Search

Familial Mediterranean fever ( FMF), inherited in an autosomal recessive manner, is a systemic auto-inflammatory disorder characterized by recurrent attacks of fever with peritonitis, pleuritis, synovitis and erysipeloid rash. The marenostrin-encoding fever ( MEFV) gene, located on chromosome 16p13.3, is the only gene in which mutations are currently known to cause FMF. To correlate specific genotypes with adverse phenotypes of affected populations residing in the Western United States, a retrospective case series review was conducted of all MEFV gene mutation testing completed at UCLA Clinical Molecular Diagnostic Laboratory between February 2002 and February 2012, followed by clinical chart review of all subjects who either have a single or double mutation. All 12 common mutations in the MEFV gene were analyzed and the M694V variant was found to be associated with an adverse FMF clinical outcome in the Armenian-American population, manifested by earlier onset of disease, increased severity of disease, and renal amyloidosis. [ABSTRACT FROM AUTHOR]

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

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., (© 2018 by the American Diabetes Association.)

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., (© 2018 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

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., (© 2017 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.)

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.

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.

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 (β = -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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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.

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.)., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

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 10 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 (β=-0.29; 95% CI -0.38 to -0.20; p<0.0001) and C peptide (β=-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.

Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and ∼2.5 million genotyped or imputed single nucleotide polymorphisms among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488-47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P = 9.29 × 10(-13)), ALDH2/MYL2 (rs671, P = 3.40 × 10(-11); rs12229654, P = 4.56 × 10(-9)), ITIH4 (rs2535633, P = 1.77 × 10(-10)) and NT5C2 (rs11191580, P = 3.83 × 10(-8)) genes. The association of BMI with rs2237892, rs671 and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed eight loci at the genome-wide significance level (P < 5.0 × 10(-8)) and an additional 14 at P < 1.0 × 10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.

Aims/hypothesis: Candidate gene and genome-wide association studies have identified ∼60 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.

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., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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.

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-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.

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 (∼730K 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.

Background: Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes., Methods: A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy., Results: No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, -1.3±0.23 (beta ± standard error), p = 6.6×10(-9). Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r(2) ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension., Conclusions: This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Rapid progress in genomics and nanotechnology continue to advance our approach to patient care, from diagnosis and prognosis, to targeting and personalization of therapeutics. However, the clinical application of molecular diagnostics in ophthalmology has been limited even though there have been demonstrations of disease risk and pharmacogenetic associations. There is a high clinical need for therapeutic personalization and dosage optimization in ophthalmology and may be the focus of individualized medicine in this specialty. In several retinal conditions, such as age-related macular degeneration, diabetic macular edema, retinal vein occlusion and pre-threshold retinopathy of prematurity, anti-vascular endothelial growth factor therapeutics have resulted in enhanced outcomes. In glaucoma, recent advances in cytoskeletal agents and prostaglandin molecules that affect outflow and remodel the trabecular meshwork have demonstrated improved intraocular pressure control. Application of recent developments in nanoemulsion and polymeric micelle for targeted delivery and drug release are models of dosage optimization, increasing efficacy and improving outcomes in these major eye diseases.

In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4-ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR-ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia.

