03306nas a2200493 4500008004100000022001400041245007000055210006800125260001300193300001000206490000800216520195600224653003902180653000902219653002202228653002102250653001902271653002302290653001502313653001902328653000902347653004002356653001102396653001102407653001702418653002002435653002502455653002502480653000902505653002402514653001902538653001502557653002402572653001702596653001802613100001802631700002402649700002102673700002102694700001802715700002202733700002202755856003502777 2003 eng d a0161-642000aEarly age-related maculopathy in the cardiovascular health study.0 aEarly agerelated maculopathy in the cardiovascular health study c2003 Jan a25-330 v1103 a
OBJECTIVE: To describe the prevalence of early age-related maculopathy (ARM) and its relation to atherosclerosis, lipids, hypertension, and inflammatory factors in a population studied for cardiovascular disease risk factors and outcomes.
DESIGN: Population-based cohort study.
PARTICIPANTS: A biracial population of 2361 adults (ranging from 69-97 years of age; 1998 whites and 363 blacks) living in four US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were examined during the interval from 1997 to 1998.
METHODS: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of one eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System.
MAIN OUTCOME MEASURES: Early ARM.
RESULTS: Early ARM was present in 15.5% and late ARM in 1.3% of the cohort. The overall prevalence of any ARM was lower in blacks (9.1%) compared with whites (18.2%). While controlling for age, race, gender, and total calories consumed in the diet, factors associated with ARM were cerebral white matter disease as detected by magnetic resonance imaging (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.05, 2.16, P = 0.027), and lower serum total cholesterol (OR, per 10 mg/dl increase 0.95; 95% CI, 0.91, 0.98, P = 0.02). There were no associations between hypertension, blood pressure, common carotid artery plaque, or any systemic inflammatory factors studied and early ARM.
CONCLUSIONS: This population-based study documents the higher prevalence of ARM in whites compared with blacks. Although an association was found between signs of white matter disease and early ARM, there was no evidence of an association of ARM with either hypertension or inflammatory factors.
10aAfrican Continental Ancestry Group10aAged10aAged, 80 and over10aArteriosclerosis10aBlood Pressure10aC-Reactive Protein10aCalifornia10aCohort Studies10aDiet10aEuropean Continental Ancestry Group10aFemale10aHumans10aHypertension10aLeukocyte Count10aLongitudinal Studies10aMacular Degeneration10aMale10aMid-Atlantic Region10aNorth Carolina10aPrevalence10aProspective Studies10aRisk Factors10aSerum Albumin1 aKlein, Ronald1 aKlein, Barbara, E K1 aMarino, Emily, K1 aKuller, Lewis, H1 aFurberg, Curt1 aBurke, Gregory, L1 aHubbard, Larry, D uhttps://chs-nhlbi.org/node/71803855nas a2200481 4500008004100000022001400041245015500055210006900210260001300279300001000292490000800302520246000310653000902770653002202779653001502801653001902816653002802835653002102863653002802884653002802912653001302940653001102953653001502964653001102979653001702990653001903007653000903026653002703035653001603062653001903078653002703097653001703124100002003141700002803161700001803189700001903207700002103226700002403247700002203271700002403293700002103317856003503338 2005 eng d a1549-471300aCardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies.0 aCardiovascular risk factors for retinal vein occlusion and arter c2005 Apr a540-70 v1123 aOBJECTIVE: To examine the associations of retinal vein occlusion and arteriolar emboli with cardiovascular disease.
DESIGN: Population-based cross-sectional study.
PARTICIPANTS: Pooled from the Atherosclerosis Risk in Communities Study (n = 12,642; mean age, 60 years) and the Cardiovascular Health Study (n = 2824; mean age, 79 years).
METHODS: Retinal vein occlusion and arteriolar emboli were identified from a single nonmydriatic retinal photograph using a standardized protocol. Photographs were also graded for arteriovenous nicking and focal arteriolar narrowing. All participants had a comprehensive systemic evaluation, including standardized carotid ultrasonography.
MAIN OUTCOME MEASURES: Retinal vein occlusion and arteriolar emboli.
