ABSTRACT
To identify functionally related genes associated with diabetic retinopathy (DR) risk using gene set enrichment analyses applied to genome-wide association study meta-analyses. METHODS: We analyzed DR GWAS meta-analyses performed on 3246 Europeans and 2611 African Americans with type 2 diabetes. Gene sets relevant to 5 key DR pathophysiology processes were investigated: tissue injury, vascular events, metabolic events and glial dysregulation, neuronal dysfunction, and inflammation. Keywords relevant to these processes were queried in 4 pathway and ontology databases. Two GSEA methods, Meta-Analysis Gene set Enrichment of variaNT Associations (MAGENTA) and Multi-marker Analysis of GenoMic Annotation (MAGMA), were used. Gene sets were defined to be enriched for gene associations with DR if the P value corrected for multiple testing (Pcorr) was <.05. RESULTS: Five gene sets were significantly enriched for numerous modest genetic associations with DR in one method (MAGENTA or MAGMA) and also at least nominally significant (uncorrected P < .05) in the other method. These pathways were regulation of the lipid catabolic process (2-fold enrichment, Pcorr = .014); nitric oxide biosynthesis (1.92-fold enrichment, Pcorr = .022); lipid digestion, mobilization, and transport (1.6-fold enrichment, P = .032); apoptosis (1.53-fold enrichment, P = .041); and retinal ganglion cell degeneration (2-fold enrichment, Pcorr = .049). The interferon gamma (IFNG) gene, previously implicated in DR by protein-protein interactions in our GWAS, was among the top ranked genes in the nitric oxide pathway (best variant P = .0001). CONCLUSIONS: These GSEA indicate that variants in genes involved in oxidative stress, lipid transport and catabolism, and cell degeneration are enriched for genes associated with DR risk. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.
Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Retinopathy , Diabetes Mellitus, Type 2/genetics , Diabetic Retinopathy/genetics , Genome-Wide Association Study , Humans , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Background: Evaluating women with symptoms suggestive of coronary artery disease (CAD) remains challenging. A blood-based precision medicine test yielding an age/sex/gene expression score (ASGES) has shown clinical validity in the diagnosis of obstructive CAD. We assessed the effect of the ASGES on the management of women with suspected obstructive CAD in a community-based registry. Materials and Methods: The prospective PRESET (A Registry to Evaluate Patterns of Care Associated with the Use of Corus® CAD in Real World Clinical Care Settings) Registry (NCT01677156) enrolled 566 patients presenting with symptoms suggestive of stable obstructive CAD from 21 United States primary care practices from 2012 to 2014. Demographics, clinical characteristics, and referrals to cardiology or further functional and/or anatomical cardiac studies after ASGES testing were collected for this subgroup analysis of women from the PRESET Registry. Patients were followed for 1-year post-ASGES testing. Results: This study cohort included 288 women with a median age 57 years. The median body mass index was 29.2, with hyperlipidemia and hypertension present in 48% and 43% of patients, respectively. Median ASGES was 8.5 (range 1-40), with 218 (76%) patients having low (≤15) ASGES. Clinicians referred 9% (20/218) low ASGES versus 44% (31/70) elevated ASGES women for further cardiac evaluation (odds ratio 0.14, p < 0.0001, adjusted for patient demographics and clinical covariates). Across the score range, higher ASGES were associated with a higher likelihood of posttest cardiac referral. At 1-year follow-up, low ASGES women experienced fewer major adverse cardiac events than elevated ASGES women (1.3% vs. 4.2% respectively, p = 0.16). Conclusions: Incorporation of ASGES into the diagnostic workup demonstrated clinical utility by helping clinicians identify women less likely to benefit from further cardiac evaluation.
Subject(s)
Coronary Artery Disease/diagnosis , Gene Expression Profiling/methods , Precision Medicine/methods , Adult , Aged , Aged, 80 and over , Clinical Decision-Making , Cohort Studies , Coronary Artery Disease/genetics , Female , Follow-Up Studies , Hematologic Tests/methods , Humans , Middle Aged , Prospective Studies , Registries , Sex Characteristics , United States/epidemiologyABSTRACT
To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 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 P value <1 × 10-5 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 (NVL) was associated with DR in European discovery cohorts (P = 2.1 × 10-9), 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 (P = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Genome-Wide Association Study/methods , Blood Glucose/metabolism , Diabetes Mellitus, Type 2/metabolism , Diabetic Retinopathy , Genetic Predisposition to Disease , Genotype , Glycated Hemoglobin/metabolism , Humans , Meta-Analysis as Topic , Polymorphism, Single Nucleotide/genetics , Protein BindingABSTRACT
PURPOSE: Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. METHODS: A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. RESULTS: Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05 × 10-9 . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values = 7.41 × 10-8 and 1.23 × 10-8 , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p = 0.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p = 0.429). CONCLUSION: This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.
