@article {782, title = {Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the Sleep Heart Health Study.}, journal = {Sleep}, volume = {27}, year = {2004}, month = {2004 May 01}, pages = {467-73}, abstract = {

STUDY OBJECTIVE: Sleep apnea and milder forms of sleep-disordered breathing (SDB) have been associated with overt clinical cardiovascular disease, but it is unknown whether SDB is associated with arterial microvascular pathology. We examined the relation between SDB and retinal microvascular abnormalities.

DESIGN: Cross-sectional study.

PARTICIPANTS: Subjects were 2,927 men and women, aged 51 to 97 years, who participated in the Sleep Heart Health Study and had retinal photographs taken within approximately 3 years of overnight, unattended, at-home polysomnography.

MEASUREMENTS AND RESULTS: A respiratory disturbance index (RDI), calculated as the average number of apneas and hypopneas per hour of sleep, was used as an indicator of SDB in analysis. The overall prevalence of retinopathy was slightly higher in people with higher RDI values (5.4\%, 4.9\%, 8.6\%, and 7.6\%, respectively, in increasing quartiles of RDI), but after adjustment for age, body-mass index, hypertension, diabetes, and other factors, the presence of retinopathy was not associated with SDB. With the possible exceptions of microaneurysms and generalized arteriolar narrowing, as measured by lower arteriole-to-venule ratio, specific retinal abnormalities were not associated consistently with the RDI. Relative to the first quartile of RDI, the adjusted odds ratios (95\% confidence interval) for the presence of microaneurysm in the second, third, and fourth quartiles of RDI were 1.05 (0.44-2.55), 1.97 (0.89-4.37), and 1.79 (0.78-4.10), respectively. An increase of RDI from 0 to 10 was associated with a predicted decrease in arteriole-to-venule ratio of 0.01. Results were similar when analyses were conducted in normotensive and nondiabetic persons separately.

CONCLUSIONS: These data do not demonstrate a notable relation between SDB and retinal abnormalities. However, since this is the first investigation of a link between retinopathy and SDB, similar studies should be conducted in other population samples to demonstrate either consistency or inconsistency of our findings across studies.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Coronary Disease, Cross-Sectional Studies, Female, Humans, Hypoxia, Middle Aged, Polysomnography, Positive-Pressure Respiration, Retina, Retinal Vessels, Sleep Apnea Syndromes}, issn = {0161-8105}, doi = {10.1093/sleep/27.3.467}, author = {Boland, Lori L and Shahar, Eyal and Wong, Tien Y and Klein, Ronald and Punjabi, Naresh and Robbins, John A and Newman, Anne B} } @article {854, title = {Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study.}, journal = {Am J Kidney Dis}, volume = {46}, year = {2005}, month = {2005 Aug}, pages = {214-24}, abstract = {

BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals.

METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling.

RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20\% or greater decline in eGFR (odds ratio, 3.20; 95\% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95\% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function.

CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.

}, keywords = {African Americans, Aged, Aged, 80 and over, Aging, Antihypertensive Agents, Capillaries, Cohort Studies, Comorbidity, Creatinine, Diabetes Mellitus, Disease Progression, European Continental Ancestry Group, Female, Glomerular Filtration Rate, Humans, Hypertension, Kidney, Male, Photography, Prospective Studies, Proteinuria, Retina, Retinal Diseases, Retinal Vessels}, issn = {1523-6838}, doi = {10.1053/j.ajkd.2005.05.005}, author = {Edwards, Matthew S and Wilson, David B and Craven, Timothy E and Stafford, Jeanette and Fried, Linda F and Wong, Tien Y and Klein, Ronald and Burke, Gregory L and Hansen, Kimberley J} } @article {935, title = {Apolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study.}, journal = {Arch Ophthalmol}, volume = {125}, year = {2007}, month = {2007 Jan}, pages = {68-73}, abstract = {

OBJECTIVE: To examine the association between the apolipoprotein E (APOE) gene and age-related maculopathy (ARM) in an older population.