RESULTS: Prevalences of retinal vein occlusion and arteriolar emboli were 0.3% (n = 39 cases) and 0.2% (n = 34 cases), respectively. After adjusting for age, retinal vein occlusion was associated with hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI], 1.43-6.14), systolic blood pressure (BP) (OR, 4.12; 95% CI, 1.40-12.16; highest quartile vs. lowest), diastolic BP (OR, 2.64; 95% CI, 1.07-6.46; highest quartile vs. lowest), carotid artery plaque (OR, 5.62; 95% CI, 2.60-12.16), body mass index (OR, 3.88; 95% CI, 1.23-12.18; highest quartile vs. lowest), plasma fibrinogen (OR, 3.29; 95% CI, 1.08-10.02; highest quartile vs. lowest), arteriovenous nicking (OR, 4.09; 95% CI, 2.00-8.36), and focal arteriolar narrowing (OR, 5.17; 95% CI, 2.59-10.29). After adjusting for age, retinal arteriolar emboli were associated with hypertension (OR, 3.14; 95% CI, 1.44-6.84), systolic BP (OR, 3.46; 95% CI, 1.13-10.65; highest quartile vs. lowest), prevalent coronary heart disease (OR, 2.33; 95% CI, 1.01-5.42), carotid artery plaque (OR, 4.62; 95% CI, 1.85-11.57), plasma lipoprotein (a) (OR, 3.69; 95% CI, 1.20-11.41; highest quartile vs. lowest), plasma fibrinogen (OR, 3.09; 95% CI, 0.98-9.76; highest quartile vs. lowest), and current cigarette smoking (OR, 3.08; 95% CI, 1.47-6.47). Approximately a quarter of participants with retinal vein occlusion and arteriolar emboli had evidence of carotid artery plaque as defined from ultrasound.
CONCLUSIONS: Retinal vein occlusion and retinal arteriolar emboli are associated with carotid artery disease, hypertension, and other cardiovascular risk factors.
10aAged10aAged, 80 and over10aArterioles10aBlood Pressure10aCardiovascular Diseases10aCarotid Stenosis10aCoronary Artery Disease10aCross-Sectional Studies10aEmbolism10aFemale10aFibrinogen10aHumans10aHypertension10aLipoprotein(a)10aMale10aMeta-Analysis as Topic10aMiddle Aged10aRetinal Artery10aRetinal Vein Occlusion10aRisk Factors1 aWong, Tien, Yin1 aLarsen, Emily, K Marino1 aKlein, Ronald1 aMitchell, Paul1 aCouper, David, J1 aKlein, Barbara, E K1 aHubbard, Larry, D1 aSiscovick, David, S1 aSharrett, Richey uhttps://chs-nhlbi.org/node/82602454nas a2200445 4500008004100000022001400041245010900055210006900164260001300233300001000246490000800256520118900264653002201453653000901475653002201484653001201506653002201518653002201540653002201562653002801584653004001612653001101652653001301663653001101676653002501687653000901712653001501721653002601736653001701762100002401779700001401803700002201817700001801839700002401857700002801881700002401909700002201933700001801955856003501973 2007 eng d a0003-995000aApolipoprotein e gene and age-related maculopathy in older individuals: the cardiovascular health study.0 aApolipoprotein e gene and agerelated maculopathy in older indivi c2007 Jan a68-730 v1253 aOBJECTIVE: 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.
10aAfrican Americans10aAged10aAged, 80 and over10aAlleles10aApolipoprotein E210aApolipoprotein E310aApolipoprotein E410aCardiovascular Diseases10aEuropean Continental Ancestry Group10aFemale10aGenotype10aHumans10aMacular Degeneration10aMale10aOdds Ratio10aPolymorphism, Genetic10aRisk Factors1 aTikellis, Gabriella1 aSun, Cong1 aGorin, Michael, B1 aKlein, Ronald1 aKlein, Barbara, E K1 aLarsen, Emily, K Marino1 aSiscovick, David, S1 aHubbard, Larry, D1 aWong, Tien, Y uhttps://chs-nhlbi.org/node/93503099nas a2200469 4500008004100000022001400041245012000055210006900175260001300244300001100257490000700268520174700275653000902022653002202031653002002053653002802073653001902101653001602120653002802136653001502164653001102179653002802190653001102218653000902229653002102238653002602259653002902285653002102314653002702335653001702362653002402379653001802403100001402421700002402435700001802459700002302477700002802500700002402528700002402552700001802576856003502594 2007 eng d a1064-748100aAre microvascular abnormalities in the retina associated with depression symptoms? The Cardiovascular Health Study.0 aAre microvascular abnormalities in the retina associated with de c2007 Apr a335-430 v153 aOBJECTIVE: 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.