Purpose: To investigate the associations of serum amyloid A (SAA) protein and soluble tumor necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF-R2) with diabetic retinopathy (DR) in Hispanics., Design: Prospective, nonrandomized, cross-sectional, family-based observational cohort study., Participants: A total of 473 Hispanic type II diabetic subjects in families ascertained via proband with DR., Methods: Levels of SAA, sTNF-R1, and sTNF-R2 were measured with enzyme-linked immunosorbent assay. Diabetic retinopathy was assessed by fundus photography and graded using modified Airlie House classification., Main Outcome Measures: Levels of SAA, sTNF-R1, and sTNF-R2 to severity of DR with and without covariates., Results: A direct association of sTNF-R1 (2.37±0.13, 2.15±0.09, 3.09±0.24, 3.25±0.46, 5.02±0.61 ng/ml; P < 0.0001) and sTNF-R2 (6.04±0.20, 6.25±0.52, 7.96±0.70, 8.14±1.13, 14.83±1.68 ng/ml; P < 0.0001) was found for no DR, mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR, respectively. These associations remained significant after adjusting for age, gender, body mass index, glycosylated hemoglobin, diabetes duration, systolic blood pressure, and serum creatinine (P < 0.0001 for sTNF-R1 and P=0.0004 for sTNF-R2). A similar pattern was observed when we adjusted for urinary albumin:creatinine ratio in place of serum creatinine (P=0.005 for sTNF-R1 and P=0.02 for sTNF-R2)., Conclusions: Levels of sTNF-R1 and sTNF-R2 are highly correlated with the severity of DR, suggesting that inflammation and insulin resistance may play a critical role in the development of DR. These may be useful biomarkers for DR, aiding in etiologic studies and possibly identifying at-risk patients for active intervention., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

In the past decade, significant strides have been made in the area of cardiovascular pharmacogenomic research, with the discovery of associations between certain genotypes and drug-response phenotypes. While the motivations for personalized and predictive medicine are promising for patient care and support a model of health system efficiency, the implementation of pharmacogenomics for cardiovascular therapeutics on a population scale faces substantial challenges. The greatest obstacle to clinical implementation of cardiovascular pharmacogenetics may be the lack of both reproducibility and agreement about the validity and utility of the findings. In this review, we present the scientific evidence in the literature for diagnostic variants for the US FDA-labeled cardiovascular therapies, namely CYP2C19 and clopidogrel, CYP2C9/VKORC1 and warfarin, and CYP2D6/ADRB1 and β-blockers. We also discuss the effect of HMGCR/LDLR in decreasing the effectiveness of low-density lipoprotein cholesterol with statin therapy, the SLCO1B1 genotype and simvastatin myotoxicity, and ADRB1/ADD1 for antihypertensive response.

Purpose: To report the anatomical and functional outcomes of intravitreal bevacizumab in both young and old Chinese patients with myopic choroidal neovascularization., Methods: Consecutive series of 56 eyes (52 patients) with myopic choroidal neovascularization treated exclusively with intravitreal bevacizumab were reviewed retrospectively. Data from clinical examination, fundus photography, fluorescein angiography, and optical coherence tomography were collected., Results: Vision significantly improved after intravitreal bevacizumab in this patient series (P < 0.0001), with an average of 2.2 injections. Higher myopia was positively correlated to a worse outcome (r = -0.3, P = 0.036). Stratifying by age, the correlation between spherical equivalent and final outcome showed statistical significance (r = -0.44, P = 0.027) only in younger patients. In younger patients, both spherical equivalent (P = 0.036) and initial visual acuity (P = 0.004) were predictive factors for visual outcome after adjusting for age, spherical equivalent, and number of injections, whereas in older patients, only initial visual acuity (P < 0.0001) was predictive of visual outcome after similar adjustments., Conclusion: Younger patients do not have a better outcome when compared with older patients. Initial visual acuity, regardless of age, plays a more significant role. Both initial visual acuity and spherical equivalent are predictive factors for final visual acuity in young Chinese patients.

