Genetic and Early Life Influences on the Human Retinal Microcirculation


  • Alun D. Hughes

    1. International Centre for Circulatory Health, NHLI Division, Faculty of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK
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Author for correspondence: Alun D. Hughes, International Centre for Circulatory Health, National Heart & Lung Institute, Imperial College London, London W2 1LA, UK (fax +44 (0) 20 7594 3392, e-mail


Abstract:  The retinal fundus offers a rare opportunity to visualize the microcirculation in man using minimally invasive approaches. The purpose of this MiniReview is to summarize recent work on genetic and early life influences on the retinal microcirculation and to suggest how these observations may help inform our understanding of the human microcirculation in health and disease.

The principal role of the circulation is to transport and allow exchange of materials with organs and tissues. The microcirculation, generally defined as small blood vessels with diameters less than a few hundred micrometres [1], is crucial to this function – indeed, Carl Wiggers commented ‘in our zeal to interpret the importance of the heart and great vessels, it should never be forgotten that the more obvious phenomena of the circulation are but a means through which the real object of maintaining an adequate capillary flow is attained’ (quoted Johnson [2]). Abnormalities of the microcirculation can precede macrovascular disease, and it is argued that microcirculatory dysfunction may play a key role in the pathogenesis of macrovascular disease [3].

The purpose of this MiniReview is to summarize recent work on genetic and early life influences on the retinal microcirculation and to suggest how these observations may inform our understanding of the microcirculation in health and disease. As a consequence of the limited scope of this review, a number of important topics, for example, the effect on the retinal microcirculation of classical cardiovascular risk factors and systemic diseases, such as diabetes, hypertension, sepsis or autoimmune conditions, or retinal diseases such as retinopathy of prematurity, age-related macular degeneration and glaucoma, will not be discussed; these are well covered by recent reviews [4–8].

The Retinal Microcirculation

The retinal fundus offers a relatively rare opportunity to visualize the microcirculation in man using non-invasive or minimally invasive approaches, and there is accumulating evidence that quantitative retinal assessment may help to predict cardiovascular disease [9,10]. A number of structural and functional imaging approaches exist, including laser Doppler flowmetry, optical coherence tomography, retinal oximetry and retinal photography, but with the exception of retinal photography, these approaches are generally used in small-scale studies. Using digital retinal photography, it is possible to take measurements on small blood vessels in the range 50–300 μm with the advantage that these blood vessels are displayed in a relatively planar two-dimensional network (fig. 1). Various quantitative measures can be made: (i) vessel diameter, either averaged across various generations or used to estimate the central retinal arteriolar or central venular diameter by a formula validated in normal individuals [11]; (ii) vessel density assessed using vessel number over a region of the retina [12], tree density [13], branching angles [14] or fractal dimension [15]; (iii) vessel network architecture (e.g. vessel branching exponent or optimality deviation), a putative indicator of microvascular endothelial function [16]; and (iv) vessel tortuosity [17]. More recently, it has also been suggested that vessel wall-to-lumen ratio can be assessed using scanning laser Doppler [18], although the relationship of the optical measures with anatomical structures needs to be confirmed.

Figure 1.

 The retinal microvasculature. (A) Schematic depiction of the anatomy of the eye in cross-section. (B) Red-free fundus image showing the optic disc and retinal blood vessels.

While studies of the retinal microcirculation do provide insight into microcirculatory function, it is important to remember that there is considerable specialization of the microcirculation within tissues and the retinal microcirculation is no exception. For example, the retinal microvasculature, unlike the choroidal circulation, is not innervated by the sympathetic nerves, and a variety of paracrine factors regulate its function [19].

Genetic Influences on the Retinal Microcirculation

Monogenic influences.

Numerous rare congenital conditions affect the retinal microcirculation, while there is often some overlap in phenotype, for example, increased vascular tortuosity, most of these diseases also have unique features. In some cases, their effects on the retinal microvasculature are likely to be secondary to interference with normal retinal visual function or anatomy. In others, the abnormalities result from a more generalized systemic impairment of microcirculatory development or function. In some conditions (e.g. hereditary haemorrhagic telangiectasia – associated with systemic arterio-venous malformations, pulmonary hypertension and stroke [20,21]; macular telangiectasia (MacTel) – associated with hypertension, diabetes and coronary artery disease [22]; and Norrie disease – reported co-segregation with idiopathic pulmonary hypertension [23]), there are reported associations with a variety of systemic or pulmonary circulatory diseases.

