Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo

M. Kamran Ikram, Sim Xueling, Richard A. Jensen, Mary Frances Cotch, Alex W. Hewitt, M. Arfan Ikram, Jie Jin Wang, Ronald Klein, Barbara E K Klein, Monique M B Breteler, Ning Cheung, Gerald Liew, Paul Mitchell, Andre G. Uitterlinden, Fernando Rivadeneira, Albert Hofman, Paulus T V M de Jong, Cornelia M. van Duijn, Linda Kao, Ching Yu Cheng & 37 others Albert Vernon Smith, Nicole L. Glazer, Thomas Lumley, Barbara McKnight, Bruce M. Psaty, Fridbert Jonasson, Gudny Eiriksdottir, Thor Aspelund, Tamara B. Harris, Lenore J. Launer, Kent D. Taylor, Xiaohui Li, Sudha K. Iyengar, Quansheng Xi, Theru A. Sivakumaran, David A. MacKey, Stuart MacGregor, Nicholas G. Martin, Terri L. Young, Josh C. Bis, Kerri L. Wiggins, Susan R. Heckbert, Christopher J. Hammond, Toby Andrew, Samantha Fahy, John Attia, Elizabeth G. Holliday, Rodney J. Scott, F. M Amirul Islam, Jerome I. Rotter, Annie K. McAuley, Eric Boerwinkle, E. Shyong Tai, Vilmundur Gudnason, David S. Siscovick, Johannes R. Vingerling, Tien Y. Wong

Research output: Contribution to journalArticle

Abstract

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

Original languageEnglish (US)
Article numbere1001184
Pages (from-to)1-12
Number of pages12
JournalPLoS Genetics
Volume6
Issue number10
DOIs
StatePublished - Oct 2010

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cardiovascular disease
Microcirculation
Retinal Vessels
Cardiovascular Diseases
Genome-Wide Association Study
loci
Single Nucleotide Polymorphism
Endophenotypes
genome
Photography
hypertension
Population
Coronary Disease
cardiovascular diseases
Epidemiology
Software
epidemiology
photography
Hypertension
genomics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Kamran Ikram, M., Xueling, S., Jensen, R. A., Cotch, M. F., Hewitt, A. W., Ikram, M. A., ... Wong, T. Y. (2010). Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo. PLoS Genetics, 6(10), 1-12. [e1001184]. https://doi.org/10.1371/journal.pgen.1001184

Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo. / Kamran Ikram, M.; Xueling, Sim; Jensen, Richard A.; Cotch, Mary Frances; Hewitt, Alex W.; Ikram, M. Arfan; Wang, Jie Jin; Klein, Ronald; Klein, Barbara E K; Breteler, Monique M B; Cheung, Ning; Liew, Gerald; Mitchell, Paul; Uitterlinden, Andre G.; Rivadeneira, Fernando; Hofman, Albert; de Jong, Paulus T V M; van Duijn, Cornelia M.; Kao, Linda; Cheng, Ching Yu; Smith, Albert Vernon; Glazer, Nicole L.; Lumley, Thomas; McKnight, Barbara; Psaty, Bruce M.; Jonasson, Fridbert; Eiriksdottir, Gudny; Aspelund, Thor; Harris, Tamara B.; Launer, Lenore J.; Taylor, Kent D.; Li, Xiaohui; Iyengar, Sudha K.; Xi, Quansheng; Sivakumaran, Theru A.; MacKey, David A.; MacGregor, Stuart; Martin, Nicholas G.; Young, Terri L.; Bis, Josh C.; Wiggins, Kerri L.; Heckbert, Susan R.; Hammond, Christopher J.; Andrew, Toby; Fahy, Samantha; Attia, John; Holliday, Elizabeth G.; Scott, Rodney J.; Islam, F. M Amirul; Rotter, Jerome I.; McAuley, Annie K.; Boerwinkle, Eric; Tai, E. Shyong; Gudnason, Vilmundur; Siscovick, David S.; Vingerling, Johannes R.; Wong, Tien Y.

In: PLoS Genetics, Vol. 6, No. 10, e1001184, 10.2010, p. 1-12.