We previously have described a model of multiple sclerosis (MS) in which constitutive expression of murine interleukin (IL)-2 by herpes simplex virus type 1 (HSV-1) (HSV-IL-2) causes central nervous system (CNS) demyelination in different strains of mice. In the current study, we investigated whether this HSV-IL-2-induced demyelination can be blocked using recombinant viruses expressing different cytokines or by injection of plasmid DNA. We have found that coinfection of HSV-IL-2-infected mice with recombinant viruses expressing IL-12p35, IL-12p40 or IL-12p35+IL-12p40 did not block the CNS demyelination, and that coinfection with a recombinant virus expressing interferon (IFN)-γ exacerbated it. In contrast, coinfection with a recombinant virus expressing IL-4 reduced demyelination, whereas coinfection of HSV-IL-2-infected mice with a recombinant HSV-1 expressing the IL-12 heterodimer (HSV-IL-12p70) blocked the CNS demyelination in a dose-dependent manner. Similarly, injection of IL-12p70 DNA blocked HSV-IL-2-induced CNS demyelination in a dose-dependent manner and injection of IL-35 DNA significantly reduced CNS demyelination. Injection of mice with IL-12p35 DNA, IL-12p40 DNA, IL-12p35+IL-12p40 DNA or IL-23 DNA did not have any effect on HSV-IL-2-induced demyelination, whereas injection of IL-27 DNA increased the severity of the CNS demyelination in the HSV-IL-2-infected mice. This study demonstrates for the first time that IL-12p70 can block HSV-IL-2-induced CNS demyelination and that IL-35 can also reduce this demyelination, whereas IFN-γ and IL-27 exacerbated the demyelination in the CNS of the HSV-IL-2-infected mice. Our results suggest a potential role for IL-12p70 and IL-35 signaling in the inhibition of HSV-IL-2-induced immunopathology by preventing development of autoaggressive T cells.

Purpose: To investigate the clinical settings, treatment given, and visual outcomes for eyes with Pseudomonas aeruginosa endophthalmitis in Taiwan., Methods: This is a retrospective, noncomparative, consecutive case series. Medical records were reviewed in 72 eyes of 71 patients with culture-proven P. aeruginosa endophthalmitis between January 1997 and December 2007., Results: The clinical settings included keratitis/scleritis (44.4%), cataract surgery (15.3%), penetrating keratoplasty (13.9%), endogenous source (12.5%), trauma (6.9%), penetrating keratoplasty with cataract surgery (2.8%), trabeculectomy with cataract surgery (1.4%), trabeculectomy (1.4%), and secondary implant (1.4%). Initial visual acuity ranged from counting fingers to no light perception. Final visual acuity was better than 5/200 in 6 of 72 eyes (8.3%), 4/200 to hand motions in 4 eyes (5.6%), and light perception to no light perception in 62 eyes (86.1%). In vitro testing, the susceptibility patterns of organisms isolated were as follows: ceftazidime (100%), cefepime (100%), aztreonam (100%), imipenem (99%), amikacin (94%), and gentamicin (86%). Five of 16 eyes (31.3%) that underwent primary or secondary pars plana vitrectomy with intravitreal antibiotics achieved a final visual acuity of 5/200 or better compared with 1 of 45 eyes (2.2%) treated with 1 or multiple vitreous tap(s) and intravitreal antibiotics (Fisher's exact test, P = 0.004)., Conclusion: Despite early diagnosis and treatment with intravitreal antibiotics, visual acuity outcomes were generally poor.

Aim: To compare the serum concentration of bevacizumab after intravitreal injection of bevacizumab (IVB) in an experimental model of branch retinal vein occlusion (BRVO) with control injections in albino rats., Methods: BRVO was created in one eye of each of the 24 albino rats. Another 24 rats served as controls. The BRVO was generated by argon laser photothrombosis after intravenous injection with Rose Bengal. Three days later, IVB (5 μl) was administered to both BRVO and control eyes. The serum concentration of bevacizumab was examined at baseline, 6 h, 1 day, 3 days, 7 days, 14 days, and 28 days after IVB., Results: At baseline, no serum bevacizumab was detected in either group. The serum concentration of bevacizumab reached a peak concentration at 1 day with 5,020 ± 1,602 ng/ml in the BRVO group and 4,103 ± 1,790 ng/ml in the control group (p < 0.001). The concentration decreased subsequently on days 3, 7, 14 and 28. The serum concentration of bevacizumab was significantly higher in BRVO rats up to 28 days after IVB., Conclusions: The serum concentration of bevacizumab after IVB reached its peak on day 1 in both BRVO and control eyes. This value was significantly higher in BRVO rats than in control rats up to 28 days after intravitreal injection., (Copyright © 2010 S. Karger AG, Basel.)