Increasingly, the genetic basis for such congenital abnormalities has been determined (table 1), but frequently, the link between genotype and vascular phenotype remains obscure. Nevertheless, many of the gene defects identified may in time provide valuable insights into the genetic determinants of microvascular development in the eye and elsewhere.

Table 1. 
Congenital abnormalities of the retinal microcirculation.
ConditionRetinal microvascular featuresGenetic abnormalityRef
Von Hippel–Lindau disease (VHL; MIM no. 193300)Retinal haemangioblastomasMutations in VHL gene on 3p25–26[24]
Bloom’s syndrome (BS; MIM no. 210900)Retinoblastoma; non-proliferative diabetic retinopathyMutation in gene encoding DNA helicase RecQ protein-like-3 on 15q26.1[25]
Hereditary haemorrhagic telangiectasia (types 1–4)
HHT1 (MIM no. 187300)
HHT2 (MIM no. 600376)
HHT3 (MIM no. 601101)
HHT4 (MIM no. 610655)
Retinal telangiectasiaHHT1 – mutations in endoglin gene (ENG) on 9q34
HHT2 – mutations in ALK1 gene (ACVRL1) on 12q
HHT3 – candidate locus mapped to a 5.4-cM disease interval on 5q31.3–q32
HHT4 – candidate disease locus mapped to a 7-Mb region on 7p14
Macular telangiectasia (Mactel types 1–3); idiopathic juxtafoveal (or juxtafoveolar) telangiectasiaRetinal telangiectasia, tortuous and dilated retinal vessels, macular pigment changes, macular oedema and in some cases macular holesUnknown[28]
Retinal telangiectasia associated with hypogammaglobulinaemia (MIM no. 267900)Retinal telangiectasia associated with hypogammaglobulinaemiaUnknown[29]
Facioscapulohumeral muscular dystrophy 1a; FSHMD1A (MIM no. 158900)Retinal telangiectasia, arteriolar tortuosity, microaneurysms, exudative retinopathyContraction of the D4Z4 macrosatellite repeat subtelomeric region of 4q35 resulting in inappropriate transcriptional derepression of 4q35 genes[30]
Norrie disease (ND; MIM no. 310600); X-linked familial exudative vitreoretinopathy 2 (EVR2; MIM no. 305390); idiopathic retinal telangiectasia; Coat’s disease (MIM no. 300216); and related conditionsVariable manifestations including retinal vascular dysgenesis, hyaloid vessels, retinal neovascularization, retinal telangiectasia,Mutations in the NDP gene (300658) on Xp11[31]
Exudative vitreoretinopathy 1 (EVR1; MIM no. 133780)Peripheral retinal avascularity, neovascularization, acute-angle vascular branching, exudative retinopathyMutations in the frizzled-4 gene (FZD4) on 11q14[32]
Exudative vitreoretinopathy 3 (EVR3; MIM %605750)Peripheral retinal avascularity, neovascularization, exudative retinopathyLocus mapped to 11p13–p12, approximately 30 cM from the EVR1 locus[32]
Exudative vitreoretinopathy 4 (EVR4; MIM no. 601813)Peripheral retinal avascularity, neovascularization, exudative retinopathyMutations in the low-density lipoprotein receptor–related protein 5 gene (LRP5) on 11q13.4[33]
Silver–Russell syndrome (SRS, MIM no. 180860)Retinal vascular tortuosityVarious (involving chromosomes 1, 7, 8, 11, 15, 17 and 18) resulting in hypomethylation of the H19 imprinting control region (H19-ICR) at 11p15, and reduced expression of IGF2[34]
Severe juvenile arteriosclerosis (MIM %208060)Retinal vascular tortuosityUnknown[35]
Velocardiofacial syndrome (VCFS; MIM no. 192430)Retinal vascular tortuosity1.5- to 3.0-Mb hemizygous deletion of chromosome 22q11.2. Haploinsufficiency of the TBX1 gene is probably mainly responsible for manifestations[36]
Gillespie syndrome (MIM no. 206700)Retinal vascular tortuosity, retinal hypopigmentationSplice site mutation in the PAX6 gene on 11p13[37]
Williams–Beuren syndrome (WBS; MIM no. 194050)Retinal vascular tortuosityHemizygous deletion of 1.5–1.8 Mb on chromosome 7q11.23, which contains approximately 28 genes[38]
Galactosialidosis (GSL; MIM no. 256540)Retinal vascular tortuosityMutations in cathepsin A (CTSA) on 20q13.1[39]
Fabry’s disease (MIM no. 301500)Retinal vascular tortuosityMutations in the gene encoding alpha-galactosidase A (GLA) on Xq22[40]
Brain small vessel disease with haemorrhage (MIM no. 607595)Retinal vascular tortuosityMutation in the COL4A1 gene on 13q34[41]
Leber’s congenital amaurosis (LCA)Retinal dystrophy with retinopathy, retinal arteriolar narrowing and abnormal retinal vessels probably secondary to retinal degenerationAutosomal recessively inherited, genetically heterogeneous group of conditions including 14 different mutations in various genes[42]
Retinitis pigmentosa (RP)Attenuated retinal vesselsGenetically heterogeneous group of conditions including 58 different mutations in various genes[43]
Incomplete congenital stationary night blindness (CSNB2A; MIM no. 300071)Attenuated retinal vessels, optic disc atrophy [2]Mutations in CACN1F on Xp11.23–p11.22[44]
Cerebral arteriopathy with subcortical infarcts and leucoencephalopathy (CASIDIL; MIM no. 125310)Arteriolar narrowing, arterio-venous nicking, tortuous retinal arteriolesMutations of the NOTCH3 gene on 19q12[45,46]
Knobloch syndrome (MIM no. 267750)Diffuse narrowing of retinal arteriolesHomozygous splice site mutation in the COL18A1 gene on chromosome 21q22.3[47,48]
Papillorenal syndrome (MIM no. 120330)Rudimentary or absent central retinal vesselsMutation in PAX2 gene on 10q24.3–q25.1[49]
Alagille’s syndrome 1 (ALGS1; MIM no. 118450)Angulated retinal vessels, retinopathy, chorioretinal atrophyMutations in JAG1 gene on 20p12[50]
Laron syndrome (MIM no. 262500)Reduced number of retinal branching pointsMutations in growth hormone receptor gene (GHR) on 5p13–p12[51]
Congenital growth hormone deficiencyReduced number of retinal branching pointsNot reported[52]
Sorsby’s fundus dystrophy (MIM no. 136900)Peripheral atrophy, subretinal neovascularizationMutations in TIMP3 gene on 22q12.1–q13.2[53]
Pseudoxanthoma elasticum (MIM no. 264800)Focal chorioretinal atrophy (salmon spots), choroidal neovascularizationMutations in the ABCC6 gene on 16p13.1[54]