10aAged10aAged, 80 and over10aBody Mass Index10aCardiovascular Diseases10aCohort Studies10aComorbidity10aCross-Sectional Studies10aDepression10aFemale10aFluorescein Angiography10aHumans10aMale10aMicrocirculation10aPersonality Inventory10aRetinal Artery Occlusion10aRetinal Diseases10aRetinal Vein Occlusion10aRisk Factors10aStatistics as Topic10aUnited States1 aSun, Cong1 aTikellis, Gabriella1 aKlein, Ronald1 aSteffens, David, C1 aLarsen, Emily, K Marino1 aSiscovick, David, S1 aKlein, Barbara, E K1 aWong, Tien, Y uhttps://chs-nhlbi.org/node/94903109nas a2200409 4500008004100000022001400041245011700055210006900172260001300241300001100254490000700265520193500272653000902207653002202216653002802238653001402266653002802280653001302308653001102321653001102332653002502343653000902368653002102377653002902398653002002427653001702447100002302464700002802487700002102515700001802536700002402554700002402578700002102602700002102623700002002644856003502664 2007 eng d a1524-462800aRetinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study.0 aRetinal microvascular signs cognitive function and dementia in o c2007 Jul a2041-70 v383 aBACKGROUND AND PURPOSE: Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals.
METHODS: In the population-based Cardiovascular Health Study, 2211 persons aged 69 to 97 years at recruitment had retinal photography. Photographs were evaluated for retinopathy (eg, microaneurysms, retinal hemorrhages), focal arteriolar narrowing, arteriovenous nicking, and retinal arteriolar and venular caliber. Cognitive status was determined from the Digit-Symbol Substitution Test and Modified Mini-Mental State Examination. Participants were also further evaluated for the presence of dementia with detailed neuropsychological testing. Persons with a prior stroke or taking antipsychotic or antidepressant medications were excluded.
RESULTS: After adjusting for age, gender, race, field center, education level, internal carotid intima-media thickness, body mass index, hypertension, diabetes, and cigarette smoking status, persons with retinopathy had lower mean Digit-Symbol Substitution Test scores but not Modified Mini-Mental State Examination than those without retinopathy (39 versus 41, P=0.002). In hypertensive persons, retinopathy (multivariable-adjusted OR, 2.10; 95% CI, 1.04 to 4.24) and focal arteriolar narrowing (OR, 3.02; 95% CI, 1.51 to 6.02) were associated with dementia. These associations were not present in individuals without hypertension.
CONCLUSIONS: In older persons, our study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia. These data support a possible role of cerebral microvascular disease in the pathogenesis of impaired cognitive function and dementia in older hypertensive persons.
10aAged10aAged, 80 and over10aCardiovascular Diseases10aCognition10aCross-Sectional Studies10aDementia10aFemale10aHumans10aLongitudinal Studies10aMale10aMicrocirculation10aNeuropsychological Tests10aRetinal Vessels10aRisk Factors1 aBaker, Michelle, L1 aLarsen, Emily, K Marino1 aKuller, Lewis, H1 aKlein, Ronald1 aKlein, Barbara, E K1 aSiscovick, David, S1 aBernick, Charles1 aManolio, Teri, A1 aWong, Tien, Yin uhttps://chs-nhlbi.org/node/96503237nas a2200481 4500008004100000022001400041245007900055210006900134260001600203300001100219490000800230520194800238653001002186653000902196653001502205653001502220653002102235653001102256653001102267653000902278653001602287653003202303653002002335653001702355653001602372653001202388100002102400700001702421700002102438700001502459700001802474700002402492700001902516700001902535700002802554700002602582700003002608700002702638700001902665700001702684700001802701856003602719 2009 eng d a1539-370400aMeta-analysis: retinal vessel caliber and risk for coronary heart disease.0 aMetaanalysis retinal vessel caliber and risk for coronary heart c2009 Sep 15 a404-130 v1513 aBACKGROUND: 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.
10aAdult10aAged10aArterioles10aBiomarkers10aCoronary Disease10aFemale10aHumans10aMale10aMiddle Aged10aProportional Hazards Models10aRetinal Vessels10aRisk Factors10aSex Factors10aVenules1 aMcGeechan, Kevin1 aLiew, Gerald1 aMacaskill, Petra1 aIrwig, Les1 aKlein, Ronald1 aKlein, Barbara, E K1 aWang, Jie, Jin1 aMitchell, Paul1 aVingerling, Johannes, R1 aDejong, Paulus, T V M1 aWitteman, Jacqueline, C M1 aBreteler, Monique, M B1 aShaw, Jonathan1 aZimmet, Paul1 aWong, Tien, Y uhttps://chs-nhlbi.org/node/112902649nas a2200445 4500008004100000022001400041245013600055210006900191260001600260300001200276490000800288520134100296653000901637653002801646653001101674653001601685653003001701653003201731653001901763653001701782653002001799653001701819653001101836100002101847700001701868700002101885700001501906700001801921700002401939700001901963700001901982700002802001700002702029700003002056700002702086700001902113700001702132700001802149856003602167 2009 eng d a1476-625600aPrediction of incident stroke events based on retinal vessel caliber: a systematic review and individual-participant meta-analysis.0 aPrediction of incident stroke events based on retinal vessel cal c2009 Dec 01 a1323-320 v1703 aThe 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.
