlamudi, Swarooparani ;

Buchkovich, Martin L. ;

Wolford, Brooke N. ;

Welch, Ryan P. ;

Morken, Mario A. ;

Kwon, Grace J. ;

Varshney, Arushi ;

Kursawe, Romy ;

Wu, Ying ;

Jackson, Anne U. ;

Erdos, Michael R. ;

Kuusisto, Johanna ;

Laakso, Markku ;

Scott, Laura J. ;

Boehnke, Michael ;

Collins, Francis S. ;

Parker, Stephen C. J. ;

Stitzel, Michael L. ;

Mohlke, Karen L. .

DIABETES, 2017, 66 (09) :2521-2530

[42] Differential oestrogen receptor binding is associated with clinical outcome in breast cancer [J].

Ross-Innes, Caryn S. ;

Stark, Rory ;

Teschendorff, Andrew E. ;

Holmes, Kelly A. ;

Ali, H. Raza ;

Dunning, Mark J. ;

Brown, Gordon D. ;

Gojis, Ondrej ;

Ellis, Ian O. ;

Green, Andrew R. ;

Ali, Simak ;

Chin, Suet-Feung ;

Palmieri, Carlo ;

Caldas, Carlos ;

Carroll, Jason S. .

NATURE, 2012, 481 (7381) :389-U177

[43] GREGOR: evaluating global enrichment of trait-associated variants in epigenomic features using a systematic, data-driven approach [J].

Schmidt, Ellen M. ;

Zhang, Ji ;

Zhou, Wei ;

Chen, Jin ;

Mohlke, Karen L. ;

Chen, Y. Eugene ;

Willer, Cristen J. .

BIOINFORMATICS, 2015, 31 (16) :2601-2606

[44] The genetic regulatory signature of type 2 diabetes in human skeletal muscle [J].

Scott, Laura J. ;

Erdos, Michael R. ;

Huyghe, Jeroen R. ;

Welch, Ryan P. ;

Beck, Andrew T. ;

Wolford, Brooke N. ;

Chines, Peter S. ;

Didion, John P. ;

Narisu, Narisu ;

Stringham, Heather M. ;

Taylor, D. Leland ;

Jackson, Anne U. ;

Vadlamudi, Swarooparani ;

Bonnycastle, Lori L. ;

Kinnunen, Leena ;

Saramies, Jouko ;

Sundvall, Jouko ;

Albanus, Ricardo D'Oliveira ;

Kiseleva, Anna ;

Hensley, John ;

Crawford, Gregory E. ;

Jiang, Hui ;

Wen, Xiaoquan ;

Watanabe, Richard M. ;

Lakka, Timo A. ;

Mohlke, Karen L. ;

Laakso, Markku ;

Tuomilehto, Jaakko ;

Koistinen, Heikki A. ;

Boehnke, Michael ;

Collins, Francis S. ;

Parker, Stephen C. J. .

NATURE COMMUNICATIONS, 2016, 7

[45] An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans [J].

Scott, Robert A. ;

Scott, Laura J. ;

Maegi, Reedik ;

Marullo, Letizia ;

Gaulton, Kyle J. ;

Kaakinen, Marika ;

Pervjakova, Natalia ;

Pers, Tune H. ;

Johnson, Andrew D. ;

Eicher, John D. ;

Jackson, Anne U. ;

Ferreira, Teresa ;

Lee, Yeji ;

Ma, Clement ;

Steinthorsdottir, Valgerdur ;

Thorleifsson, Gudmar ;

Qi, Lu ;

Van Zuydam, Natalie R. ;

Mahajan, Anubha ;

Chen, Han ;

Almgren, Peter ;

Voight, Ben F. ;

Grallert, Harald ;

Mueller-Nurasyid, Martina ;

Ried, Janina S. ;

Rayner, Nigel W. ;

Robertson, Neil ;

Karssen, Lennart C. ;

Van Leeuwen, Elisabeth M. ;

Willems, Sara M. ;

Fuchsberger, Christian ;

Kwan, Phoenix ;

Teslovich, Tanya M. ;

Chanda, Pritam ;

Li, Man ;

Lu, Yingchang ;

Dina, Christian ;

Thuillier, Dorothee ;

Yengo, Loic ;

Jiang, Longda ;

Sparso, Thomas ;

Kestler, Hans A. ;

Chheda, Himanshu ;

Eisele, Lewin ;

Gustafsson, Stefan ;

Franberg, Mattias ;

Strawbridge, Rona J. ;

Benediktsson, Rafn ;

Hreidarsson, Astradur B. ;

Kong, Augustine .

DIABETES, 2017, 66 (11) :2888-2902

[46] Global Epigenomic Analysis of Primary Human Pancreatic Islets Provides Insights into Type 2 Diabetes Susceptibility Loci [J].

Stitzel, Michael L. ;

Sethupathy, Praveen ;

Pearson, Daniel S. ;

Chines, Peter S. ;

Song, Lingyun ;

Erdos, Michael R. ;

Welch, Ryan ;

Parker, Stephen C. J. ;

Boyle, Alan P. ;

Scott, Laura J. ;

Margulies, Elliott H. ;

Boehnke, Michael ;

Furey, Terrence S. ;

Crawford, Gregory E. ;

Collins, Francis S. .

CELL METABOLISM, 2010, 12 (05) :443-455

[47] TFBSTools: an R/bioconductor package for transcription factor binding site analysis [J].

Tan, Ge ;

Lenhard, Boris .

BIOINFORMATICS, 2016, 32 (10) :1555-1556

[48] Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci [J].

Thurner, Matthias ;

van de Bunt, Martijn ;

Torres, Jason M. ;

Mahajan, Anubha ;

Nylander, Vibe ;

Bennett, Amanda J. ;

Gaulton, Kyle J. ;

Barrett, Amy ;

Burrows, Carla ;

Bell, Christopher G. ;

Lowe, Robert ;

Beck, Stephan ;

Rakyan, Vardhman K. ;

Gloyn, Anna L. ;

McCarthy, Mark I. .

ELIFE, 2018, 7

[49] The chromatin accessibility signature of human immune aging stems from CD8+ T cells [J].

Ucar, Duygu ;

Marquez, Eladio J. ;

Chung, Cheng-Han ;

Marches, Radu ;

Rossi, Robert J. ;

Uyar, Asli ;

Wu, Te-Chia ;

George, Joshy ;

Stitzel, Michael L. ;

Palucka, A. Karolina ;

Kuchel, George A. ;

Banchereau, Jacques .

JOURNAL OF EXPERIMENTAL MEDICINE, 2017, 214 (10) :3123-3144

[50] Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors [J].

van de Bunt, Martijn ;

Fox, Jocelyn E. Manning ;

Dai, Xiaoqing ;

Barrett, Amy ;

Grey, Caleb ;

Li, Lei ;

Bennett, Amanda J. ;

Johnson, Paul R. ;

Rajotte, Raymond V. ;

Gaulton, Kyle J. ;

Dermitzakis, Emmanouil T. ;

MacDonald, Patrick E. ;

McCarthy, Mark I. ;

Gloyn, Anna L. .

PLOS GENETICS, 2015, 11 (12)

← 1 2 3 4 5 6 →