Subject(s)
Diabetes Mellitus, Type 2/complications , Diabetic Retinopathy/genetics , NADPH Oxidase 4/genetics , Polymorphism, Single Nucleotide , Adult , Diabetic Retinopathy/etiology , Diabetic Retinopathy/surgery , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotyping Techniques , Humans , Laser Coagulation , Male , Middle Aged , Scotland , White People/geneticsABSTRACT
BACKGROUND: Diagnosing obstructive coronary artery disease (CAD) is challenging in elderly adults, and current diagnostic approaches for CAD expose these individuals to risks from contrast dye and invasive procedures. DESIGN: A Registry to Evaluate Patterns of Care Associated with the Use of Corus CAD in Real World Clinical Care Settings (PRESET; NCT01677156), pragmatic clinical trial. SETTING: Community, 21 primary care practices. PARTICIPANTS: Of 566 stable, nonacute outpatients presenting with symptoms suggestive of obstructive CAD, the 176 who were aged 65 and older (median age 70, 61% female) were the current study participants. INTERVENTION: Blood-based precision medicine test, incorporating age, sex, and gene expression score (ASGES) to improve clinical decision-making and quality of care. MEASUREMENTS: Information on demographic characteristics, clinical factors, ASGES results (range 1-40; low (≤15), high (>15)), referral patterns to cardiology and advanced cardiac testing, and major adverse cardiac events (MACEs) was collected in a subgroup analysis of elderly adults in the PRESET Registry. Follow-up was for 1 year after ASGES testing. RESULTS: Median ASGES was 25, and 40 (23%) participants had a low score. Clinicians referred 12.5% of participants with a low ASGES and 49.3% with a high ASGES to cardiology or advanced cardiac testing (odds ratio for referral = 0.12, P < .001, adjusted for participants demographics and clinical covariates). Higher scores were associated with greater likelihood of posttest cardiac referral. At 1-year follow-up, the incidence of a MACE or revascularization was 10% (13/136) in the high ASGES group and 0% (0/40) in the low ASGES group (P = .04). CONCLUSION: The ASGES test showed potential clinical utility in the evaluation of elderly outpatients with symptoms suggestive of obstructive CAD. Test use may reduce unnecessary referrals and the risk of procedure-related complications in individuals with low ASGES, who are unlikely to benefit from further testing, while also identifying individuals who may benefit from further cardiac evaluation and management.
Subject(s)
Coronary Artery Disease/diagnosis , Gene Expression Profiling/methods , Precision Medicine , Risk Assessment , Aged , Clinical Decision-Making , Female , Humans , Male , Prospective Studies , RegistriesABSTRACT
To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.
Subject(s)
Coronary Disease/genetics , Diabetes Mellitus, Type 2/genetics , Genome-Wide Association Study , Asia/epidemiology , Asian People/genetics , Biomarkers , Comorbidity , Coronary Disease/epidemiology , Coronary Disease/etiology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/etiology , Europe/epidemiology , Genetic Loci/genetics , Genetic Predisposition to Disease , HLA-DRB5 Chains/genetics , Humans , Metabolic Networks and Pathways/genetics , Metabolic Syndrome/epidemiology , Metabolic Syndrome/genetics , Molecular Targeted Therapy , Mutation, Missense , Polymorphism, Single Nucleotide , Risk Factors , White People/geneticsABSTRACT
PURPOSE: To examine the relationship between proportion of African ancestry (PAA) and proliferative diabetic retinopathy (PDR) and to identify genetic loci associated with PDR using admixture mapping in African Americans with type 2 diabetes (T2D). METHODS: Between 1993 and 2013, 1440 participants enrolled in four different studies had fundus photographs graded using the Early Treatment Diabetic Retinopathy Study scale. Cases (n = 305) had PDR while controls (n = 1135) had nonproliferative diabetic retinopathy (DR) or no DR. Covariates included diabetes duration, hemoglobin A1C, systolic blood pressure, income, and education. Genotyping was performed on the Affymetrix platform. The association between PAA and PDR was evaluated using logistic regression. Genome-wide admixture scanning was performed using ANCESTRYMAP software. RESULTS: In the univariate analysis, PDR was associated with increased PAA (odds ratio [OR] = 1.36, 95% confidence interval [CI] = 1.16-1.59, P = 0.0002). In multivariate regression adjusting for traditional DR risk factors, income and education, the association between PAA and PDR was attenuated and no longer significant (OR = 1.21, 95% CI = 0.59-2.47, P = 0.61). For the admixture analyses, the maximum genome-wide score was 1.44 on chromosome 1. CONCLUSIONS: In this largest study of PDR in African Americans with T2D to date, an association between PAA and PDR is not present after adjustment for clinical, demographic, and socioeconomic factors. No genome-wide significant locus (defined as having a locus-genome statistic > 5) was identified with admixture analysis. Further analyses with even larger sample sizes are needed to definitively assess if any admixture signal for DR is present.
