Centre for Eye Research Australia (CERA) - Research Publications

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Author: CHEUNG, DANNY × Author: Hewitt, Alexander × Start date: 2010 ×

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    Genome-Wide Association Study of Retinopathy in Individuals without Diabetes
    Jensen, RA ; Sim, X ; Li, X ; Cotch, MF ; Ikram, MK ; Holliday, EG ; Eiriksdottir, G ; Harris, TB ; Jonasson, F ; Klein, BEK ; Launer, LJ ; Smith, AV ; Boerwinkle, E ; Cheung, N ; Hewitt, AW ; Liew, G ; Mitchell, P ; Wang, JJ ; Attia, J ; Scott, R ; Glazer, NL ; Lumley, T ; McKnight, B ; Psaty, BM ; Taylor, K ; Hofman, A ; de Jong, PTVM ; Rivadeneira, F ; Uitterlinden, AG ; Tay, W-T ; Teo, YY ; Seielstad, M ; Liu, J ; Cheng, C-Y ; Saw, S-M ; Aung, T ; Ganesh, SK ; O'Donnell, CJ ; Nalls, MA ; Wiggins, KL ; Kuo, JZ ; van Duijn, CM ; Gudnason, V ; Klein, R ; Siscovick, DS ; Rotter, JI ; Tai, ES ; Vingerling, J ; Wong, TY ; Mittal, B (PUBLIC LIBRARY SCIENCE, 2013-02-05)
    BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. CONCLUSIONS: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.
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    Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo
    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 ; Rotter, JI ; McAuley, AK ; Boerwinkle, E ; Tai, ES ; Gudnason, V ; Siscovick, DS ; Vingerling, JR ; Wong, TY ; McCarthy, MI (PUBLIC LIBRARY SCIENCE, 2010-10)
    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.