METHODS: Two thousand one hundred seventy persons 65 years and older sampled from 4 US communities had ARM signs assessed from retinal photographs using a modified Wisconsin Age-Related Maculopathy Grading System. DNA extracted from blood samples was analyzed for common APOE alleles.

RESULTS: After controlling for age, sex, cigarette smoking, and other factors, white participants carrying the epsilon2 allele had an increased risk of late ARM (odds ratio, 2.53 [95\% confidence interval, 1.08-5.90]) while carriers of the epsilon4 allele had a lower risk of late ARM (odds ratio, 0.69 [95\% confidence interval, 0.19-2.50]). There were too few late ARM cases in African American individuals for analysis.

CONCLUSION: APOE polymorphism is associated with late ARM in older white persons 65 years and older. Consistent with previous studies, the APOE epsilon2 allele is associated with a significant increased risk of late ARM development, whereas the epsilon4 allele may confer some protection.

}, keywords = {African Americans, Aged, Aged, 80 and over, Alleles, Apolipoprotein E2, Apolipoprotein E3, Apolipoprotein E4, Cardiovascular Diseases, European Continental Ancestry Group, Female, Genotype, Humans, Macular Degeneration, Male, Odds Ratio, Polymorphism, Genetic, Risk Factors}, issn = {0003-9950}, doi = {10.1001/archopht.125.1.68}, author = {Tikellis, Gabriella and Sun, Cong and Gorin, Michael B and Klein, Ronald and Klein, Barbara E K and Larsen, Emily K Marino and Siscovick, David S and Hubbard, Larry D and Wong, Tien Y} } @article {1003, title = {Apolipoprotein E gene and retinal microvascular signs in older people: the Cardiovascular Health Study.}, journal = {Mol Vis}, volume = {13}, year = {2007}, month = {2007 Nov 12}, pages = {2105-11}, abstract = {

PURPOSE: To examine the association between apolipoprotein E (APOE) gene polymorphism and retinal microvascular signs in an older population.

METHODS: Retinal photographs were taken of 2,152 participants (1,831 whites, and 321 African-Americans), aged 69-96 years, who were participating in a population-based study of four United States communities. We used standardized protocols to assess photographs for the presence of retinal microvascular signs (retinopathy, arterio-venous nicking, and focal arteriolar narrowing) and a computer-assisted method to measure retinal vessel diameters. We analyzed DNA extracted from blood samples of participants for common allelic variants of the APOE gene.

RESULTS: After adjusting for age, gender, systolic blood pressure, smoking, total serum cholesterol, and other risk factors, we found white participants carrying the epsilon2 and epsilon4 alleles were more likely to have arterio-venous nicking than the epsilon3/epsilon3 homozygotes, with odds ratio (OR) of 1.70 and confidence interval (CI) 95\% (1.03-2.83) for the epsilon2 carriers and OR 1.74 (95\% CI 1.06-2.84) for the epsilon4 carriers. Among white participants without hypertension, the associations remained significant for the epsilon4 carriers (OR 2.32, 95\% CI 1.18-4.57). Whites, normotensive carriers of the epsilon2 allele had significantly narrower retinal arteriolar diameters (adjusted mean arteriolar diameter of 163.5 mum, 95\% CI 160.1-167.0, p=0.03) compared to the epsilon3/epsilon3 homozygotes (167.8 mum, 95\% CI 166.0-169.6). APOE gene polymorphism was not associated with retinopathy, focal narrowing, or retinal venular diameters in white participants. There were insufficient numbers of African-Americans for separate multivariate analysis.

CONCLUSIONS: This study provides little evidence that the APOE gene polymorphism plays a significant role in the pathogenesis of retinal microvascular changes in the general population. In the older white population, APOE epsilon2 and epsilon4 allele carriers were more likely to have arterio-venous nicking. Other retinal signs, however, were not related to APOE gene polymorphism.