Research output: Contribution to journalArticle

Kamran Ikram, M, Xueling, S, Jensen, RA, Cotch, MF, Hewitt, AW, Ikram, MA, Wang, JJ, Klein, R, Klein, BEK, Breteler, MMB, Cheung, N, Liew, G, Mitchell, P, Uitterlinden, AG, Rivadeneira, F, Hofman, A, de Jong, PTVM, van Duijn, CM, Kao, L, Cheng, CY, Smith, AV, Glazer, NL, Lumley, T, McKnight, B, Psaty, BM, Jonasson, F, Eiriksdottir, G, Aspelund, T, Harris, TB, Launer, LJ, Taylor, KD, Li, X, Iyengar, SK, Xi, Q, Sivakumaran, TA, MacKey, DA, MacGregor, S, Martin, NG, Young, TL, Bis, JC, Wiggins, KL, Heckbert, SR, Hammond, CJ, Andrew, T, Fahy, S, Attia, J, Holliday, EG, Scott, RJ, Islam, FMA, Rotter, JI, McAuley, AK, Boerwinkle, E, Tai, ES, Gudnason, V, Siscovick, DS, Vingerling, JR & Wong, TY 2010, 'Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo', PLoS Genetics, vol. 6, no. 10, e1001184, pp. 1-12. https://doi.org/10.1371/journal.pgen.1001184
Kamran Ikram M, Xueling S, Jensen RA, Cotch MF, Hewitt AW, Ikram MA et al. Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo. PLoS Genetics. 2010 Oct;6(10):1-12. e1001184. https://doi.org/10.1371/journal.pgen.1001184
Kamran Ikram, M. ; Xueling, Sim ; Jensen, Richard A. ; Cotch, Mary Frances ; Hewitt, Alex W. ; Ikram, M. Arfan ; Wang, Jie Jin ; Klein, Ronald ; Klein, Barbara E K ; Breteler, Monique M B ; Cheung, Ning ; Liew, Gerald ; Mitchell, Paul ; Uitterlinden, Andre G. ; Rivadeneira, Fernando ; Hofman, Albert ; de Jong, Paulus T V M ; van Duijn, Cornelia M. ; Kao, Linda ; Cheng, Ching Yu ; Smith, Albert Vernon ; Glazer, Nicole L. ; Lumley, Thomas ; McKnight, Barbara ; Psaty, Bruce M. ; Jonasson, Fridbert ; Eiriksdottir, Gudny ; Aspelund, Thor ; Harris, Tamara B. ; Launer, Lenore J. ; Taylor, Kent D. ; Li, Xiaohui ; Iyengar, Sudha K. ; Xi, Quansheng ; Sivakumaran, Theru A. ; MacKey, David A. ; MacGregor, Stuart ; Martin, Nicholas G. ; Young, Terri L. ; Bis, Josh C. ; Wiggins, Kerri L. ; Heckbert, Susan R. ; Hammond, Christopher J. ; Andrew, Toby ; Fahy, Samantha ; Attia, John ; Holliday, Elizabeth G. ; Scott, Rodney J. ; Islam, F. M Amirul ; Rotter, Jerome I. ; McAuley, Annie K. ; Boerwinkle, Eric ; Tai, E. Shyong ; Gudnason, Vilmundur ; Siscovick, David S. ; Vingerling, Johannes R. ; Wong, Tien Y. / Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo. In: PLoS Genetics. 2010 ; Vol. 6, No. 10. pp. 1-12.
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abstract = "There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0{\%}-3.2{\%} of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.",
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TY - JOUR

T1 - Four novel loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation In vivo

AU - Kamran Ikram, M.

AU - Xueling, Sim

AU - Jensen, Richard A.

AU - Cotch, Mary Frances

AU - Hewitt, Alex W.

AU - Ikram, M. Arfan

AU - Wang, Jie Jin

AU - Klein, Ronald

AU - Klein, Barbara E K

AU - Breteler, Monique M B

AU - Cheung, Ning

AU - Liew, Gerald

AU - Mitchell, Paul

AU - Uitterlinden, Andre G.

AU - Rivadeneira, Fernando

AU - Hofman, Albert

AU - de Jong, Paulus T V M

AU - van Duijn, Cornelia M.

AU - Kao, Linda

AU - Cheng, Ching Yu

AU - Smith, Albert Vernon

AU - Glazer, Nicole L.

AU - Lumley, Thomas

AU - McKnight, Barbara

AU - Psaty, Bruce M.

AU - Jonasson, Fridbert

AU - Eiriksdottir, Gudny

AU - Aspelund, Thor

AU - Harris, Tamara B.

AU - Launer, Lenore J.

AU - Taylor, Kent D.

AU - Li, Xiaohui

AU - Iyengar, Sudha K.

AU - Xi, Quansheng

AU - Sivakumaran, Theru A.

AU - MacKey, David A.

AU - MacGregor, Stuart

AU - Martin, Nicholas G.

AU - Young, Terri L.

AU - Bis, Josh C.

AU - Wiggins, Kerri L.

AU - Heckbert, Susan R.

AU - Hammond, Christopher J.

AU - Andrew, Toby

AU - Fahy, Samantha

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - Scott, Rodney J.

AU - Islam, F. M Amirul

AU - Rotter, Jerome I.

AU - McAuley, Annie K.

AU - Boerwinkle, Eric

AU - Tai, E. Shyong

AU - Gudnason, Vilmundur

AU - Siscovick, David S.

AU - Vingerling, Johannes R.

AU - Wong, Tien Y.

PY - 2010/10

Y1 - 2010/10

N2 - There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

AB - There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p-8) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p = 1.61×10-25, within the RASIP1 locus), rs225717 (6q24; p = 1.25×10-16, adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15×10-13, in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10-16, adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

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