10aAged10aFluorescein Angiography10aHumans10aMiddle Aged10aPredictive Value of Tests10aProportional Hazards Models10aRetinal Artery10aRetinal Vein10aRetinal Vessels10aRisk Factors10aStroke1 aMcGeechan, Kevin1 aLiew, Gerald1 aMacaskill, Petra1 aIrwig, Les1 aKlein, Ronald1 aKlein, Barbara, E K1 aWang, Jie, Jin1 aMitchell, Paul1 aVingerling, Johannes, R1 ade Jong, Paulus, T V M1 aWitteman, Jacqueline, C M1 aBreteler, Monique, M B1 aShaw, Jonathan1 aZimmet, Paul1 aWong, Tien, Y uhttps://chs-nhlbi.org/node/114205209nas a2201129 4500008004100000022001400041245009100055210006900146260001600215300001300231490000600244520200900250653001502259653001002274653000902284653002202293653002802315653001002343653002102353653003202374653003202406653003102438653003102469653001902500653004002519653001102559653001702570653003402587653001102621653000902632653002702641653002102668653001602689653003602705653002002741653001602761100001802777700001702795700001702812700002302829700002502852700002002877700002002897700001902917700001802936700002402954700002702978700001703005700001703022700001903039700002803058700002603086700001903112700002703131700002303158700001503181700002003196700002603216700002203242700001903264700002203283700002003305700002303325700002403348700001903372700002203391700002203413700002003435700001603455700002203471700001803493700002603511700002103537700002203558700002403580700002003604700001703624700002203641700002303663700002803686700001703714700001903731700001603750700002703766700002103793700002303814700002203837700002203859700002103881700001903902700002403921700002403945700002803969700001803997710002804015856003604043 2010 eng d a1553-740400aFour novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo.0 aFour novel Loci 19q13 6q24 12q24 and 5q14 influence the microcir c2010 Oct 28 ae10011840 v63 aThere 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.
10aAdolescent10aAdult10aAged10aAged, 80 and over10aCardiovascular Diseases10aChild10aChild, Preschool10aChromosomes, Human, Pair 1210aChromosomes, Human, Pair 1910aChromosomes, Human, Pair 510aChromosomes, Human, Pair 610aCohort Studies10aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aHumans10aMale10aMeta-Analysis as Topic10aMicrocirculation10aMiddle Aged10aPolymorphism, Single Nucleotide10aRetinal Vessels10aYoung Adult1 aIkram, Kamran1 aSim, Xueling1 aXueling, Sim1 aJensen, Richard, A1 aCotch, Mary, Frances1 aHewitt, Alex, W1 aIkram, Arfan, M1 aWang, Jie, Jin1 aKlein, Ronald1 aKlein, Barbara, E K1 aBreteler, Monique, M B1 aCheung, Ning1 aLiew, Gerald1 aMitchell, Paul1 aUitterlinden, André, G1 aRivadeneira, Fernando1 aHofman, Albert1 ade Jong, Paulus, T V M1 aDuijn, Cornelia, M1 aKao, Linda1 aCheng, Ching-Yu1 aSmith, Albert, Vernon1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aJonasson, Fridbert1 aEiriksdottir, Gudny1 aAspelund, Thor1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aLi, Xiaohui1 aIyengar, Sudha, K1 aXi, Quansheng1 aSivakumaran, Theru, A1 aMackey, David, A1 aMacgregor, Stuart1 aMartin, Nicholas, G1 aYoung, Terri, L1 aBis, Josh, C1 aWiggins, Kerri, L1 aHeckbert, Susan, R1 aHammond, Christopher, J1 aAndrew, Toby1 aFahy, Samantha1 aAttia, John1 aHolliday, Elizabeth, G1 aScott, Rodney, J1 aIslam, F, M Amirul1 aRotter, Jerome, I1 aMcAuley, Annie, K1 aBoerwinkle, Eric1 aTai, Shyong, E1 aGudnason, Vilmundur1 aSiscovick, David, S1 aVingerling, Johannes, R1 aWong, Tien, Y1 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/124304387nas a2201021 4500008004100000022001400041245005800055210005700113260000900170300001100179490000600190520154700196653000901743653002201752653001501774653003101789653004001820653001101860653001701871653003401888653001301922653001101935653000901946653003101955653002101986653001602007653002002023653002002043100001702063700002302080700001802103700002502121700001602146700002202162700001402184700002602198700002102224700001902245700001802264700002402282700002202306700001902328700002202347700002002369700002702389700001902416700002602435700002802461700002302489700001902512700002402531700002202555700002302577700002202600700001602622700001902638700002002657700002702677700002002704700002202724700002102746700002402767700001202791700002302803700002202826700001702848700002002865700002002885700002402905700002502929700001402954700002002968700002102988700002703009700002103036700002303057700002203080700002203102700001903124700002403143700002803167700002403195700001903219700001803238710004503256710002803301856003603329 2013 eng d a1932-620300aGenetic loci for retinal arteriolar microcirculation.0 aGenetic loci for retinal arteriolar microcirculation c2013 ae658040 v83 aNarrow 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 <5×10(-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 = 2.11×10(-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.
