Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

Kari E. North; Nora Franceschini; Christy L. Avery; Lisa Baird; Mariaelisa Graff; Mark Leppert; Jay H. Chung; Jinghui Zhang; Craig Hanis; Eric Boerwinkle; Kelly A. Volcik; Megan L. Grove; Thomas H. Mosley; Charles Gu; Gerardo Heiss; James S. Pankow; David J. Couper; Christie M. Ballantyne; W. H. Linda Kao; Alan B. Weder; Richard S. Cooper; Georg B. Ehret; Ashley A. O'Connor; Aravinda Chakravarti; Steven C. Hunt

doi:10.1007/s00592-009-0162-z

Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

Kari E. North, Nora Franceschini, Christy L. Avery, Lisa Baird, Mariaelisa Graff, Mark Leppert, Jay H. Chung, Jinghui Zhang, Craig Hanis, Eric Boerwinkle, Kelly A. Volcik, Megan L. Grove, Thomas H. Mosley, Charles Gu, Gerardo Heiss, James S. Pankow, David J. Couper, Christie M. Ballantyne, W. H. Linda Kao, Alan B. WederRichard S. Cooper, Georg B. Ehret, Ashley A. O'Connor, Aravinda Chakravarti, Steven C. Hunt

Epidemiology & Community Health

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age², sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.

Original language	English (US)
Pages (from-to)	S199-S207
Journal	Acta Diabetologica
Volume	47
Issue number	SUPPL. 1
DOIs	https://doi.org/10.1007/s00592-009-0162-z
State	Published - Dec 2010

Bibliographical note

Funding Information:
The following investigators are associated with the Family Blood Pressure Program: GenNet Network: Alan B. Weder (Network Director), Lillian Gleiberman (Network Coordinator), Anne E. Kwitek, Aravinda Chakravarti, Richard S. Cooper, Carolina Delgado, Howard J. Jacob, and Nicholas J. Schork. GENOA Network: Eric Boerwinkle (Network Director), Tom Mosley, Alanna Morrison, Kathy Klos, Craig Hanis, Sharon Kardia, and Stephen Turner. HyperGEN Network: Steven C. Hunt (Network Director), Janet Hood, Donna Arnett, John H. Eckfeldt, R. Curtis Ellison, Chi Gu, Gerardo Heiss, Paul Hopkins, Aldi T. Kraja, Jean-Marc Lalouel, Mark Leppert, Albert Oberman, Michael A. Province, D.C. Rao, Treva Rice, and Robert Weiss.SAPPHIRe Network: David Curb (Network Director), David Cox, Timothy Donlon, Victor Dzau, John Grove, Kamal Masaki, Richard Myers, Richard Olshen, Richard Pratt, Tom Quertermous, Neil Risch and Beatriz Rodriguez. National Heart, Lung, and Blood Institute: Dina Paltoo and Cashell E. Jaquish. Web Site: http://www.biostat.wustl.edu/fbpp/FBPP.shtml . The Family Blood Pressure Program Project is supported by cooperative agreement grants HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 from the National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the FBPP and ARIC study for their important contributions.

Keywords

Atherosclerosis Risk in Communities Study
CHEK2 SNPs
CHEK2 gene
Family Blood Pressure Program
Type 2 diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Publisher link

10.1007/s00592-009-0162-z

Find It

Find It at U of M Libraries

Cite this

North, K. E., Franceschini, N., Avery, C. L., Baird, L., Graff, M., Leppert, M., Chung, J. H., Zhang, J., Hanis, C., Boerwinkle, E., Volcik, K. A., Grove, M. L., Mosley, T. H., Gu, C., Heiss, G., Pankow, J. S., Couper, D. J., Ballantyne, C. M., Linda Kao, W. H., ... Hunt, S. C. (2010). Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations. Acta Diabetologica, 47(SUPPL. 1), S199-S207. https://doi.org/10.1007/s00592-009-0162-z

North, KE, Franceschini, N, Avery, CL, Baird, L, Graff, M, Leppert, M, Chung, JH, Zhang, J, Hanis, C, Boerwinkle, E, Volcik, KA, Grove, ML, Mosley, TH, Gu, C, Heiss, G, Pankow, JS, Couper, DJ, Ballantyne, CM, Linda Kao, WH, Weder, AB, Cooper, RS, Ehret, GB, O'Connor, AA, Chakravarti, A & Hunt, SC 2010, 'Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations', Acta Diabetologica, vol. 47, no. SUPPL. 1, pp. S199-S207. https://doi.org/10.1007/s00592-009-0162-z