Subject(s)
Black or African American/genetics , Diabetic Retinopathy/ethnology , Diabetic Retinopathy/genetics , Adult , Black or African American/statistics & numerical data , Aged , Blood Pressure/genetics , Case-Control Studies , Chromosome Mapping , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged , Odds Ratio , Regression Analysis , Risk FactorsABSTRACT
CONTEXT AND OBJECTIVE: Insulin resistance and chronic inflammation are key elements in the pathogenesis of type 2 diabetes. We hypothesized that similar mechanisms could have a role in the development of diabetic retinopathy (DR), an important microvascular complication in Latinos with type 2 diabetes. DESIGN AND SETTING: A cross-sectional, family-based, observational cohort study. PATIENTS: Latino subjects with type 2 diabetes (n = 507), ascertained in families via a proband with known diabetes duration of 10 years or more and/or with DR, were included. MAIN OUTCOME MEASURES: Serum adiponectin was measured and insulin sensitivity was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). DR was assessed by seven-field digital fundus photography and graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Scale (range of severity levels, 10-85). RESULTS: Fasting adiponectin concentrations were elevated in patients with DR compared to those without (12.9 ± 0.5 vs 10.5 ± 0.5 µg/mL; P = .0004) and remained significant after adjusting for multiple covariates (age, gender, body mass index, glycosylated hemoglobin, diabetes duration, statin use, blood pressure, and renal function; P = .013 to .018). Adiponectin was also positively correlated with severity of DR in patients with nonproliferative DR (P < .0003), significant also after all covariate adjustments (P = .018). When the proliferative DR group was included, this relationship was attenuated by adjustments, possibly an influence of estimated glomerular filtration rate reduction in the proliferative DR group. HOMA-IR was not different in the DR and non-DR groups. Although elevated, adiponectin retained a typical inverse relationship with HOMA-IR in DR, similar to that seen in the non-DR group. CONCLUSIONS: Serum adiponectin is elevated in DR, is positively correlated with DR severity in Latinos with type 2 diabetes, and maintains a relationship to insulin sensitivity. Adiponectin, whether as a marker or biological mediator, may play an important role in DR, which appears to be independent of its relationship to insulin sensitivity.
Subject(s)
Adiponectin/blood , Diabetes Mellitus, Type 2/blood , Diabetic Retinopathy/diagnosis , Insulin Resistance/physiology , Blood Pressure/physiology , Body Mass Index , Cross-Sectional Studies , Diabetes Mellitus, Type 2/physiopathology , Diabetic Retinopathy/blood , Diabetic Retinopathy/physiopathology , Female , Hispanic or Latino , Humans , Insulin/blood , Male , Middle Aged , Risk Factors , Severity of Illness IndexABSTRACT
PURPOSE: To perform a quantitative trait locus (QTL) analysis and evaluate whether a locus between SIX1 and SIX6 is associated with retinal nerve fiber layer (RNFL) thickness in individuals of European descent. DESIGN: Observational, multicenter, cross-sectional study. METHODS: A total of 231 participants were recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. Association of rs10483727 in SIX1-SIX6 with global and sectoral RNFL thickness was performed. Quantitative trait analysis with the additive model of inheritance was analyzed using linear regression. Trend analysis was performed to evaluate the mean global and sectoral RNFL thickness with 3 genotypes of interest (T/T, C/T, C/C). All models were adjusted for age and sex. RESULTS: Direction of association between T allele and RNFL thickness was consistent in the global and different sectoral RNFL regions. Each copy of the T risk allele in rs10483727 was associated with -0.16 µm thinner global RNFL thickness (ß = -0.16, 95% confidence interval: -0.28 to -0.03; P = .01). Similar patterns were found for the sectoral regions, including inferior (P = .03), inferior-nasal (P = .017), superior-nasal (P = .0025), superior (P = .002) and superior-temporal (P = .008). The greatest differences were observed in the superior and inferior quadrants, supporting clinical observations for RNFL thinning in glaucoma. Thinner global RNFL was found in subjects with T/T genotypes compared to subjects with C/T and C/C genotypes (P = .044). CONCLUSIONS: Each copy of the T risk allele has an additive effect and was associated with thinner global and sectoral RNFL. Findings from this QTL analysis further support a genetic contribution to glaucoma pathophysiology.