Polygenic influences.

The hereditability of the various aspects of the retinal microcirculation has not been studied extensively. Some twin studies [55–57] have concluded that the heritability of retinal arteriolar and venular calibre is around 70%. A recent study [57] also found that approximately 77% of the co-variance between arteriolar and venular diameter was because of additive genetic factors.

Despite the relatively high hereditability of retinal arteriolar and venular calibre, attempts to identify common gene variants influencing the retinal microvasculature have met with only limited success so far. In the Atherosclerosis Risk in Communities (ARIC) study, apolipoprotein E (Apo E) epsilon 4 was weakly associated with retinopathy in persons without diabetes, but not other retinal microvascular abnormalities [58]; however, Apo E polymorphisms were not predictive of retinal arteriolar or venular diameter. A similar lack of associations between Apo E polymorphisms and retinal microvascular abnormalities or retinal vessel diameters was also seen in the Cardiovascular Health Study (CHS) [59]. Further analysis of the CHS data found no association between single nucleotide polymorphisms in three candidate hypertension genes, alpha-adducin (ADD1/G460W), beta2-adrenergic receptor (ADRB2/Arg16Gly and Gln27Glu) and G-protein beta3 subunit (GNB3/C825T) and retinal arteriolar and venular calibre. In a relatively small study of 368 participants of the Funagata study, Tanabe et al. [60]. reported that retinal arteriolar diameter was significantly narrower in individuals with the deletion (D/D) genotype of the angiotensin-converting enzyme (ACE) gene compared to individuals with insertion/deletion (I/D) or insertion (I/I) genotypes after multivariable adjustment. The significance of this observation is unclear because while the D/D polymorphism leads to increased expression of ACE, it does not affect circulating levels of angiotensin II, although it may affect the degradation of bradykinin [61]. A more recent study [62] of 15,358 unrelated Caucasian individuals (members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium) found no significant genetic associations with retinal arteriolar calibre. Four loci (19q13, 6q24, 12q24 and 5q14) were reproducibly shown to be associated with retinal venular calibre, but the loci identified only explained 1.0–3.2% of the variation in retinal venular calibre. Interestingly, locus 12q24 was also associated with coronary heart disease and hypertension in two independent samples. An admixture mapping scan of African American ancestry in ARIC failed to show any significant admixture association with arteriolar or venular calibre but identified a significant association between greater African ancestry at chromosome 6p21.1 and wider venular diameter in people with hypertension [63].

