@article {1243, title = {Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.}, journal = {PLoS Genet}, volume = {6}, year = {2010}, month = {2010 Oct 28}, pages = {e1001184}, 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{\texttimes}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{\texttimes}10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25{\texttimes}10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15{\texttimes}10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32{\texttimes}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.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Cardiovascular Diseases, Child, Child, Preschool, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 19, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, Cohort Studies, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Microcirculation, Middle Aged, Polymorphism, Single Nucleotide, Retinal Vessels, Young Adult}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1001184}, author = {Ikram, M Kamran and Sim, Xueling and Xueling, Sim and Jensen, Richard A and Cotch, Mary Frances and Hewitt, Alex W and Ikram, M Arfan and Wang, Jie Jin and Klein, Ronald and Klein, Barbara E K and Breteler, Monique M B and Cheung, Ning and Liew, Gerald and Mitchell, Paul and Uitterlinden, Andr{\'e} G and Rivadeneira, Fernando and Hofman, Albert and de Jong, Paulus T V M and van Duijn, Cornelia M and Kao, Linda and Cheng, Ching-Yu and Smith, Albert Vernon and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Jonasson, Fridbert and Eiriksdottir, Gudny and Aspelund, Thor and Harris, Tamara B and Launer, Lenore J and Taylor, Kent D and Li, Xiaohui and Iyengar, Sudha K and Xi, Quansheng and Sivakumaran, Theru A and Mackey, David A and Macgregor, Stuart 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 Andrew, Toby and Fahy, Samantha and Attia, John and Holliday, Elizabeth G and Scott, Rodney J and Islam, F M Amirul and Rotter, Jerome I and McAuley, Annie K and Boerwinkle, Eric and Tai, E Shyong and Gudnason, Vilmundur and Siscovick, David S and Vingerling, Johannes R and Wong, Tien Y} } @article {6027, title = {Genetic loci for retinal arteriolar microcirculation.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e65804}, abstract = {

Narrow arterioles in the retina have been shown to predict hypertension as well as other vascular diseases, likely through an increase in the peripheral resistance of the microcirculatory flow. In this study, we performed a genome-wide association study in 18,722 unrelated individuals of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium and the Blue Mountain Eye Study, to identify genetic determinants associated with variations in retinal arteriolar caliber. Retinal vascular calibers were measured on digitized retinal photographs using a standardized protocol. One variant (rs2194025 on chromosome 5q14 near the myocyte enhancer factor 2C MEF2C gene) was associated with retinal arteriolar caliber in the meta-analysis of the discovery cohorts at genome-wide significance of P-value <5{\texttimes}10(-8). This variant was replicated in an additional 3,939 individuals of European ancestry from the Australian Twins Study and Multi-Ethnic Study of Atherosclerosis (rs2194025, P-value = 2.11{\texttimes}10(-12) in combined meta-analysis of discovery and replication cohorts). In independent studies of modest sample sizes, no significant association was found between this variant and clinical outcomes including coronary artery disease, stroke, myocardial infarction or hypertension. In conclusion, we found one novel loci which underlie genetic variation in microvasculature which may be relevant to vascular disease. The relevance of these findings to clinical outcomes remains to be determined.

}, keywords = {Aged, Aged, 80 and over, Arterioles, Chromosomes, Human, Pair 5, European Continental Ancestry Group, Female, Genetic Loci, Genome-Wide Association Study, Genotype, Humans, Male, MEF2 Transcription Factors, Microcirculation, Middle Aged, Models, Genetic, Retinal Vessels}, issn = {1932-6203}, doi = {10.1371/journal.pone.0065804}, author = {Sim, Xueling and Jensen, Richard A and Ikram, M Kamran and Cotch, Mary Frances and Li, Xiaohui and Macgregor, Stuart and Xie, Jing and Smith, Albert Vernon and Boerwinkle, Eric and Mitchell, Paul and Klein, Ronald and Klein, Barbara E K and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and de Jong, Paulus T V M and Hofman, Albert and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and van Duijn, Cornelia M and Aspelund, Thor and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Launer, Lenore J and Attia, John and Baird, Paul N and Harrap, Stephen and Holliday, Elizabeth G and Inouye, Michael and Rochtchina, Elena and Scott, Rodney J and Viswanathan, Ananth and Li, Guo and Smith, Nicholas L and Wiggins, Kerri L and Kuo, Jane Z and Taylor, Kent D and Hewitt, Alex W and Martin, Nicholas G and Montgomery, Grant W and Sun, Cong and Young, Terri L and Mackey, David A and van Zuydam, Natalie R and Doney, Alex S F and Palmer, Colin N A and Morris, Andrew D and Rotter, Jerome I and Tai, E Shyong and Gudnason, Vilmundur and Vingerling, Johannes R and Siscovick, David S and Wang, Jie Jin and Wong, Tien Y} } @article {6072, title = {Genome-wide association study of retinopathy in individuals without diabetes.}, journal = {PLoS One}, volume = {8}, year = {2013}, month = {2013}, pages = {e54232}, abstract = {

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{\textpm}0.23 (beta {\textpm} standard error), p = 6.6{\texttimes}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.