10aAged10aAged, 80 and over10aArterioles10aChromosomes, Human, Pair 510aEuropean Continental Ancestry Group10aFemale10aGenetic Loci10aGenome-Wide Association Study10aGenotype10aHumans10aMale10aMEF2 Transcription Factors10aMicrocirculation10aMiddle Aged10aModels, Genetic10aRetinal Vessels1 aSim, Xueling1 aJensen, Richard, A1 aIkram, Kamran1 aCotch, Mary, Frances1 aLi, Xiaohui1 aMacgregor, Stuart1 aXie, Jing1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aMitchell, Paul1 aKlein, Ronald1 aKlein, Barbara, E K1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 ade Jong, Paulus, T V M1 aHofman, Albert1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aDuijn, Cornelia, M1 aAspelund, Thor1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aLauner, Lenore, J1 aAttia, John1 aBaird, Paul, N1 aHarrap, Stephen1 aHolliday, Elizabeth, G1 aInouye, Michael1 aRochtchina, Elena1 aScott, Rodney, J1 aViswanathan, Ananth1 aLi, Guo1 aSmith, Nicholas, L1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aTaylor, Kent, D1 aHewitt, Alex, W1 aMartin, Nicholas, G1 aMontgomery, Grant, W1 aSun, Cong1 aYoung, Terri, L1 aMackey, David, A1 avan Zuydam, Natalie, R1 aDoney, Alex, S F1 aPalmer, Colin, N A1 aMorris, Andrew, D1 aRotter, Jerome, I1 aTai, Shyong, E1 aGudnason, Vilmundur1 aVingerling, Johannes, R1 aSiscovick, David, S1 aWang, Jie, Jin1 aWong, Tien, Y1 aWellcome Trust Case Control Consortium 21 aGlobal BPgen Consortium uhttps://chs-nhlbi.org/node/602704413nas a2200889 4500008004100000022001400041245008200055210006900137260000900206300001100215490000600226520194300232653000902175653002202184653001102206653003402217653001302251653002502264653001102289653001702300653000902317653003602326653002302362653002102385100002302406700001702429700001602446700002502462700001802487700002702505700002402532700002202556700002302578700002402601700002202625700002602647700002102673700001702694700002002711700001702731700001902748700001902767700001602786700001802802700002202820700001902842700002202861700002002883700001702903700001902920700002702939700002602966700002802992700001803020700001903038700002003057700001703077700002003094700001903114700001403133700002203147700003003169700001903199700002203218700001703240700002303257700002403280700001803304700002403322700002203346700001503368700002503383700001803408710003903426710002203465856003603487 2013 eng d a1932-620300aGenome-wide association study of retinopathy in individuals without diabetes.0 aGenomewide association study of retinopathy in individuals witho c2013 ae542320 v83 aBACKGROUND: 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.