Subject(s)
Eye Proteins/genetics , Glaucoma, Open-Angle/genetics , Homeodomain Proteins/genetics , Nerve Fibers/pathology , Polymorphism, Single Nucleotide , Quantitative Trait Loci , Retinal Ganglion Cells/pathology , Aged , Cross-Sectional Studies , Female , Genotyping Techniques , Glaucoma, Open-Angle/diagnosis , Glaucoma, Open-Angle/physiopathology , Humans , Male , Middle Aged , Nerve Tissue Proteins/genetics , Trans-Activators/genetics , White People , Homeobox Protein SIX3ABSTRACT
PURPOSE: We determined if quantitative measurements of biogeographic ancestry (BGA) correlate with variations in optic disc area, corneal thickness (CCT), and retinal nerve fiber layer (RNFL) thickness. METHODS: Data were obtained from 656 participants in the African Descent and Glaucoma Evaluation Study (ADAGES) cohort who consented to BGA testing. Data for CCT, optic disc area, and RNFL thickness were obtained from subjects in the ADAGES study who also had participated in the current substudy. A total of 31 ancestry informative markers (AIMs) with large allele frequencies differences between populations was used to calculate admixture proportion (implemented in STRUCTURE). Correlations with BGA adjusted for diagnosis, age, and sex for CCT and optic disc area using the whole group and RNFL thickness adjusted for age and sex for the normal study participants were determined. RESULTS: The mean percentage of African admixture was 79.6% in the self-described African Descent (AD) group and 3.5% in the European Descent (ED) group. Percent African ancestry was significantly correlated with CCT (ρ = -0.27, P < 0.0001) and disc area (ρ = 0.15, P < 0.0001), but only marginally associated with RNFL thickness (ρ = 0.20, P = 0.092) in adjusted models. CONCLUSIONS: The BGA correlates with variation in ocular features that significantly differ across racial groups and that have been associated with the development of glaucoma. While BGA can provide an objective measurement of the biologic component of self-described race for ocular research, for most nongenetic epidemiologic studies, self-described race may adequately describe the associations with these ocular characteristics. (ClinicalTrials.gov number, NCT00221923.).
Subject(s)
Black People , Cornea/pathology , Glaucoma, Open-Angle/ethnology , Nerve Fibers/pathology , Optic Disk/pathology , Retinal Ganglion Cells/pathology , Aged , Cohort Studies , Female , Glaucoma, Open-Angle/genetics , Glaucoma, Open-Angle/pathology , Humans , Male , Middle Aged , Regression AnalysisABSTRACT
OBJECTIVE: Residual insulin secretion provides important protection against the development of diabetic retinopathy in type 1 diabetes. The data to support this in type 2 diabetes are unclear. We therefore tested in type 2 diabetes whether markers of residual beta-cell function are associated with the development of diabetic retinopathy, an important microvascular complication of diabetes. DESIGN: Prospective, cross-sectional, family-based study. PARTICIPANTS: 585 Latino type 2 diabetic participants, ascertained in families via a proband either with known diabetes duration of greater than 10â years and/or with diabetic retinopathy. OUTCOME MEASURES: CIRCULATING LEVELS OF FASTING INSULIN AND C PEPTIDE MEASURED AND CORRELATED TO DEGREE OF DIABETIC RETINOPATHY, ASSESSED BY DIGITAL FUNDUS PHOTOGRAPHY AND GRADED USING THE MODIFIED AIRLIE HOUSE CLASSIFICATION AND THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY SCALE (RANGE: levels 10-85). RESULTS: Fasting plasma insulin (ß=-0.29; 95% CI -0.38 to -0.20; p<0.0001) and C peptide (ß=-0.21; 95% CI -0.30 to -0.13; p<0.0001) concentrations in these diabetic participants were significantly correlated with retinopathy and its degree of severity. This relationship remained significant after adjusting for potential covariates including age, gender, glycosylated hemoglobin, duration of diabetes, blood pressure, and renal function. CONCLUSIONS: These data suggest that residual endogenous insulin secretion is associated with the presence of diabetic retinopathy and its severity in Latinos with familial type 2 diabetes. It remains to be proven whether beta-cell targeted therapies, to maintain beta-cell mass and/or function in addition to glycemic control, will further the goal of preventing diabetic microvascular disease.