}, keywords = {Aged, Aged, 80 and over, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, European Continental Ancestry Group, Female, Gene Frequency, Genotype, Heterozygote, Homozygote, Humans, Male, Microcirculation, Polymorphism, Genetic, Retinal Diseases, Retinal Vessels}, issn = {1090-0535}, author = {Sun, Cong and Tikellis, Gabriella and Liew, Gerald and Klein, Ronald and Larsen, Emily K Marino and Wong, Tien Y} } @article {949, title = {Are microvascular abnormalities in the retina associated with depression symptoms? The Cardiovascular Health Study.}, journal = {Am J Geriatr Psychiatry}, volume = {15}, year = {2007}, month = {2007 Apr}, pages = {335-43}, abstract = {

OBJECTIVE: Depression has been linked with vascular risk factors and stroke. The authors examined the relationship between retinal microvascular abnormalities and depression symptoms in an elderly population.

METHODS: The Cardiovascular Health Study is a population-based study conducted in four U.S. communities initiated in 1989-1990. A total of 2,420 persons aged 65 years and older were included in the current analyses. During the 1997-1998 examination, retinal photographs were performed and assessed for retinal microvascular abnormalities (retinopathy, focal arteriolar narrowing, arteriovenous nicking, generalized retinal arteriolar narrowing, and generalized retinal venular dilation) according to standardized methods. Depression symptoms were assessed by a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998 and was defined as a CES-D score of >9.

RESULTS: Participants with retinal microvascular abnormalities were not more likely to have depression symptoms, with adjusted odds ratio (OR) (95\% confidence intervals) of 1.08 (0.71-1.65) for retinopathy, OR 1.09 (0.71-1.68) for focal arteriolar narrowing, OR 0.85 (0.52-1.40) for arteriovenous nicking, OR 0.97 (0.70-1.34) for generalized arteriolar narrowing, and OR 0.79 (0.56-1.12) for generalized venular dilation. Retinal microvascular abnormalities were not related to depression symptoms in multinomial logistic regression comparing the three top quartiles of the depression CES-D scores with the lowest quartile.

CONCLUSIONS: Our study did not find an association between retinal microvascular abnormalities and depression symptoms in older people.

}, keywords = {Aged, Aged, 80 and over, Body Mass Index, Cardiovascular Diseases, Cohort Studies, Comorbidity, Cross-Sectional Studies, Depression, Female, Fluorescein Angiography, Humans, Male, Microcirculation, Personality Inventory, Retinal Artery Occlusion, Retinal Diseases, Retinal Vein Occlusion, Risk Factors, Statistics as Topic, United States}, issn = {1064-7481}, doi = {10.1097/01.JGP.0000247161.98311.0f}, author = {Sun, Cong and Tikellis, Gabriella and Klein, Ronald and Steffens, David C and Larsen, Emily K Marino and Siscovick, David S and Klein, Barbara E K and Wong, Tien Y} } @article {968, title = {Depressive symptoms and age-related macular degeneration in older people: the cardiovascular health study.}, journal = {Ophthalmic Epidemiol}, volume = {14}, year = {2007}, month = {2007 May-Jun}, pages = {127-33}, abstract = {

PURPOSE: To examine the association between age-related macular degeneration (AMD) and depressive symptoms.

METHODS: Population-based, cross-sectional study. A total of 2,194 persons aged 69-97 years were included in the current analyses. During the 1997-1998 examination, retinal photography from one randomly selected eye was graded for presence of early and late AMD using a modified Wisconsin AMD by Grading System. Depressive symptoms were assessed via a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998. Depressive symptoms were defined as a CES-D score of >9 (top quartile of CES-D score) at the 1997-1998 examination.