10aAged10aAged, 80 and over10aFemale10aGenome-Wide Association Study10aGenotype10aHistone Deacetylases10aHumans10aHypertension10aMale10aPolymorphism, Single Nucleotide10aRepressor Proteins10aRetinal Diseases1 aJensen, Richard, A1 aSim, Xueling1 aLi, Xiaohui1 aCotch, Mary, Frances1 aIkram, Kamran1 aHolliday, Elizabeth, G1 aEiriksdottir, Gudny1 aHarris, Tamara, B1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore, J1 aSmith, Albert, Vernon1 aBoerwinkle, Eric1 aCheung, Ning1 aHewitt, Alex, W1 aLiew, Gerald1 aMitchell, Paul1 aWang, Jie, Jin1 aAttia, John1 aScott, Rodney1 aGlazer, Nicole, L1 aLumley, Thomas1 aMcKnight, Barbara1 aPsaty, Bruce, M1 aTaylor, Kent1 aHofman, Albert1 ade Jong, Paulus, T V M1 aRivadeneira, Fernando1 aUitterlinden, André, G1 aTay, Wan-Ting1 aTeo, Yik, Ying1 aSeielstad, Mark1 aLiu, Jianjun1 aCheng, Ching-Yu1 aSaw, Seang-Mei1 aAung, Tin1 aGanesh, Santhi, K1 aO'Donnell, Christopher, J1 aNalls, Mike, A1 aWiggins, Kerri, L1 aKuo, Jane, Z1 aDuijn, Cornelia, M1 aGudnason, Vilmundur1 aKlein, Ronald1 aSiscovick, David, S1 aRotter, Jerome, I1 aTai, Shong1 aVingerling, Johannes1 aWong, Tien, Y1 aBlue Mountains Eye Study GWAS Team1 aCKDGen Consortium uhttps://chs-nhlbi.org/node/607204392nas a2200841 4500008004100000022001400041245013900055210006900194260000900263300001100272490000600283520190900289653002202198653002402220653003802244653003402282653001302316653001102329653003902340653002502379653002602404653003602430653001302466653001702479653002902496100002702525700002102552700002302573700003202596700002302628700001702651700001902668700001402687700001902701700002102720700002102741700002302762700002402785700002402809700001902833700002002852700002002872700002302892700002402915700001902939700001602958700001702974700001902991700002203010700002203032700001903054700002003073700002203093700002203115700002103137700001703158700001703175700001903192700002803211700002403239700001603263700002803279700002603307700001903333700002103352700001803373700002503391700001803416700001603434700001903450710004503469856003603514 2013 eng d a1932-620300aInsights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.0 aInsights into the genetic architecture of early stage agerelated c2013 ae538300 v83 aGenetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P = 1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P = 4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P = 1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P = 8.9×10(-6)) and upstream of GLI2 (rs6721654; P = 6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P = 3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
10aApolipoproteins E10aComplement Factor H10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aGenotype10aHumans10aKruppel-Like Transcription Factors10aMacular Degeneration10aNerve Tissue Proteins10aPolymorphism, Single Nucleotide10aProteins10aRisk Factors10aZinc Finger Protein Gli31 aHolliday, Elizabeth, G1 aSmith, Albert, V1 aCornes, Belinda, K1 aBuitendijk, Gabriëlle, H S1 aJensen, Richard, A1 aSim, Xueling1 aAspelund, Thor1 aAung, Tin1 aBaird, Paul, N1 aBoerwinkle, Eric1 aCheng, Ching, Yu1 aDuijn, Cornelia, M1 aEiriksdottir, Gudny1 aGudnason, Vilmundur1 aHarris, Tamara1 aHewitt, Alex, W1 aInouye, Michael1 aJonasson, Fridbert1 aKlein, Barbara, E K1 aLauner, Lenore1 aLi, Xiaohui1 aLiew, Gerald1 aLumley, Thomas1 aMcElduff, Patrick1 aMcKnight, Barbara1 aMitchell, Paul1 aPsaty, Bruce, M1 aRochtchina, Elena1 aRotter, Jerome, I1 aScott, Rodney, J1 aTay, Wanting1 aTaylor, Kent1 aTeo, Yik, Ying1 aUitterlinden, André, G1 aViswanathan, Ananth1 aXie, Sophia1 aVingerling, Johannes, R1 aKlaver, Caroline, C W1 aTai, Shyong, E1 aSiscovick, David1 aKlein, Ronald1 aCotch, Mary, Frances1 aWong, Tien, Y1 aAttia, John1 aWang, Jie, Jin1 aWellcome Trust Case Control Consortium 2 uhttps://chs-nhlbi.org/node/587503624nas a2200613 4500008004100000022001400041245010500055210006900160260001500229300001200244490000700256520193600263653001002199653000902209653002202218653002402240653000802264653001802272653001102290653001902301653003802320653001302358653001102371653002502382653000902407653001602416653001402432653003602446653001502482653002402497653001302521653001702534653001802551100002402569700002202593700002002615700002202635700001902657700002102676700002002697700002302717700002002740700002302760700002402783700001802807700001802825700002002843700002302863700001802886700002402904700002402928700002202952856003602974 2014 eng d a1552-578300aGenetic determinants of age-related macular degeneration in diverse populations from the PAGE study.0 aGenetic determinants of agerelated macular degeneration in diver c2014 Sep 9 a6839-500 v553 aPURPOSE: 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=3.05×10(-8) and P=6.36×10(-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.
