Annie K. McAuley

Four Novel Loci (19q13, 6q24, 12q24, and 5q14) Influence the Microcirculation In Vivo

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n = 6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10−8) 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.

Methodology and early findings of the Diabetes Management Project: a cohort study investigating the barriers to optimal diabetes care in diabetic patients with and without diabetic retinopathy

Background:  The Diabetes Management Project is investigating the clinical, behavioural and psychosocial barriers to optimal diabetes care in individuals with and without diabetic retinopathy.

Vitreous biomarkers in diabetic retinopathy: a systematic review and meta-analysis.

The aim of this study was to perform a systematic meta-analysis of biomarkers investigated with diabetic retinopathy (DR) in the vitreous, and to explore the molecular pathway interactions of these markers found to be consistently associated with DR. Relevant databases [PubMed and ISI web of science] were searched for all published articles investigating molecular biomarkers of the vitreous associated with DR. Based on set exclusion/inclusion criteria available data from studies with human vitreous samples were extracted and used for our meta-analysis. The interactions of significant biomarkers in DR were investigated via STRING and KEGG pathway analysis. Our meta-analysis of DR identifies eleven biomarkers as potential therapeutic candidates alternate to current anti-VEGF therapy. Four of these are deemed viable therapeutic targets for PDR; ET receptors (ET A and ET B), anti-PDGF-BB, blocking TGF-β using cell therapy and PEDF. The identification of supplementary or synergistic therapeutic candidates to anti VEGF in the treatment of DR may aid in the development of future treatment trials.

Replication of genetic loci implicated in diabetic retinopathy

PURPOSE Recent genome-wide association studies for diabetic retinopathy (DR) have identified novel single nucleotide polymorphisms (SNPs) associated with this potentially blinding disease. These markers could prove useful in risk profiling, if the association are validated by replication. To date, these associations have not been well assessed in independent cohorts. The objective of this study was to ascertain any association of these polymorphisms with advanced stages of DR. METHODS A total of 463 patients who had either type 1 (n = 46) or 2 (n = 417) diabetes were genotyped for 24 SNPs previously implicated in DR. Cases (n = 163) were defined as people with severe nonproliferative DR or proliferative DR. Control participants (n = 300) with a confirmed duration of diabetes of at least 5 years had either no evidence of DR or only mild DR. RESULTS Two SNPs (rs1073203 and rs4838605) were found to be significantly associated with DR in patients with diabetes after adjusting for covariants; rs1073203-G (P = 0.012, odds ratio [OR] = 0.317, 95% confidence interval [95% CI]: 0.129-0.778), rs1073203 in a dominant model (P = 0.005, OR = 0.251, 95% CI: 0.096-0.655), rs4838605 in an additive model (P = 0.047, OR = 1.650, 95% CI: 1.007-2.703), In a dominant model rs1073203 (P = 0.027, OR = 1.400, 95% CI: 0.101-0.857), was significantly associated with DR in type 2 diabetes after adjustment for covariants. This study was sufficiently powered to replicate previous findings. CONCLUSIONS This study confirmed that two variants (rs1073203 and rs4838605) are associated with advanced stages of DR in our cohort. The underlying genes in these candidate regions provide interesting future gene association targets for understanding the pathogenesis of DR.

A genetic variant regulating miR-126 is associated with sight threatening diabetic retinopathy:

Background: The regulation of miR-126 by rs4636297 single nucleotide polymorphism (SNP) has been implicated in the pathogenesis of neovascularisation by promoting vascular endothelial growth factor, suggesting it could be associated with sight threatening diabetic retinopathy (STDR), but has not been previously investigated or reported. Materials and methods: A case control study of 531 individuals with diabetes was genotyped for the rs4636297 SNP, using the Sequenom iPLEX Gold chemistry. STDR included people with severe non-proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR). Association was tested using logistic regression analysis, adjusting for confounding variables. Results: In an additive model, the A allele of rs4636297 SNP is significantly associated with STDR compared to people with none or mild diabetic retinopathy (DR) (odds ratio (OR) = 2.02, 95% confidence interval (CI) = 1.22–3.35, p = 0.006). Conclusion: The A allele of rs4636297, known to be the non-functional allele for post-translational regulation of miR-126, is associated with STDR. This finding suggests that this locus would be a potential therapeutic target for inhibiting the development of DR.

Association of retinal vessel calibre with diabetic retinopathy in an urban Australian indigenous population.

Purpose:  To assess the relationship of retinal vessel diameter and diabetic retinopathy (DR) in a subgroup of participants recruited through the Darwin Region Urban Indigenous Diabetes study.