RESULTS: There were 338 (15.6\%) individuals with early AMD and 29 (1.3\%) with late AMD. Among them, 368 (16.8\%) persons had depressive symptoms at the 1997-1998 examination. Depressive symptoms were not associated with early AMD (multivariable adjusted odds ratio [OR]: 0.97; 95\% confidence intervals [CI]: 0.69-1.36) or late AMD (OR: 1.15; 95\% CI: 0.38-3.46). Including persons using anti-depressive medications did not alter these associations (OR: 0.98; 95\% CI: 0.74-1.32 for early AMD and OR: 0.97; 95\% CI: 0.35-2.67 for late AMD). There was no association in multinomial logistic regression models of increasing quartiles of the CES-D scores with early or late AMD status.

CONCLUSIONS: Our study did not find an association between early AMD and depressive symptoms in older people.

}, keywords = {Aged, Aged, 80 and over, Cardiovascular Diseases, Cross-Sectional Studies, Depressive Disorder, Female, Health Surveys, Humans, Intelligence Tests, Macular Degeneration, Male, Photography, United States}, issn = {0928-6586}, doi = {10.1080/09286580601186742}, author = {Sun, Cong and Tikellis, Gabriella and Klein, Ronald and Steffens, David C and Larsen, Emily K Marino and Wong, Tien Y} } @article {1111, title = {Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study.}, journal = {Ophthalmology}, volume = {116}, year = {2009}, month = {2009 Oct}, pages = {1913-9}, abstract = {

PURPOSE: To examine the associations of age-related macular degeneration (AMD) with incident coronary heart disease (CHD) and stroke in the Cardiovascular Health Study.

DESIGN: Population-based prospective cohort study.

PARTICIPANTS: A total of 1786 white and African-American participants free of CHD or 2228 participants free of stroke, aged 69 to 97 years.

METHODS: AMD was evaluated from photographs taken in 1997 and 1998.

MAIN OUTCOME MEASURES: Incident CHD and stroke ascertained using standardized methods.

RESULTS: Of the 1786 persons free of CHD, 303 developed incident CHD over 7 years. Participants with early AMD (n = 277) had a higher cumulative incidence of CHD than participants without early AMD (25.8\% vs. 18.9\%, P = 0.001). By adjusting for age, gender, race, systolic and diastolic blood pressure, hypertension status, fasting glucose, triglyceride, low-density lipoprotein cholesterol, cigarette smoking, pack years of smoking, and C-reactive protein, the presence of early AMD was associated with an increased risk of incident CHD (hazard ratio 1.57; 95\% confidence interval, 1.17-2.22). Late AMD (n = 25) was not associated with incident CHD (hazard ratio 0.78; 95\% confidence interval, 0.25-2.48). Among 2228 persons at risk, 198 developed incident stroke; neither early nor late AMD was associated with incident stroke.

CONCLUSIONS: This study suggests persons with early AMD have a higher risk of CHD but not stroke in a population aged 69 to 97 years. This provides further support that AMD is associated with underlying systemic vascular disease.

}, keywords = {African Americans, Age Factors, Aged, Aged, 80 and over, Blood Pressure, Cholesterol, LDL, Coronary Disease, European Continental Ancestry Group, Female, Humans, Incidence, Macular Degeneration, Male, Prospective Studies, Risk Factors, Sex Factors, Stroke, Triglycerides, United States}, issn = {1549-4713}, doi = {10.1016/j.ophtha.2009.03.046}, author = {Sun, Cong and Klein, Ronald and Wong, Tien Y} } @article {1129, title = {Meta-analysis: retinal vessel caliber and risk for coronary heart disease.}, journal = {Ann Intern Med}, volume = {151}, year = {2009}, month = {2009 Sep 15}, pages = {404-13}, abstract = {

BACKGROUND: Retinal vessel caliber may be a novel marker of coronary heart disease (CHD) risk. However, the sex-specific effect, magnitude of association, and effect independent of traditional CHD disease risk factors remain unclear.

PURPOSE: To determine the association between retinal vessel caliber and risk for CHD.