10aAdult10aAged10aAged, 80 and over10aComplement Factor H10aDNA10aEthnic Groups10aFemale10aGene Frequency10aGenetic Predisposition to Disease10aGenotype10aHumans10aMacular Degeneration10aMale10aMiddle Aged10aPhenotype10aPolymorphism, Single Nucleotide10aPrevalence10aProspective Studies10aProteins10aRisk Factors10aUnited States1 aRestrepo, Nicole, A1 aSpencer, Kylee, L1 aGoodloe, Robert1 aGarrett, Tiana, A1 aHeiss, Gerardo1 aBůzková, Petra1 aJorgensen, Neal1 aJensen, Richard, A1 aMatise, Tara, C1 aHindorff, Lucia, A1 aKlein, Barbara, E K1 aKlein, Ronald1 aWong, Tien, Y1 aCheng, Ching-Yu1 aCornes, Belinda, K1 aTai, E-Shyong1 aRitchie, Marylyn, D1 aHaines, Jonathan, L1 aCrawford, Dana, C uhttps://chs-nhlbi.org/node/701903468nas a2200541 4500008004100000022001400041245007100055210006900126260001300195300001000208490000600218520192500224100002302149700001702172700002602189700001602215700002602231700002002257700002302277700002502300700002202325700001802347700001902365700002002384700002202404700002202426700002002448700002402468700002202492700001402514700002002528700002402548700002502572700001602597700001902613700002802632700001602660700001902676700001902695700002402714700002202738700002102760700002302781700002002804700001802824710004802842856003602890 2016 eng d a1942-326800aNovel Genetic Loci Associated With Retinal Microvascular Diameter.0 aNovel Genetic Loci Associated With Retinal Microvascular Diamete c2016 Feb a45-540 v93 aBACKGROUND: There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.
METHODS AND RESULTS: This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in TEAD1 (P=3.1×10(-) (11); minor allele frequency=0.43), rs201259422 in TSPAN10 (P=4.4×10(-9); minor allele frequency=0.27), rs5442 in GNB3 (P=7.0×10(-10); minor allele frequency=0.05), and rs1800407 in OCA2 (P=3.4×10(-8); minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (P=6.5×10(-12)). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (P=0.001) and diastolic blood pressures (P=8.3×10(-04)).
CONCLUSIONS: Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
1 aJensen, Richard, A1 aSim, Xueling1 aSmith, Albert, Vernon1 aLi, Xiaohui1 aJakobsdottir, Johanna1 aCheng, Ching-Yu1 aBrody, Jennifer, A1 aCotch, Mary, Frances1 aMcKnight, Barbara1 aKlein, Ronald1 aWang, Jie, Jin1 aKifley, Annette1 aHarris, Tamara, B1 aLauner, Lenore, J1 aTaylor, Kent, D1 aKlein, Barbara, E K1 aRaffel, Leslie, J1 aLi, Xiang1 aIkram, Arfan, M1 aKlaver, Caroline, C1 avan der Lee, Sven, J1 aMutlu, Unal1 aHofman, Albert1 aUitterlinden, André, G1 aLiu, Chunyu1 aKraja, Aldi, T1 aMitchell, Paul1 aGudnason, Vilmundur1 aRotter, Jerome, I1 aBoerwinkle, Eric1 aDuijn, Cornelia, M1 aPsaty, Bruce, M1 aWong, Tien, Y1 aCHARGE Exome Chip Blood Pressure Consortium uhttps://chs-nhlbi.org/node/690003502nas a2200793 4500008004100000022001400041245011400055210006900169260001200238300001400250490000700264520132200271653000901593653002501602653001101627653003401638653001101672653001101683653000901694653003701703653001601740653003601756653000901792100001801801700002001819700001401839700001601853700002201869700002201891700002001913700001501933700001901948700002001967700001801987700001702005700001702022700001402039700001302053700002102066700002102087700001702108700001702125700001902142700001702161700002102178700002402199700001502223700002402238700001402262700001602276700002602292700002002318700001802338700002302356700001802379700002502397700001902422700001702441700001902458700002202477700002202499700001802521700002002539700002302559700002002582700002002602710005002622856003602672 2017 eng d a1939-327X00aGenetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.0 aGenetically Determined Plasma Lipid Levels and Risk of Diabetic c2017 12 a3130-31410 v663 aResults from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist.
