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

Kamran Ikram; S Xueling; RA Jensen; MF Cotch; AW Hewitt; Arfan Ikram; JJ Wang; R Klein; BEK Klein; Monique Breteler; N Cheung; G Liew; P Mitchell; André Uitterlinden; Fernando Rivadeneira; Bert Hofman; PTVM (Paulus) de Jong; Cornelia Duijn; L Kao; CY (Ching-Yu) Cheng; AV Smith; NL Glazer; T Lumley; B McKnight; BM Psaty; F Jonasson; G Eiriksdottir; T Aspelund; TB Harris; LJ (Lenore) Launer; KD Taylor; XH Li; SK Iyengar; QS Xi; TA Sivakumaran; DA Mackey; S Macgregor; NG Martin; TL Young; JC Bis; KL Wiggins; SR Heckbert; CJ Hammond; T Andrew; S Fahy; J Attia; EG Holliday; RJ Scott; FMA Islam; JI Rotter; AK McAuley; E Boerwinkle; ES Tai; V Gudnason; DS Siscovick; Hans Vingerling; TY Wong

doi:10.1371/journal.pgen.1001184

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

Kamran Ikram, S Xueling, RA Jensen, MF Cotch, AW Hewitt, Arfan Ikram, JJ Wang, R Klein, BEK Klein, Monique Breteler, N Cheung, G Liew, P Mitchell, André Uitterlinden, Fernando Rivadeneira, Bert Hofman, PTVM (Paulus) de Jong, Cornelia Duijn, L Kao, CY (Ching-Yu) ChengAV Smith, NL Glazer, T Lumley, B McKnight, BM Psaty, F Jonasson, G Eiriksdottir, T Aspelund, TB Harris, LJ (Lenore) Launer, KD Taylor, XH Li, SK Iyengar, QS Xi, TA Sivakumaran, DA Mackey, S Macgregor, NG Martin, TL Young, JC Bis, KL Wiggins, SR Heckbert, CJ Hammond, T Andrew, S Fahy, J Attia, EG Holliday, RJ Scott, FMA Islam, JI Rotter, AK McAuley, E Boerwinkle, ES Tai, V Gudnason, DS Siscovick, Hans Vingerling, TY Wong

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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<5.0x10(-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 = 1.61x10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25x10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15x10(-13), in the region of ATXN2, SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32x10(-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	Undefined/Unknown
Pages (from-to)	e1001184
Journal	PLoS Genetics (print)
Volume	6
Issue number	10
DOIs	https://doi.org/10.1371/journal.pgen.1001184
Publication status	Published - 2010

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Ikram, K., Xueling, S., Jensen, RA., Cotch, MF., Hewitt, AW., Ikram, A., Wang, JJ., Klein, R., Klein, BEK., Breteler, M., Cheung, N., Liew, G., Mitchell, P., Uitterlinden, A., Rivadeneira, F., Hofman, B., de Jong, PTVM., Duijn, C., Kao, L., ... Wong, TY. (2010). Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo. PLoS Genetics (print), 6(10), e1001184. https://doi.org/10.1371/journal.pgen.1001184

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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<5.0x10(-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 = 1.61x10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25x10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15x10(-13), in the region of ATXN2, SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32x10(-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 = "Kamran Ikram and S Xueling and RA Jensen and MF Cotch and AW Hewitt and Arfan Ikram and JJ Wang and R Klein and BEK Klein and Monique Breteler and N Cheung and G Liew and P Mitchell and Andr{\'e} Uitterlinden and Fernando Rivadeneira and Bert Hofman and {de Jong}, {PTVM (Paulus)} and Cornelia Duijn and L Kao and Cheng, {CY (Ching-Yu)} and AV Smith and NL Glazer and T Lumley and B McKnight and BM Psaty and F Jonasson and G Eiriksdottir and T Aspelund and TB Harris and Launer, {LJ (Lenore)} and KD Taylor and XH Li and SK Iyengar and QS Xi and TA Sivakumaran and DA Mackey and S Macgregor and NG Martin and TL Young and JC Bis and KL Wiggins and SR Heckbert and CJ Hammond and T Andrew and S Fahy and J Attia and EG Holliday and RJ Scott and FMA Islam and JI Rotter and AK McAuley and E Boerwinkle and ES Tai and V Gudnason and DS Siscovick and Hans Vingerling and TY Wong",

year = "2010",

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

language = "Undefined/Unknown",

volume = "6",

pages = "e1001184",

journal = "PLoS Genetics",

issn = "1553-7390",

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Ikram, K, Xueling, S, Jensen, RA, Cotch, MF, Hewitt, AW, Ikram, A, Wang, JJ, Klein, R, Klein, BEK, Breteler, M, Cheung, N, Liew, G, Mitchell, P, Uitterlinden, A , Rivadeneira, F , Hofman, B, de Jong, PTVM, Duijn, C, 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, XH, Iyengar, SK, Xi, QS, 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, H & Wong, TY 2010, 'Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo', PLoS Genetics (print), vol. 6, no. 10, pp. e1001184. 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, Kamran

AU - Xueling, S

AU - Jensen, RA

AU - Cotch, MF

AU - Hewitt, AW

AU - Ikram, Arfan

AU - Wang, JJ

AU - Klein, R

AU - Klein, BEK

AU - Breteler, Monique

AU - Cheung, N

AU - Liew, G

AU - Mitchell, P

AU - Uitterlinden, André

AU - Rivadeneira, Fernando

AU - Hofman, Bert

AU - de Jong, PTVM (Paulus)

AU - Duijn, Cornelia

AU - Kao, L

AU - Cheng, CY (Ching-Yu)

AU - Smith, AV

AU - Glazer, NL

AU - Lumley, T

AU - McKnight, B

AU - Psaty, BM

AU - Jonasson, F

AU - Eiriksdottir, G

AU - Aspelund, T

AU - Harris, TB

AU - Launer, LJ (Lenore)

AU - Taylor, KD

AU - Li, XH

AU - Iyengar, SK

AU - Xi, QS

AU - Sivakumaran, TA

AU - Mackey, DA

AU - Macgregor, S

AU - Martin, NG

AU - Young, TL

AU - Bis, JC

AU - Wiggins, KL

AU - Heckbert, SR

AU - Hammond, CJ

AU - Andrew, T

AU - Fahy, S

AU - Attia, J

AU - Holliday, EG

AU - Scott, RJ

AU - Islam, FMA

AU - Rotter, JI

AU - McAuley, AK

AU - Boerwinkle, E

AU - Tai, ES

AU - Gudnason, V

AU - Siscovick, DS

AU - Vingerling, Hans

AU - Wong, TY

PY - 2010

Y1 - 2010

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<5.0x10(-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 = 1.61x10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25x10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15x10(-13), in the region of ATXN2, SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32x10(-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<5.0x10(-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 = 1.61x10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25x10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p = 2.15x10(-13), in the region of ATXN2, SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32x10(-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 - 1553-7390

VL - 6

SP - e1001184

JO - PLoS Genetics

JF - PLoS Genetics

IS - 10

ER -