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Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.

Ikram MK, Sim X, Xueling S, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, Jonasson F, Eiriksdottir G, Aspelund T, Global BPgen ConsortiumHarris 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 FM, Rotter JI, McAuley AK, Boerwinkle E, Tai ES, Gudnason V, Siscovick DS, Vingerling JR, Wong TY - PLoS Genet. (2010)

Bottom Line: Four out of these five loci were confirmed in independent replication samples.In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension.These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

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.

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Regional association plots for the four novel loci.(a) Chromosome 19q13, (b) chromosome 6q24, (c) chromosome 12q24, and (d) chromosome 5q14. The blue diamonds show stage 1 p-values (discovery phase) for the top SNP at each locus, whereas the grey diamonds show the p-values following stage 2 meta-analysis including the replication cohorts for that top SNP. P-values from stage 1 for additional SNPs at each locus are colour-coded according to their linkage disequilibrium with the top SNP as follows: r2<0.2 white, 0.2<r2<0.5 yellow, 0.5<r2<orange-red, r2>0.8 red.
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pgen-1001184-g002: Regional association plots for the four novel loci.(a) Chromosome 19q13, (b) chromosome 6q24, (c) chromosome 12q24, and (d) chromosome 5q14. The blue diamonds show stage 1 p-values (discovery phase) for the top SNP at each locus, whereas the grey diamonds show the p-values following stage 2 meta-analysis including the replication cohorts for that top SNP. P-values from stage 1 for additional SNPs at each locus are colour-coded according to their linkage disequilibrium with the top SNP as follows: r2<0.2 white, 0.2<r2<0.5 yellow, 0.5<r2<orange-red, r2>0.8 red.

Mentions: The regional association plots for these four loci are presented in Figure 2A–2D. After additional adjustments for hypertension and diabetes mellitus, the associations between the four replicated loci and retinal venular caliber remained the same (Table S1).


Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.

Ikram MK, Sim X, Xueling S, Jensen RA, Cotch MF, Hewitt AW, Ikram MA, Wang JJ, Klein R, Klein BE, Breteler MM, Cheung N, Liew G, Mitchell P, Uitterlinden AG, Rivadeneira F, Hofman A, de Jong PT, van Duijn CM, Kao L, Cheng CY, Smith AV, Glazer NL, Lumley T, McKnight B, Psaty BM, Jonasson F, Eiriksdottir G, Aspelund T, Global BPgen ConsortiumHarris 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 FM, Rotter JI, McAuley AK, Boerwinkle E, Tai ES, Gudnason V, Siscovick DS, Vingerling JR, Wong TY - PLoS Genet. (2010)

Regional association plots for the four novel loci.(a) Chromosome 19q13, (b) chromosome 6q24, (c) chromosome 12q24, and (d) chromosome 5q14. The blue diamonds show stage 1 p-values (discovery phase) for the top SNP at each locus, whereas the grey diamonds show the p-values following stage 2 meta-analysis including the replication cohorts for that top SNP. P-values from stage 1 for additional SNPs at each locus are colour-coded according to their linkage disequilibrium with the top SNP as follows: r2<0.2 white, 0.2<r2<0.5 yellow, 0.5<r2<orange-red, r2>0.8 red.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2965750&req=5

pgen-1001184-g002: Regional association plots for the four novel loci.(a) Chromosome 19q13, (b) chromosome 6q24, (c) chromosome 12q24, and (d) chromosome 5q14. The blue diamonds show stage 1 p-values (discovery phase) for the top SNP at each locus, whereas the grey diamonds show the p-values following stage 2 meta-analysis including the replication cohorts for that top SNP. P-values from stage 1 for additional SNPs at each locus are colour-coded according to their linkage disequilibrium with the top SNP as follows: r2<0.2 white, 0.2<r2<0.5 yellow, 0.5<r2<orange-red, r2>0.8 red.
Mentions: The regional association plots for these four loci are presented in Figure 2A–2D. After additional adjustments for hypertension and diabetes mellitus, the associations between the four replicated loci and retinal venular caliber remained the same (Table S1).

Bottom Line: Four out of these five loci were confirmed in independent replication samples.In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension.These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands.

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.

Show MeSH
Related in: MedlinePlus