10aAged10aDiabetic Retinopathy10aFemale10aGenome-Wide Association Study10aHumans10aLipids10aMale10aMendelian Randomization Analysis10aMiddle Aged10aPolymorphism, Single Nucleotide10aRisk1 aSobrin, Lucia1 aChong, Yong, He1 aFan, Qiao1 aGan, Alfred1 aStanwyck, Lynn, K1 aKaidonis, Georgia1 aCraig, Jamie, E1 aKim, Jihye1 aLiao, Wen-Ling1 aHuang, Yu-Chuen1 aLee, Wen-Jane1 aHung, Yi-Jen1 aGuo, Xiuqing1 aHai, Yang1 aIpp, Eli1 aPollack, Samuela1 aHancock, Heather1 aPrice, Alkes1 aPenman, Alan1 aMitchell, Paul1 aLiew, Gerald1 aSmith, Albert, V1 aGudnason, Vilmundur1 aTan, Gavin1 aKlein, Barbara, E K1 aKuo, Jane1 aLi, Xiaohui1 aChristiansen, Mark, W1 aPsaty, Bruce, M1 aSandow, Kevin1 aJensen, Richard, A1 aKlein, Ronald1 aCotch, Mary, Frances1 aWang, Jie, Jin1 aJia, Yucheng1 aChen, Ching, J1 aChen, Yii-Der Ida1 aRotter, Jerome, I1 aTsai, Fuu-Jen1 aHanis, Craig, L1 aBurdon, Kathryn, P1 aWong, Tien, Yin1 aCheng, Ching-Yu1 aAsian Genetic Epidemiology Network Consortium uhttps://chs-nhlbi.org/node/759004450nas a2201069 4500008004100000022001400041245015100055210006900206260001300275300001200288490000700300520139200307100002101699700001901720700002301739700002301762700001601785700002001801700001901821700002101840700002501861700002301886700002101909700001801930700002201948700001701970700002701987700002202014700001702036700002102053700002002074700002002094700001502114700001402129700001702143700001602160700001702176700001702193700002102210700001702231700001302248700002002261700002102281700001902302700002302321700001402344700002102358700001902379700002302398700001802421700001802439700003202457700002702489700001702516700002202533700001602555700001902571700002302590700002102613700001902634700002102653700002202674700001802696700002002714700002202734700001702756700002002773700001702793700001902810700002102829700001902850700002002869700001902889700002402908700002302932700001802955700002202973700002102995700002103016700002503037700001903062700002303081700001803104700002403122700001803146700002203164700002203186700002003208700001803228710009803246856003603344 2019 eng d a1939-327X00aMultiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.0 aMultiethnic GenomeWide Association Study of Diabetic Retinopathy c2019 Feb a441-4560 v683 aTo identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts ( = 3,246) and seven African American cohorts ( = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a value <1 × 10 were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like () was associated with DR in European discovery cohorts ( = 2.1 × 10), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity ( = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
1 aPollack, Samuela1 aIgo, Robert, P1 aJensen, Richard, A1 aChristiansen, Mark1 aLi, Xiaohui1 aCheng, Ching-Yu1 aC Y Ng, Maggie1 aSmith, Albert, V1 aRossin, Elizabeth, J1 aSegrè, Ayellet, V1 aDavoudi, Samaneh1 aTan, Gavin, S1 aChen, Yii-Der Ida1 aKuo, Jane, Z1 aDimitrov, Latchezar, M1 aStanwyck, Lynn, K1 aMeng, Weihua1 aHosseini, Mohsen1 aImamura, Minako1 aNousome, Darryl1 aKim, Jihye1 aHai, Yang1 aJia, Yucheng1 aAhn, Jeeyun1 aLeong, Aaron1 aShah, Kaanan1 aPark, Kyu, Hyung1 aGuo, Xiuqing1 aIpp, Eli1 aTaylor, Kent, D1 aAdler, Sharon, G1 aSedor, John, R1 aFreedman, Barry, I1 aLee, I-Te1 aSheu, Wayne, H-H1 aKubo, Michiaki1 aTakahashi, Atsushi1 aHadjadj, Samy1 aMarre, Michel1 aTrégouët, David-Alexandre1 aMcKean-Cowdin, Roberta1 aVarma, Rohit1 aMcCarthy, Mark, I1 aGroop, Leif1 aAhlqvist, Emma1 aLyssenko, Valeriya1 aAgardh, Elisabet1 aMorris, Andrew1 aDoney, Alex, S F1 aColhoun, Helen, M1 aToppila, Iiro1 aSandholm, Niina1 aGroop, Per-Henrik1 aMaeda, Shiro1 aHanis, Craig, L1 aPenman, Alan1 aChen, Ching, J1 aHancock, Heather1 aMitchell, Paul1 aCraig, Jamie, E1 aChew, Emily, Y1 aPaterson, Andrew, D1 aGrassi, Michael, A1 aPalmer, Colin1 aBowden, Donald, W1 aYaspan, Brian, L1 aSiscovick, David1 aCotch, Mary, Frances1 aWang, Jie, Jin1 aBurdon, Kathryn, P1 aWong, Tien, Y1 aKlein, Barbara, E K1 aKlein, Ronald1 aRotter, Jerome, I1 aIyengar, Sudha, K1 aPrice, Alkes, L1 aSobrin, Lucia1 aFamily Investigation of Nephropathy and Diabetes-Eye Research Group, DCCT/EDIC Research Group uhttps://chs-nhlbi.org/node/7990