ABSTRACT
IMPORTANCE: In the past decade, significant progress in genomic medicine and technologic developments has revolutionized our approach to common complex disorders in many areas of medicine, including ophthalmology. A disorder that still needs major genetic progress is diabetic retinopathy (DR), one of the leading causes of blindness in adults. OBJECTIVE: To perform a literature review, present the current findings, and highlight some key challenges in DR genetics. DESIGN, SETTING, AND PARTICIPANTS: We performed a thorough literature review of the genetic factors for DR, including heritability scores, twin studies, family studies, candidate gene studies, linkage studies, and genome-wide association studies (GWASs). MAIN OUTCOME MEASURES: Environmental and genetic factors for DR. RESULTS: Although there is clear demonstration of a genetic contribution in the development and progression of DR, the identification of susceptibility loci through candidate gene approaches, linkage studies, and GWASs is still in its infancy. The greatest obstacles remain a lack of power because of small sample size of available studies and a lack of phenotype standardization. CONCLUSIONS AND RELEVANCE: The field of DR genetics is still in its infancy and is a challenge because of the complexity of the disease. This review outlines some strategies and lessons for future investigation to improve our understanding of this complex genetic disorder.
Subject(s)
Diabetic Retinopathy/genetics , Genetic Linkage , Genome-Wide Association Study , Humans , Molecular Biology , Quantitative Trait, Heritable , Transcriptome , Twin Studies as TopicABSTRACT
AIMS/HYPOTHESIS: Candidate gene and genome-wide association studies have identified â¼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population. METHODS: A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression. RESULTS: We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1. CONCLUSIONS/INTERPRETATION: These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.
Subject(s)
Asian People/genetics , Cyclin-Dependent Kinase 5/genetics , Diabetes Mellitus, Type 2/genetics , Polymorphism, Single Nucleotide , White People/genetics , Aged , Blood Glucose/metabolism , DNA Mutational Analysis , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/ethnology , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotyping Techniques , Humans , Insulin/blood , Male , tRNA MethyltransferasesABSTRACT
PURPOSE: To describe the relationships of selected candidate genes to the prevalence of early age-related macular degeneration (AMD) in a cohort of whites, blacks, Hispanics, and Chinese Americans. DESIGN: Cross-sectional study. METHODS: setting: Multicenter study. study population: A total of 2456 persons aged 45-84 years with genotype information and fundus photographs. procedures: Twelve of 2862 single nucleotide polymorphisms (SNPs) from 11 of 233 candidate genes for cardiovascular disease were selected for analysis based on screening with marginal unadjusted P value <.001 within 1 or more racial/ethnic groups. Logistic regression models tested for association in case-control samples. main outcome measure: Prevalence of early AMD. RESULTS: Early AMD was present in 4.0% of the cohort and varied from 2.4% in blacks to 6.0% in whites. The odds ratio increased from 2.3 for 1 to 10.0 for 4 risk alleles in a joint effect analysis of Age-Related Maculopathy Susceptibility 2 rs10490924 and Complement Factor H Y402H (P for trend = 4.2×10(-7)). Frequencies of each SNP varied among the racial/ethnic groups. Adjusting for age and other factors, few statistically significant associations of the 12 SNPs with AMD were consistent across all groups. In a multivariate model, most candidate genes did not attenuate the comparatively higher odds of AMD in whites. The higher frequency of risk alleles for several SNPs in Chinese Americans may partially explain their AMD frequency's approaching that of whites. CONCLUSIONS: The relationships of 11 candidate genes to early AMD varied among 4 racial/ethnic groups, and partially explained the observed variations in early AMD prevalence among them.
Subject(s)
Atherosclerosis/genetics , Ethnicity/genetics , Macular Degeneration/ethnology , Macular Degeneration/genetics , Polymorphism, Single Nucleotide , Racial Groups/genetics , Aged , Aged, 80 and over , Alleles , C-Reactive Protein/metabolism , Cross-Sectional Studies , Female , Genotype , Humans , Male , Middle Aged , Prevalence , Risk FactorsABSTRACT
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 <5×10(-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-valueâ=â2.11×10(-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.
