Hepatocyte Growth Factor and Retinal Arteriolar Diameter in Singapore Chinese
ABSTRACT To assess if natural genetic variation in hepatocyte growth factor (HGF) is associated with altered retinal vessel diameter.
Two-stage cohort study.
Discovery set (set 1, n = 682 children) and confirmatory set (set 2, n = 1293 adults).
Children in the discovery set were genotyped for a panel of genetic markers within HGF. Markers that were found to be associated significantly with altered retinal vessel diameter then were genotyped in the confirmatory set.
Increased or decreased retinal vessel diameter.
In the discovery set (n = 682 Chinese children aged 7 to 12 years), the variant allele of 4 HGF single nucleotide polymorphisms (SNPs) demonstrated association with larger retinal arteriolar diameter. The effect of the variant allele seems to be strongest within a recessive model of inheritance (P(min) = 4.6x10(-3)) for all 4 SNPs. When these 4 SNPs were assessed in a confirmatory study comprising 1293 Chinese adults, successful replication was observed for one of them (HGF +63962; rs5745752); the variant allele was observed to correlate with significantly larger retinal arteriolar diameter, with its effect again strongest within a model of recessive inheritance (P = 0.049). Analyzed as a quantitative trait, recessive carriage at HGF +63962 resulted in on average a 3.5-microm increase in retinal arteriolar diameter among children and a 2.5-microm increase in adults (P = 7.0x10(-3), analysis of variance; P = 3.0x10(-3), Kruskal-Wallis test).
This study suggests that natural variation within HGF is involved in the control of retinal arteriolar diameter and may be important in the pathogenesis of microvascular disease in individuals of Chinese descent.
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ABSTRACT: Retinal arteriolar and venular calibers are highly heritable and associated with cardiovascular disease. This study was designed to investigate the relative influence of genetic and environmental factors on the high phenotypic correlation (r = 0.59) between these two traits and to assess the shared and specific influence of established and novel cardiovascular disease risk factors on them. A total of 1463 Caucasian female twins (706 monozygotic and 757 dizygotic), between 24 and 79 years of age, underwent retinal photography from which retinal arteriolar (mean, 153.75 ± 22.1 μm, SD) and venular (mean, 232.1 ± 36.6 μm) calibers were measured with semiautomated software. A bivariate heritability model was used to assess the genetic and environmental influences underlying both specific trait variance and the covariance between the vessel traits. The investigation was an assessment of phenotypic associations between retinal arteriolar and venular calibers and cardiovascular disease risk factors. Additive genetic factors accounted for approximately three fourths of the covariance between retinal arteriolar and venular calibers within the cohort. This finding was replicated in a sample of 1981 twins from the Australian Twins Eye Study. The partial correlation showed that known risk factors accounted for only 5% of the covariance between arteriolar and venular calibers. Novel associations were found between venular caliber and β-cell function (P = 0.011) and insulin sensitivity (P = 0.002). These results suggest that future gene-mapping studies may identify pleiotropic genetic variants influencing both retinal arteriolar and venular calibers. Genetic variants associated with retinal caliber and (risk factors for) cardiovascular disease should provide new etiologic insights into this complex disease.Investigative ophthalmology & visual science 10/2010; 52(2):975-81. DOI:10.1167/iovs.10-5927 · 3.66 Impact Factor