}, keywords = {Aged, Aged, 80 and over, Female, Genome-Wide Association Study, Genotype, Histone Deacetylases, Humans, Hypertension, Male, Polymorphism, Single Nucleotide, Repressor Proteins, Retinal Diseases}, issn = {1932-6203}, doi = {10.1371/journal.pone.0054232}, author = {Jensen, Richard A and Sim, Xueling and Li, Xiaohui and Cotch, Mary Frances and Ikram, M Kamran and Holliday, Elizabeth G and Eiriksdottir, Gudny and Harris, Tamara B and Jonasson, Fridbert and Klein, Barbara E K and Launer, Lenore J and Smith, Albert Vernon and Boerwinkle, Eric and Cheung, Ning and Hewitt, Alex W and Liew, Gerald and Mitchell, Paul and Wang, Jie Jin and Attia, John and Scott, Rodney and Glazer, Nicole L and Lumley, Thomas and McKnight, Barbara and Psaty, Bruce M and Taylor, Kent and Hofman, Albert and de Jong, Paulus T V M and Rivadeneira, Fernando and Uitterlinden, Andr{\'e} G and Tay, Wan-Ting and Teo, Yik Ying and Seielstad, Mark and Liu, Jianjun and Cheng, Ching-Yu and Saw, Seang-Mei and Aung, Tin and Ganesh, Santhi K and O{\textquoteright}Donnell, Christopher J and Nalls, Mike A and Wiggins, Kerri L and Kuo, Jane Z and van Duijn, Cornelia M and Gudnason, Vilmundur and Klein, Ronald and Siscovick, David S and Rotter, Jerome I and Tai, E Shong and Vingerling, Johannes and Wong, Tien Y} } @article {6683, title = {Multiethnic genome-wide association study of cerebral white matter hyperintensities on MRI.}, journal = {Circ Cardiovasc Genet}, volume = {8}, year = {2015}, month = {2015 Apr}, pages = {398-409}, abstract = {

BACKGROUND: The burden of cerebral white matter hyperintensities (WMH) is associated with an increased risk of stroke, dementia, and death. WMH are highly heritable, but their genetic underpinnings are incompletely characterized. To identify novel genetic variants influencing WMH burden, we conducted a meta-analysis of multiethnic genome-wide association studies.

METHODS AND RESULTS: We included 21 079 middle-aged to elderly individuals from 29 population-based cohorts, who were free of dementia and stroke and were of European (n=17 936), African (n=1943), Hispanic (n=795), and Asian (n=405) descent. WMH burden was quantified on MRI either by a validated automated segmentation method or a validated visual grading scale. Genotype data in each study were imputed to the 1000 Genomes reference. Within each ethnic group, we investigated the relationship between each single-nucleotide polymorphism and WMH burden using a linear regression model adjusted for age, sex, intracranial volume, and principal components of ancestry. A meta-analysis was conducted for each ethnicity separately and for the combined sample. In the European descent samples, we confirmed a previously known locus on chr17q25 (P=2.7{\texttimes}10(-19)) and identified novel loci on chr10q24 (P=1.6{\texttimes}10(-9)) and chr2p21 (P=4.4{\texttimes}10(-8)). In the multiethnic meta-analysis, we identified 2 additional loci, on chr1q22 (P=2.0{\texttimes}10(-8)) and chr2p16 (P=1.5{\texttimes}10(-8)). The novel loci contained genes that have been implicated in Alzheimer disease (chr2p21 and chr10q24), intracerebral hemorrhage (chr1q22), neuroinflammatory diseases (chr2p21), and glioma (chr10q24 and chr2p16).

CONCLUSIONS: We identified 4 novel genetic loci that implicate inflammatory and glial proliferative pathways in the development of WMH in addition to previously proposed ischemic mechanisms.