DATA SOURCES: Relevant studies in any language identified through MEDLINE (1950 to June 2009) and EMBASE (1950 to June 2009) databases.

STUDY SELECTION: Studies were included if they examined a general population, measured retinal vessel caliber from retinal photographs, and documented CHD risk factors and incident CHD events.

DATA EXTRACTION: 6 population-based prospective cohort studies provided data for individual participant meta-analysis.

DATA SYNTHESIS: Proportional hazards models, adjusted for traditional CHD risk factors, were constructed for retinal vessel caliber and incident CHD in women and men. Among 22,159 participants who were free of CHD and followed for 5 to 14 years, 2219 (10.0\%) incident CHD events occurred. Retinal vessel caliber changes (wider venules and narrower arterioles) were each associated with an increased risk for CHD in women (pooled multivariable-adjusted hazard ratios, 1.16 [95\% CI, 1.06 to 1.26] per 20-microm increase in venular caliber and 1.17 [CI, 1.07 to 1.28] per 20-microm decrease in arteriolar caliber) but not in men (1.02 [CI, 0.94 to 1.10] per 20-microm increase in venular caliber and 1.02 [CI, 0.95 to 1.10] per 20-microm decrease in arteriolar caliber). Women without hypertension or diabetes had higher hazard ratios.

LIMITATION: Error in the measurement of retinal vessel caliber and Framingham variables was not taken into account.

CONCLUSION: Retinal vessel caliber changes were independently associated with an increased risk for CHD events in women.

}, keywords = {Adult, Aged, Arterioles, Biomarkers, Coronary Disease, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Retinal Vessels, Risk Factors, Sex Factors, Venules}, issn = {1539-3704}, author = {McGeechan, Kevin and Liew, Gerald and Macaskill, Petra and Irwig, Les and Klein, Ronald and Klein, Barbara E K and Wang, Jie Jin and Mitchell, Paul and Vingerling, Johannes R and Dejong, Paulus T V M and Witteman, Jacqueline C M and Breteler, Monique M B and Shaw, Jonathan and Zimmet, Paul and Wong, Tien Y} } @article {1142, title = {Prediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis.}, journal = {Am J Epidemiol}, volume = {170}, year = {2009}, month = {2009 Dec 01}, pages = {1323-32}, abstract = {

The caliber of the retinal vessels has been shown to be associated with stroke events. However, the consistency and magnitude of association, and the changes in predicted risk independent of traditional risk factors, are unclear. To determine the association between retinal vessel caliber and the risk of stroke events, the investigators combined individual data from 20,798 people, who were free of stroke at baseline, in 6 cohort studies identified from a search of the Medline (National Library of Medicine, Bethesda, Maryland) and EMBASE (Elsevier B.V., Amsterdam, the Netherlands) databases. During follow-up of 5-12 years, 945 (4.5\%) incident stroke events were recorded. Wider retinal venular caliber predicted stroke (pooled hazard ratio = 1.15, 95\% confidence interval: 1.05, 1.25 per 20-micron increase in caliber), but the caliber of retinal arterioles was not associated with stroke (pooled hazard ratio = 1.00, 95\% confidence interval: 0.92, 1.08). There was weak evidence of heterogeneity in the hazard ratio for retinal venular caliber, which may be attributable to differences in follow-up strategies across studies. Inclusion of retinal venular caliber in prediction models containing traditional stroke risk factors reassigned 10.1\% of people at intermediate risk into different, mostly lower, risk categories.