Subject(s)
Arterioles/metabolism , Chromosomes, Human, Pair 5/genetics , Genetic Loci/genetics , Microcirculation/genetics , Retinal Vessels/metabolism , Aged , Aged, 80 and over , Female , Genome-Wide Association Study , Genotype , Humans , MEF2 Transcription Factors/genetics , Male , Middle Aged , Models, Genetic , White People/geneticsABSTRACT
Diabetic retinopathy (DR) is a leading cause of preventable blindness in adults. To identify genetic contributions in DR, we studied 2071 type 2 diabetics. We first conducted a genome-wide association study of 1007 individuals, comparing 570 subjects with ≥8 years duration without DR (controls) with 437 PDR (cases) in the Chinese discovery cohort. Cases and controls were similar for HbA1c, diabetes duration and body mass index. Association analysis with imputed data identified three novel loci: TBC1D4-COMMD6-UCHL3 (rs9565164, P = 1.3 × 10(-7)), LRP2-BBS5 (rs1399634, P = 2.0 × 10(-6)) and ARL4C-SH3BP4 (rs2380261, P = 2.1 × 10(-6)). Analysis of an independent cohort of 585 Hispanics diabetics with or without DR though did not confirm these signals. These genes are still of particular interest because they are involved in insulin regulation, inflammation, lipid signaling and apoptosis pathways, all of which are possibly involved with DR. Our finding nominates possible novel loci as potential DR susceptibility genes in the Chinese that are independent of the level of HbA1c and duration of diabetes and may provide insight into the pathophysiology of DR.
Subject(s)
Asian/genetics , Diabetic Retinopathy/genetics , Genome-Wide Association Study , Adult , Aged , Case-Control Studies , Chromosome Mapping , Diabetic Retinopathy/epidemiology , Female , Genetic Loci , Hispanic or Latino/genetics , Humans , Male , Meta-Analysis as Topic , Middle Aged , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
PURPOSE: Central corneal thickness (CCT) is a clinically important risk factor for primary open-angle glaucoma and keratoconus. Genetic factors controlling CCT in Latinos, the most populous minority population in the United States, are unclear. Here we describe the first genome-wide association study (GWAS) report of CCT in Latinos. METHODS: We performed a GWAS for CCT on 1768 Latinos recruited in the Los Angeles Latino Eye Study (LALES) using Illumina's HumanOmniExpress BeadChip (â¼730K markers). To discover additional associated single-nucleotide polymorphisms (SNPs), we imputed SNPs based on the 1000 Genomes Project reference panels. All subjects were 40 years of age and older. We used linear regression with adjustment for age, sex, and principal components of genetic ancestry. RESULTS: we replicated the involvement of several previously reported loci, SUCH AS RXRA-COL5A1, FOXO1, and ZNF469, for CCT in Latinos (P 0.002). moreover, we discovered novel SNPS, RS3118515, RS943423, RS3118594, AND RS3132307, THAT REACHED GWAS SIGNIFICANCE (P 5 10(8)) in the uncharacterized LOC100506532 (GENE TYPE: miscRNA) for CCT in Latinos. By conditional analysis, we demonstrate that rs3118515 in this gene is responsible for the GWAS signal in the chromosome 9 RXRA-COL5A1 region in Latinos. Moreover, multiple sources of ENCODE evidence suggest that rs3118515 is in a regulatory region. Reverse-transcription PCR products indicated that transcripts of LOC100506532 surrounding rs3118515 were expressed in human corneas. CONCLUSIONS: We discovered novel SNPs for CCT in Latinos and provided the first reported evidence of the corneal expression of LOC100506532. These results help to further increase our understanding of the genetic architecture of CCT.
Subject(s)
Cornea/anatomy & histology , Genome-Wide Association Study , Hispanic or Latino/genetics , Polymorphism, Single Nucleotide , Chromosomes, Human, Pair 9/genetics , Collagen Type V/genetics , Female , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Genetic Loci , Genotype , Humans , Los Angeles , Male , Middle Aged , Retinoid X Receptor alpha/genetics , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/geneticsABSTRACT
BACKGROUND: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. METHODS: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. RESULTS: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), pâ=â6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (â¼2%), the quality of the imputation was moderate (r(2) â¼0.7), 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.