}, keywords = {Aged, Aged, 80 and over, Chromosomes, Human, Continental Population Groups, Female, Genetic Loci, Genome-Wide Association Study, Humans, Male, Meta-Analysis as Topic, Middle Aged, Models, Genetic, Stroke, White Matter}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.114.000858}, author = {Verhaaren, Benjamin F J and Debette, Stephanie and Bis, Joshua C and Smith, Jennifer A and Ikram, M Kamran and Adams, Hieab H and Beecham, Ashley H and Rajan, Kumar B and Lopez, Lorna M and Barral, Sandra and van Buchem, Mark A and van der Grond, Jeroen and Smith, Albert V and Hegenscheid, Katrin and Aggarwal, Neelum T and de Andrade, Mariza and Atkinson, Elizabeth J and Beekman, Marian and Beiser, Alexa S and Blanton, Susan H and Boerwinkle, Eric and Brickman, Adam M and Bryan, R Nick and Chauhan, Ganesh and Chen, Christopher P L H and Chouraki, Vincent and de Craen, Anton J M and Crivello, Fabrice and Deary, Ian J and Deelen, Joris and De Jager, Philip L and Dufouil, Carole and Elkind, Mitchell S V and Evans, Denis A and Freudenberger, Paul and Gottesman, Rebecca F and Gu{\dh}nason, Vilmundur and Habes, Mohamad and Heckbert, Susan R and Heiss, Gerardo and Hilal, Saima and Hofer, Edith and Hofman, Albert and Ibrahim-Verbaas, Carla A and Knopman, David S and Lewis, Cora E and Liao, Jiemin and Liewald, David C M and Luciano, Michelle and van der Lugt, Aad and Martinez, Oliver O and Mayeux, Richard and Mazoyer, Bernard and Nalls, Mike and Nauck, Matthias and Niessen, Wiro J and Oostra, Ben A and Psaty, Bruce M and Rice, Kenneth M and Rotter, Jerome I and von Sarnowski, Bettina and Schmidt, Helena and Schreiner, Pamela J and Schuur, Maaike and Sidney, Stephen S and Sigurdsson, Sigurdur and Slagboom, P Eline and Stott, David J M and van Swieten, John C and Teumer, Alexander and T{\"o}glhofer, Anna Maria and Traylor, Matthew and Trompet, Stella and Turner, Stephen T and Tzourio, Christophe and Uh, Hae-Won and Uitterlinden, Andr{\'e} G and Vernooij, Meike W and Wang, Jing J and Wong, Tien Y and Wardlaw, Joanna M and Windham, B Gwen and Wittfeld, Katharina and Wolf, Christiane and Wright, Clinton B and Yang, Qiong and Zhao, Wei and Zijdenbos, Alex and Jukema, J Wouter and Sacco, Ralph L and Kardia, Sharon L R and Amouyel, Philippe and Mosley, Thomas H and Longstreth, W T and DeCarli, Charles C and van Duijn, Cornelia M and Schmidt, Reinhold and Launer, Lenore J and Grabe, Hans J and Seshadri, Sudha S and Ikram, M Arfan and Fornage, Myriam} } @article {7597, title = {Association of Diabetic Macular Edema and Proliferative Diabetic Retinopathy With Cardiovascular Disease: A Systematic Review and Meta-analysis.}, journal = {JAMA Ophthalmol}, volume = {135}, year = {2017}, month = {2017 Jun 01}, pages = {586-593}, abstract = {

Importance: Previous studies on the relationship between diabetic retinopathy (DR) and cardiovascular disease (CVD) focused on the early stages of DR. Understanding whether patients with type 2 diabetes and severe stages of DR (diabetic macular edema [DME] and proliferative diabetic retinopathy [PDR]) have a higher risk of CVD will allow physicians to more effectively counsel patients.

Objective: To examine the association of severe stages of DR (DME and PDR) with incident CVD in patients with type 2 diabetes.

Data Sources: English-language publications were reviewed for articles evaluating the relationship of DR and CVD in MEDLINE, EMBASE, Current Contents, and the Cochrane Library from inception (January 1, 1950) to December 31, 2014, using the search terms diabetic retinopathy OR macular edema AND stroke OR cerebrovascular disease OR coronary artery disease OR heart failure OR myocardial infarction OR angina pectoris OR acute coronary syndrome OR coronary artery disease OR cardiomyopathy.

Study Selection: Among 656 studies screened for eligibility, 7604 individuals were included from 8 prospective population-based studies with data on photographic-based DR grading, follow-up visits, and well-defined incident CVD end point.

Data Extraction and Synthesis: Two independent reviewers conducted a systematic search of the 4 databases, and a single pooled database was developed. Incidence rate ratios (IRRs) were estimated for patients with DME, PDR, and vision-threatening DR, compared with persons without these conditions, by using individual participant data followed by a standard inverse-variance meta-analysis (2-step analysis). The review and analyses were performed from January 1, 2009, to January 1, 2017.

Main Outcome and Measures: Incident CVD, including coronary heart disease, stroke, or death from cardiovascular causes.

Results: Among 7604 patients with type 2 diabetes, the prevalence of DME was 4.6\% and PDR, 7.4\%. After a mean follow-up of 5.9 years (range, 3.2-10.1 years), 1203 incident CVD events, including 916 coronary heart disease cases, were reported. Persons with DME or PDR were more likely to have incident CVD (IRR, 1.39; 95\% CI, 1.16-1.67) and fatal CVD (IRR, 2.33; 95\% CI, 1.49-3.67) compared with those without DME or PDR.

Conclusions and Relevance: Patients with type 2 diabetes and DME or PDR have an increased risk of incident CVD, which suggests that these persons should be followed up more closely to prevent CVD.

}, keywords = {Cardiovascular Diseases, Diabetic Retinopathy, Global Health, Humans, Incidence, Macular Edema, Risk Factors}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2017.0988}, author = {Xie, Jing and Ikram, M Kamran and Cotch, Mary Frances and Klein, Barbara and Varma, Rohit and Shaw, Jonathan E and Klein, Ronald and Mitchell, Paul and Lamoureux, Ecosse L and Wong, Tien Yin} }