}, keywords = {Aged, Fluorescein Angiography, Humans, Middle Aged, Predictive Value of Tests, Proportional Hazards Models, Retinal Artery, Retinal Vein, Retinal Vessels, Risk Factors, Stroke}, issn = {1476-6256}, doi = {10.1093/aje/kwp306}, author = {McGeechan, Kevin and Liew, Gerald and Macaskill, Petra and Irwig, Les and Klein, Ronald and Klein, Barbara E K and Wang, Jie Jin and Mitchell, Paul and Vingerling, Johannes R and de Jong, Paulus T V M and Witteman, Jacqueline C M and Breteler, Monique M B and Shaw, Jonathan and Zimmet, Paul and Wong, Tien Y} } @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 {6555, title = {Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study.}, journal = {Circ Cardiovasc Genet}, volume = {7}, year = {2014}, month = {2014 Jun}, pages = {374-382}, abstract = {

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38{\texttimes}) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9\% of which were rare (minor allele frequency <1\%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73{\texttimes}10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28{\texttimes}10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6\% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

}, keywords = {Aged, Aged, 80 and over, Aging, Blood Glucose, Chromosomes, Human, Pair 11, Cohort Studies, Death Domain Receptor Signaling Adaptor Proteins, Diabetes Mellitus, Type 2, Fasting, Female, Gene Frequency, Genetic Variation, Genome-Wide Association Study, Genomics, Guanine Nucleotide Exchange Factors, Heart Diseases, Humans, Insulin, Male, Middle Aged, Polymorphism, Single Nucleotide, Sequence Analysis, DNA}, issn = {1942-3268}, doi = {10.1161/CIRCGENETICS.113.000169}, author = {Cornes, Belinda K and Brody, Jennifer A and Nikpoor, Naghmeh and Morrison, Alanna C and Chu, Huan and Ahn, Byung Soo and Wang, Shuai and Dauriz, Marco and Barzilay, Joshua I and Dupuis, Jos{\'e}e and Florez, Jose C and Coresh, Josef and Gibbs, Richard A and Kao, W H Linda and Liu, Ching-Ti and McKnight, Barbara and Muzny, Donna and Pankow, James S and Reid, Jeffrey G and White, Charles C and Johnson, Andrew D and Wong, Tien Y and Psaty, Bruce M and Boerwinkle, Eric and Rotter, Jerome I and Siscovick, David S and Sladek, Robert and Meigs, James B} } @article {7019, title = {Genetic determinants of age-related macular degeneration in diverse populations from the PAGE study.}, journal = {Invest Ophthalmol Vis Sci}, volume = {55}, year = {2014}, month = {2014 Sep 9}, pages = {6839-50}, abstract = {

PURPOSE: Substantial progress has been made in identifying susceptibility variants for AMD in European populations; however, few studies have been conducted to understand the role these variants play in AMD risk in diverse populations. The present study aims to examine AMD risk across diverse populations in known and suspected AMD complement factor and lipid-related loci.

METHODS: Targeted genotyping was performed across study sites for AMD and lipid trait-associated single nucleotide polymorphism (SNPs). Genetic association tests were performed at individual sites and then meta-analyzed using logistic regression assuming an additive genetic model stratified by self-described race/ethnicity. Participants included cases with early or late AMD and controls with no signs of AMD as determined by fundus photography. Populations included in this study were European Americans, African Americans, Mexican Americans, and Singaporeans from the Population Architecture using Genomics and Epidemiology (PAGE) study.

RESULTS: Index variants of AMD, rs1061170 (CFH) and rs10490924 (ARMS2), were associated with AMD at P=3.05{\texttimes}10(-8) and P=6.36{\texttimes}10(-6), respectively, in European Americans. In general, none of the major AMD index variants generalized to our non-European populations with the exception of rs10490924 in Mexican Americans at an uncorrected P value<0.05. Four lipid-associated SNPS (LPL rs328, TRIB1 rs6987702, CETP rs1800775, and KCTD10/MVK rs2338104) were associated with AMD in African Americans and Mexican Americans (P<0.05), but these associations did not survive strict corrections for multiple testing.

CONCLUSIONS: While most associations did not generalize in the non-European populations, variants within lipid-related genes were found to be associated with AMD. This study highlights the need for larger well-powered studies in non-European populations.