@article{de96f946709e43cb8bc0882d452b3213,

title = "Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations",

abstract = "Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age2, sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.",

keywords = "Atherosclerosis Risk in Communities Study, CHEK2 SNPs, CHEK2 gene, Family Blood Pressure Program, Type 2 diabetes",

author = "North, {Kari E.} and Nora Franceschini and Avery, {Christy L.} and Lisa Baird and Mariaelisa Graff and Mark Leppert and Chung, {Jay H.} and Jinghui Zhang and Craig Hanis and Eric Boerwinkle and Volcik, {Kelly A.} and Grove, {Megan L.} and Mosley, {Thomas H.} and Charles Gu and Gerardo Heiss and Pankow, {James S.} and Couper, {David J.} and Ballantyne, {Christie M.} and {Linda Kao}, {W. H.} and Weder, {Alan B.} and Cooper, {Richard S.} and Ehret, {Georg B.} and O'Connor, {Ashley A.} and Aravinda Chakravarti and Hunt, {Steven C.}",

note = "Funding Information: The following investigators are associated with the Family Blood Pressure Program: GenNet Network: Alan B. Weder (Network Director), Lillian Gleiberman (Network Coordinator), Anne E. Kwitek, Aravinda Chakravarti, Richard S. Cooper, Carolina Delgado, Howard J. Jacob, and Nicholas J. Schork. GENOA Network: Eric Boerwinkle (Network Director), Tom Mosley, Alanna Morrison, Kathy Klos, Craig Hanis, Sharon Kardia, and Stephen Turner. HyperGEN Network: Steven C. Hunt (Network Director), Janet Hood, Donna Arnett, John H. Eckfeldt, R. Curtis Ellison, Chi Gu, Gerardo Heiss, Paul Hopkins, Aldi T. Kraja, Jean-Marc Lalouel, Mark Leppert, Albert Oberman, Michael A. Province, D.C. Rao, Treva Rice, and Robert Weiss.SAPPHIRe Network: David Curb (Network Director), David Cox, Timothy Donlon, Victor Dzau, John Grove, Kamal Masaki, Richard Myers, Richard Olshen, Richard Pratt, Tom Quertermous, Neil Risch and Beatriz Rodriguez. National Heart, Lung, and Blood Institute: Dina Paltoo and Cashell E. Jaquish. Web Site: http://www.biostat.wustl.edu/fbpp/FBPP.shtml . The Family Blood Pressure Program Project is supported by cooperative agreement grants HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 from the National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the FBPP and ARIC study for their important contributions.",

year = "2010",

month = dec,

doi = "10.1007/s00592-009-0162-z",

language = "English (US)",

volume = "47",

pages = "S199--S207",

journal = "Acta Diabetologica",

issn = "0940-5429",

publisher = "Casa Editrice II Ponte",

number = "SUPPL. 1",

}

TY - JOUR

T1 - Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

AU - North, Kari E.

AU - Franceschini, Nora

AU - Avery, Christy L.

AU - Baird, Lisa

AU - Graff, Mariaelisa

AU - Leppert, Mark

AU - Chung, Jay H.

AU - Zhang, Jinghui

AU - Hanis, Craig

AU - Boerwinkle, Eric

AU - Volcik, Kelly A.

AU - Grove, Megan L.

AU - Mosley, Thomas H.

AU - Gu, Charles

AU - Heiss, Gerardo

AU - Pankow, James S.

AU - Couper, David J.

AU - Ballantyne, Christie M.

AU - Linda Kao, W. H.

AU - Weder, Alan B.

AU - Cooper, Richard S.

AU - Ehret, Georg B.

AU - O'Connor, Ashley A.

AU - Chakravarti, Aravinda

AU - Hunt, Steven C.

N1 - Funding Information: The following investigators are associated with the Family Blood Pressure Program: GenNet Network: Alan B. Weder (Network Director), Lillian Gleiberman (Network Coordinator), Anne E. Kwitek, Aravinda Chakravarti, Richard S. Cooper, Carolina Delgado, Howard J. Jacob, and Nicholas J. Schork. GENOA Network: Eric Boerwinkle (Network Director), Tom Mosley, Alanna Morrison, Kathy Klos, Craig Hanis, Sharon Kardia, and Stephen Turner. HyperGEN Network: Steven C. Hunt (Network Director), Janet Hood, Donna Arnett, John H. Eckfeldt, R. Curtis Ellison, Chi Gu, Gerardo Heiss, Paul Hopkins, Aldi T. Kraja, Jean-Marc Lalouel, Mark Leppert, Albert Oberman, Michael A. Province, D.C. Rao, Treva Rice, and Robert Weiss.SAPPHIRe Network: David Curb (Network Director), David Cox, Timothy Donlon, Victor Dzau, John Grove, Kamal Masaki, Richard Myers, Richard Olshen, Richard Pratt, Tom Quertermous, Neil Risch and Beatriz Rodriguez. National Heart, Lung, and Blood Institute: Dina Paltoo and Cashell E. Jaquish. Web Site: http://www.biostat.wustl.edu/fbpp/FBPP.shtml . The Family Blood Pressure Program Project is supported by cooperative agreement grants HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 from the National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by NHLBI contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022. The authors thank the staff and participants of the FBPP and ARIC study for their important contributions.

PY - 2010/12

Y1 - 2010/12

N2 - Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age2, sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.

AB - Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age2, sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis.

KW - Atherosclerosis Risk in Communities Study

KW - CHEK2 SNPs

KW - CHEK2 gene

KW - Family Blood Pressure Program

KW - Type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=78751585289&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78751585289&partnerID=8YFLogxK

U2 - 10.1007/s00592-009-0162-z

DO - 10.1007/s00592-009-0162-z

M3 - Article

C2 - 19855918

AN - SCOPUS:78751585289

SN - 0940-5429

VL - 47

SP - S199-S207

JO - Acta Diabetologica

JF - Acta Diabetologica

IS - SUPPL. 1

ER -

Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

Abstract

Bibliographical note

Keywords

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

Cite this