Purpose: The purpose of this study was to assess the risk factors for central retinal vein occlusion and associated morbidity and mortality in a Chinese population., Methods: The participants included patients with central retinal vein occlusion 40 years old and younger. Predisposing factors, mortality, and systemic complications were examined in this group., Results: Unilateral (n = 19) and bilateral (n = 3) central retinal vein occlusions were identified in a total of 22 patients (25 eyes), with a mean follow-up time of 37 months. Hypercholesterolemia (65%), hypertriglyceridemia (64%), and hyperhomocysteinemia (42%) were all identified as risk factors. Three patients (14%) developed stroke and 1 (5%) developed transient ischemic attacks during follow-up. Renal failure and pulmonary hypertension resulted in the death of two patients. The mean initial and final visual acuities (+ or - standard deviation) were 20/400 (+ or - 20/250) and 20/500 (+ or - 20/320), respectively, and treatments did not result in vision improvement (P = 0.57). The poor visual prognosis was likely due to macular edema in 7 eyes (28%), optic atrophy in 4 eyes (16%), and secondary glaucoma in 3 eyes (12%)., Conclusion: Morbidity and mortality are high in young Chinese patients with central retinal vein occlusion who may have associated serious complications including stroke, blindness, and death. Central retinal vein occlusion may serve as an initial clinical presentation of serious systemic diseases.

Purpose: To determine the risk factors, especially maternal risk factors, associated with the development of retinopathy of prematurity (ROP) in premature babies., Methods: A matched case-control study involving premature patients was undertaken retrospectively. The case group consisted of premature babies with the subsequent development of ROP. The control group consisted of gestational age-matched and sex-matched premature babies that did not develop ROP during the follow-up period. Risk factors involving patient demographics and maternal characteristics were compared between the case and control groups., Results: A total of 144 patients were included in this study (72 patients in the case group and 72 patients in the control group). Among the 66 possible risk factors compared, only birth weight and maternal age were found to be significant risk factors. Birth weight was significantly lower in the case group (1,248.7 +/- 257.8 g vs. 1,335.5 +/- 297.2 g, P = 0.01), and maternal age was significantly older in the case group compared with that in the control group (31.2 +/- 5.1 years vs. 28.2 +/- 5.3 years, P < 0.001). The odds ratio of having babies with ROP was 2.9 when the maternal age was >30 years., Conclusion: Older maternal age is a newly identified risk factor for the development of ROP in premature babies.

Purpose: To evaluate the efficacy of autologous heparinized whole blood in assisting internal limiting membrane (ILM) peeling by coating the ILM for macular hole (MH) repair., Design: Prospective, interventional case series., Participants: Twenty-nine patients (32 eyes) who underwent blood-assisted ILM peeling for MH repair., Methods: Patients in whom stage 2-4 idiopathic MHs had developed and who desired surgery were enrolled in this study. After core vitrectomy, autologous heparinized whole blood was applied to cover the macula and to coat the surface of the macular area in the fluid-filled vitreous cavity. The redundant blood was removed and only a very thin film of blood was left on the macular area. The blood-coated ILM was removed by forceps in a circular fashion. To confirm the removed membrane was the ILM, the first 10 specimens were examined by electron microscopy (EM)., Main Outcome Measures: The MH closure rate, the interval mean visual acuity (before and after surgery), retinal changes, and the EM results of the ILM specimens., Results: All 32 eyes in 29 patients completed 12 months of follow-up. The ILM were coated by autologous heparinized whole blood, removed without difficulty, and confirmed by EM. The whole blood highlighted the contrast of the coated and noncoated areas during the ILM peeling procedure. The MHs were closed in all surgical eyes with a single surgery (100%). Compared with study entry, the mean logMAR best-corrected visual acuity 12 months after surgery improved significantly (1.02 and 0.53, respectively; P<0.001). At 12 months of follow-up, 31 eyes (96.9%) had stable or improved vision. No toxic fundus changes were observed during follow-up., Conclusions: Autologous heparinized whole blood coated the ILM and facilitated visibility during ILM peeling. Autologous heparinized whole blood is a cost-effective and useful tool for assisting MH surgery.