}, keywords = {Adult, Aged, Aged, 80 and over, Complement Factor H, DNA, Ethnic Groups, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Macular Degeneration, Male, Middle Aged, Phenotype, Polymorphism, Single Nucleotide, Prevalence, Prospective Studies, Proteins, Risk Factors, United States}, issn = {1552-5783}, doi = {10.1167/iovs.14-14246}, author = {Restrepo, Nicole A and Spencer, Kylee L and Goodloe, Robert and Garrett, Tiana A and Heiss, Gerardo and B{\r u}zkov{\'a}, Petra and Jorgensen, Neal and Jensen, Richard A and Matise, Tara C and Hindorff, Lucia A and Klein, Barbara E K and Klein, Ronald and Wong, Tien Y and Cheng, Ching-Yu and Cornes, Belinda K and Tai, E-Shyong and Ritchie, Marylyn D and Haines, Jonathan L and Crawford, Dana C} } @article {6665, title = {Fibrosis-related biomarkers and large and small vessel disease: the Cardiovascular Health Study.}, journal = {Atherosclerosis}, volume = {239}, year = {2015}, month = {2015 Apr}, pages = {539-46}, abstract = {

OBJECTIVE: Fibrosis has been implicated in a number of pathological, organ-based conditions of the liver, kidney, heart, and lungs. The objective of this study was to determine whether biomarkers of fibrosis are associated with vascular disease in the large and/or small vessels.

METHODS: We evaluated the associations of two circulating biomarkers of fibrosis, transforming growth factor-β (TGF-β) and procollagen type III N-terminal propeptide (PIIINP), with incident peripheral artery disease (PAD) and subclinical macrovascular (carotid intima-media thickness, flow-mediated vasodilation, ankle-brachial index, retinal vein diameter), and microvascular (retinal artery diameter and retinopathy) disease among older adults in the Cardiovascular Health Study. We measured TGF-β and PIIINP from samples collected in 1996 and ascertained clinical PAD through 2011. Measurements of large and small vessels were collected between 1996 and 1998.

RESULTS: After adjustment for sociodemographic, clinical, and biochemical risk factors, TGF-β was associated with incident PAD (hazard ratio [HR]~=~1.36 per doubling of TGF-β, 95\% confidence interval [CI]~=~1.04, 1.78) and retinal venular diameter (1.63~μm per doubling of TGF-β, CI~=~0.23, 3.02). PIIINP was not associated with incident PAD, but was associated with carotid intima-media thickness (0.102~mm per doubling of PIIINP, CI~=~0.029, 0.174) and impaired brachial artery reactivity (-0.20\% change per doubling of PIIINP, CI~=~-0.39,~-0.02). Neither TGF-β nor PIIINP were associated with retinal arteriolar diameter or retinopathy.

CONCLUSIONS: Serum concentrations of fibrosis-related biomarkers were associated with several measures of large vessel disease, including incident PAD, but not with small vessel disease. Fibrosis may contribute to large vessel atherosclerosis in older adults.

}, keywords = {Aged, Ankle Brachial Index, Biomarkers, Brachial Artery, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cross-Sectional Studies, Female, Fibrosis, Humans, Incidence, Male, Peptide Fragments, Peripheral Arterial Disease, Predictive Value of Tests, Procollagen, Prognosis, Prospective Studies, Retinal Diseases, Risk Factors, Transforming Growth Factor beta, United States, Vasodilation}, issn = {1879-1484}, doi = {10.1016/j.atherosclerosis.2015.02.020}, author = {Agarwal, Isha and Arnold, Alice and Glazer, Nicole L and Barasch, Eddy and Djouss{\'e}, Luc and Fitzpatrick, Annette L and Gottdiener, John S and Ix, Joachim H and Jensen, Richard A and Kizer, Jorge R and Rimm, Eric B and Siscovick, David S and Tracy, Russell P and Wong, Tien Y and Mukamal, Kenneth J} } @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} }