Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression

Background Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production; however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. Methods We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Results Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Conclusions Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.

Genetic Disruption of Serine Biosynthesis is a Key Driver of Macular Telangiectasia Type 2 Etiology and Progression

PurposeMacular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre, and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production, however, an independent vascular contribution is also suspected. Here we use statistical genetics to dissect the causal mechanisms underpinning this complex disease.MethodsWe integrated genetic markers for MacTel, vascular, and metabolic traits, and applied Mendelian randomization, MTAG, and conditional/interaction genome-wide association analysis to discover causal contributors to both disease, and spatial retinal imaging sub-phenotypes.ResultsSerine was a key causal driver of disease occurrence and progression, with a lesser contribution to type 2 diabetes risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis resolved three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes.DiscussionOur findings will aid in early diagnosis and accurate prognosis of MacTel, and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.

Association between hypertension and retinal vascular features in ultra-widefield fundus imaging

ObjectiveChanges to the retinal vasculature are known to be associated with hypertension independently of traditional risk factors. We investigated whether measurements of retinal vascular calibre from ultra-widefield fundus imaging were associated with hypertensive status.MethodsWe retrospectively collected and semiautomatically measured ultra-widefield retinal fundus images from a subset of participants enrolled in an ongoing population study of ageing, categorised as normotensive or hypertensive according to thresholds on systolic/diastolic blood pressure (140/90 mm Hg) measured in a clinical setting. Vascular calibre in the peripheral retina was measured to calculate the nasal–annular arteriole:venule ratio (NA-AVR), a novel combined parameter.ResultsLeft and right eyes were analysed from 440 participants (aged 50–59 years, mean age of 54.6±2.9 years, 247, 56.1% women), including 151 (34.3%) categorised as hypertensive. Arterioles were thinner and the NA-AVR was smaller in people with hypertension. The area under the receiver operating characteristic curve of NA-AVR for hypertensive status was 0.73 (95% CI 0.68 to 0.78) using measurements from left eyes, while for right eyes, it was 0.64 (95% CI 0.59 to 0.70), representing evidence of a statistically significant difference between the eyes (p=0.020).ConclusionsSemiautomated measurements of NA-AVR in ultra-widefield fundus imaging were associated with hypertension. With further development, this may help screen people attending routine eye health check-ups for high blood pressure. These individuals may then follow a care pathway for suspected hypertension. Our results showed differences between left and right eyes, highlighting the importance of investigating both eyes of a patient.

Association of Meniere’s disease and retinal vascular calibre: a prospective observational study in China

ObjectiveIt is believed that Meniere’s disease (MD) is associated with vascular disorders, but few studies have reported the relationship between retinal vascular disorders and MD. We evaluated and compared the retinal vascular calibres in patients with MD with healthy subjects matched for age, sex and vascular risk factors using retinal photographs to explore the association between MD and retinal vascular calibre.Study designA prospective study.SettingTertiary referral centre.ParticipantsSixty patients with MD and 62 healthy subjects matched for age, sex and vascular risk factors were enrolled in this study. Twenty-four patients with MD had migraines, and 36 patients with MD did not have migraines.Main outcome measureRetinal vascular calibres were calculated and compared not only between patients with MD and healthy subjects but also between subgroups of patients with MD.ResultsCompared with healthy subjects, patients with MD had a slightly larger retinal artery calibre (126.30±10.45vs 119.61±15.86, p=0.006) and a higher retinal artery/vein ratio (0.79±0.09vs 0.75±0.10, p=0.005). Among patients with MD, those with migraines had a larger retinal artery calibre (130.73±11.55vs 123.35±8.61, p=0.006) than those without migraines. Moreover, the presence of migraines and the high frequency of vertigo attacks appeared to increase the retinal artery calibre.ConclusionsOur study suggests that a relationship exists between retinal vascular calibre and MD. Although the pathophysiological relationship between migraine and MD remains unclear, the presence of migraine attacks may aggravate endolymphatic hydrops (EH) and accelerate the outflow of EH in patients with MD. More extensive studies are required to explore the association between retinal vascular calibre and MD.

Vascular risk factors are associated with retinal arteriolar narrowing and venular widening in children and adolescents with type 1 diabetes

Background:The aim of the study was to describe the relationship of retinal arteriolar and venular calibre with vascular risk factors in children and adolescents with type 1 diabetes.Methods:In this hospital-based cross-sectional study, the medical files of 483 children and adolescents with type 1 diabetes were audited to collect retinal images and relevant clinical data. Retinal vascular calibre was measured using standardised protocols.Results:After multivariable adjustments, a vascular risk profile that included: older age, higher serum creatinine, higher systolic blood pressure (SBP), higher body mass index (BMI), abnormal estimated glomerular filtration rate (eGFR), lower high-density lipoproteins (HDL) cholesterol, longer duration of diabetes and higher serum sodium was associated with narrower central retinal artery equivalent (CRAE) (95% CI=−4.10/−0.76, p=0.004). A specific risk profile, including higher total cholesterol level, higher BMI, lower physical activity level, higher HbAConclusions:In summary, these findings support evidence that cardiovascular disease may have its origins early in life. Prospective and/or intervention studies are required to confirm whether the observed associations are involved in the causal pathway for retinal vascular calibre.