Early Life Influences

Ideas regarding the importance of early life influences on adult development and disease became prominent towards the end of the 19th century [64]. In the twentieth century, work by Barker et al. [65] emphasized the extent to which prenatal exposures may influence the risk of chronic disease in adult life, possibly through intrauterine programming during susceptible periods. Birthweight or birthweight indexed for body size (e.g. ponderal index) has been widely used as a crude measure of prenatal development in such studies. The effects of birthweight appear to act across the whole range of birthweights, rather than simply reflecting the impact of substantial intrauterine growth retardation or prematurity. Nevertheless, it is clear that significant intrauterine growth retardation and prematurity are associated with persistent reduced density (rarefaction) of the retinal microcirculation [66–68]. This, in combination with observations of the persistence of retinal microvascular abnormalities associated with retinopathy of prematurity [69] or foetal alcohol syndrome [70] into later life, suggests a relative lack of plasticity of the retinal microvascular network, that is, damage to the retinal microvascular network early in life may compromise its ability to develop normally. This may have important implications for mechanisms linking early exposures to disease in later life.

Ideally, studies of the influence of early exposures should be based on longitudinal data over the life course, thereby enabling better modelling of the potential confounding influence of current exposures [71]. However, at present, no such data have been published for the retinal microcirculation, and relevant information is drawn from cross-sectional studies at various times over the life course.

Chapman et al. [72]. reported that low birthweight was associated with narrower arteriolar bifurcation angles in a randomly selected sample of 100 men aged 64–74 years who were participants in the Hertfordshire Aging study. This relationship was independent of current blood pressure and was interpreted as showing reduced arteriolar density in adults of low birthweight. Self-reported birthweight of adults in the ARIC study was also positively correlated with diameter independent of blood pressure [73]. More recently, studies have been performed in children, where relationships are, perhaps, less confounded by issues of reverse causality. These have shown that low birthweight in the normal range (i.e. excluding individuals with very low birthweight or premature infants) is associated with narrow retinal arterioles in childhood [74,75] and adolescence [76] and altered relationships of parent and daughter arterioles at bifurcations, indicative of endothelial dysfunction [77]. Low birthweight was also associated with increased arteriolar tortuosity [77] in children born at term (≥37 weeks gestation) in keeping with earlier observations in intrauterine growth retardation.


There is increasing evidence that genetic and early life influences exert effects on susceptibility to chronic diseases via changes in the microcirculation. Non-invasive assessment of the retinal microcirculation is applicable to large-scale population studies, and studies using this technique may be useful in elucidating how genes, prenatal programming and the life course influence microcirculatory physiology and pathology. However, taking high blood pressure as an example, current data suggest that the effect of an individual gene or specific early life exposure (e.g. intrauterine growth [78]) on blood pressure is small. Indeed, it has been estimated that the 29 genetic variants found so far by genome-wide association studies account for <1% of the total variance in resting systolic or diastolic blood pressure [79]. This seems paradoxical given the high estimates of blood pressure heritability. This problem of ‘missing’ heritability (which has been termed ‘the dark matter of genome-wide association studies’ [80]) is ubiquitous in the genetics of complex traits, and at present, it remains unclear whether it is attributable to technical issues (e.g. poorly detected rarer variants or structural variants), inadequate accounting for shared environment among relatives, neglect of gene–gene or gene–environment interactions, epigenetic influences or other factors [80, 81]. These issues remain a substantial challenge for workers aiming to establish the genetic and life course determinants of cardiovascular disease.


The author acknowledges the support of the NIHR Biomedical Research Centre Scheme.

Conflicts of Interest