Purpose: To evaluate the correlation between glycosylated haemoglobin (HbA1c) and central foveal thickness as measured by optical coherence tomography (OCT) in patients with diabetes., Methods: Retrospectively review of medical records of central foveal thickness as measured by OCT and laboratory data of glycosylated haemoglobin. HbA1c was compared with foveal thickness measured by OCT within the preceding 3 months. Clinically significant macular oedema (CSME) was diagnosed if central foveal retinal thickness was greater than 325 mum in OCT., Results: One hundred and two eyes of 102 patients were included in this cross-sectional study. Univariate analysis revealed that the CSME diagnosed by OCT in diabetes was not statistically significant with sex, right or left eye, DM duration over 10 years or not, and AC sugar level (over 140 or not). The HbA1C level (8 or over) and age (50 or less) showed a significant (P=0.005 and 0.006, respectively) and positive association with macular thickness in OCT. A trend towards higher risk was seen for factors of age or=8%., Conclusions: Patients with HbA1c of 8 or above had an increase in macular thickness in type 2 diabetic eyes and there was a statistical significant correlation between younger age, shorter DM duration and thicker macular thickness. Strict sugar control decreased the risk of diabetic macular retinopathy, and OCT could be an excellent detector of early diabetic macular oedema.

Purpose: To assess phacoemulsification learning curve by analysing residents' surgical completion and complication rates., Methods: This prospective study included 226 cases of phacoemulsification performed by 11 senior residents under a single supervisor during a 27-month period. Both completion and complication rates were collected to assess their surgical results. 'Short-term completion rate (STCR)', the frequency of the surgeries completed exclusively by the residents during every five consecutive cases, was used in the evaluation of the learning curve parameter., Results: These residents could complete phacoemulsification independently in 101 surgeries (44.7%). Intraoperative complications occurred in 62 cases (27.4%), of which 11 cases were complicated with vitreous loss (4.9%). By tracing different residents' individual STCRs, we found that the learning curve for phacoemulsification surgery to be of an exponential pattern, and the first STCR of 60% to be a good representation of the exponential point. Before the residents' first STCR of 60%, their average completion rate was only 16.7% and complication rate was as high as 39.2%. While after that point, the average completion rate accelerated to 76.4% and complication rate decreased to 14.2%., Conclusion: The learning curve of phacoemulsification is of an exponential pattern and the trainees' STCR can be a useful parameter to evaluate their surgical performance.

Purpose: To classify the severity of blepharophimosis, describe associated features and their effects on the incidence of amblyopia and to recommend guidelines for surgical treatment and management of surgical complications., Methods: The case records of 23 patients with blepharophimosis syndrome were examined retrospectively. Patients' photographs and measurements were reviewed to analyse the severity of blepharophimosis, surgical techniques undertaken, surgical outcomes, and complications. Statistical analyses were performed using paired-sample t-tests to evaluate the surgical outcome and Spearman correlation to examine the influence of blepharophimosis on the interpalpebral fissure height (PFH)., Results: Eighteen out of 23 (78%) patients underwent one-stage surgery before the age of 5 years. About 31% of these patients had amblyopia. Only two patients had a blepharophimosis ratio greater than 1.5 as poor result. Two out of 18 (11%) patients with PFHs more than 2 mm needed a repeat operation, but all five (100%) patients with s less than 2 mm (very severe ptosis) needed repeat operations., Conclusions: The one-stage corrective procedure provided acceptable results both in function and cosmesis. However, patients with very severe ptosis required multiple stages of reconstruction for ptosis correction at an earlier age, after which correction of telecanthus and small horizontal palpebral fissure length followed at an older age.