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; 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; Global-BPGen Consortium

doi:10.1371/journal.pgen.1001184

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 ChengAlbert 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, Global-BPGen Consortium

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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<5.0×10−8) 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 language	English
Article number	e1001184
Pages (from-to)	1-12
Number of pages	12
Journal	PL o S Genetics
Volume	6
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1001184
Publication status	Published - 28 Oct 2010

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10.1371/journal.pgen.1001184

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Ikram, M. K., Xueling, S., Jensen, R. A., Cotch, M. F., Hewitt, A. W., Ikram, M. A., Wang, J. J., Klein, R., Klein, B. E. K., Breteler, M. M. B., Cheung, N., Liew, G., Mitchell, P., Uitterlinden, A. G., Rivadeneira, F., Hofman, A., de Jong, P. T. V. M., van Duijn, C. M., Kao, L., ... Global-BPGen Consortium (2010). Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo. PL o S Genetics, 6(10), 1-12. Article e1001184. https://doi.org/10.1371/journal.pgen.1001184

@article{f9d0cbea84144014b1397ef8f855bbe3,

title = "Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo",

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<5.0×10−8) 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.",

author = "Ikram, {M. Kamran} and Sim Xueling and Jensen, {Richard A.} and Cotch, {Mary Frances} and Hewitt, {Alex W.} and Ikram, {M. Arfan} and Wang, {Jie Jin} and Ronald Klein and Klein, {Barbara E. K.} and Breteler, {Monique M. B.} and Ning Cheung and Gerald Liew and Paul Mitchell and Uitterlinden, {Andre G.} and Fernando Rivadeneira and Albert Hofman and {de Jong}, {Paulus T. V. M.} and {van Duijn}, {Cornelia M.} and Linda Kao and Ching-Yu Cheng and Smith, {Albert Vernon} and Glazer, {Nicole L.} and Thomas Lumley and Barbara McKnight and Psaty, {Bruce M.} and Fridbert Jonasson and Gudny Eiriksdottir and Thor Aspelund and Harris, {Tamara B.} and Launer, {Lenore J.} and Taylor, {Kent D.} and Xiaohui Li and Iyengar, {Sudha K.} and Quansheng Xi and Sivakumaran, {Theru A.} and Mackey, {David A.} and Stuart MacGregor and Martin, {Nicholas G.} and Young, {Terri L.} and Bis, {Josh C.} and Wiggins, {Kerri L.} and Heckbert, {Susan R.} and Hammond, {Christopher J.} and Toby Andrew and Samantha Fahy and John Attia and Holliday, {Elizabeth G.} and Scott, {Rodney J.} and Islam, {F. M. Amirul} and {Global-BPGen Consortium} and Paul O'Reilly",

year = "2010",

month = oct,

day = "28",

doi = "10.1371/journal.pgen.1001184",

language = "English",

volume = "6",

pages = "1--12",

journal = "PL o S Genetics",

issn = "1553-7404",

publisher = "Public Library of Science",

number = "10",

}

Ikram, MK, 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, C-Y, 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 & Global-BPGen Consortium 2010, 'Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo', PL o S Genetics, vol. 6, no. 10, e1001184, pp. 1-12. https://doi.org/10.1371/journal.pgen.1001184

TY - JOUR

T1 - Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

AU - Ikram, M. Kamran

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 - Global-BPGen Consortium

AU - O'Reilly, Paul

PY - 2010/10/28

Y1 - 2010/10/28

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<5.0×10−8) 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<5.0×10−8) 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.

U2 - 10.1371/journal.pgen.1001184

DO - 10.1371/journal.pgen.1001184

M3 - Article

SN - 1553-7404

VL - 6

SP - 1

EP - 12

JO - PL o S Genetics

JF - PL o S Genetics

IS - 10

M1 - e1001184

ER -

Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

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