Candidate gene study of macular response to supplemental lutein and zeaxanthin.

Supplementation with carotenoids is proposed to protect against age-related macular degeneration. There is, however, considerable variability in retinal macular pigment response, which may be due to underlying genetic variation. The purpose of this study was to determine whether genetic factors, which have been previously associated with cross-sectional macular pigment levels in the retina or serum lutein, also influence response to supplementation. To this end we conducted an association study in 310 subjects from the TwinsUK cohort between variants in 8 candidate genes and serum lutein and retinal macular pigment optical density (MPOD) levels before and after supplementation. Four variants were associated with MPOD response to supplementation (p < 0.05): rs11057841 (SCARB1), rs4926339 (RPE65), rs1929841 (ABCA1) and rs174534 (FADS1). We also confirmed previous associations between rs6564851 near BMCO1 (p < 0.001) and rs11057841 within SCARB1 (p = 0.01) and baseline measures of serum lutein; while the latter was also associated with MPOD response, none of the BMCO1 variants were. Finally, there was evidence for association between variants near RPE65 and ELOVL2 and changes in lutein concentration after supplementation. This study is the first to show association between genetic variants and response to carotenoids supplementation. Our findings suggest an important link between MP response and the biological processes of carotenoids transport and fatty acid metabolism.

Identification and replication of three novel myopia common susceptibility gene loci on chromosome 3q26 using linkage and linkage disequilibrium mapping.

Refractive error is a highly heritable quantitative trait responsible for considerable morbidity. Following an initial genome-wide linkage study using microsatellite markers, we confirmed evidence for linkage to chromosome 3q26 and then conducted fine-scale association mapping using high-resolution linkage disequilibrium unit (LDU) maps. We used a preliminary discovery marker set across the 30-Mb region with an average SNP density of 1 SNP/15 kb (Map 1). Map 1 was divided into 51 LDU windows and additional SNPs were genotyped for six regions (Map 2) that showed preliminary evidence of multi-marker association using composite likelihood. A total of 575 cases and controls selected from the tails of the trait distribution were genotyped for the discovery sample. Malecot model estimates indicate three loci with putative common functional variants centred on MFN1 (180,566 kb; 95% confidence interval 180,505-180, 655 kb), approximately 156 kb upstream from alternate-splicing SOX2OT (182,595 kb; 95% CI 182,533-182,688 kb) and PSARL (184,386 kb; 95% CI 184,356-184,411 kb), with the loci showing modest to strong evidence of association for the Map 2 discovery samples (p<10(-7), p<10(-10), and p = 0.01, respectively). Using an unselected independent sample of 1,430 individuals, results replicated for the MFN1 (p = 0.006), SOX2OT (p = 0.0002), and PSARL (p = 0.0005) gene regions. MFN1 and PSARL both interact with OPA1 to regulate mitochondrial fusion and the inhibition of mitochondrial-led apoptosis, respectively. That two mitochondrial regulatory processes in the retina are implicated in the aetiology of myopia is surprising and is likely to provide novel insight into the molecular genetic basis of common myopia.

The role of heredity in determining central retinal thickness.

AIMS: To examine the relative roles of genetic and environmental factors in central retinal thickness, by performing a classical twin study. METHODS: 310 subjects were recruited from the TwinsUK adult registry at St Thomas' Hospital. Optical coherence tomography (Zeiss, stratus OCT3) was used to measure the average retinal thickness in the central 1 mm diameter area. The covariance of central retinal thickness (CRT), within MZ and DZ twin pairs, was compared and genetic modelling techniques were used to determine the relative contributions of genes and environment to the variation in CRT observed in this population. MAIN OUTCOME MEASURE: CRT (average retinal thickness in the central 1 mm diameter area, centred on the fovea). RESULTS: The mean CRT of all subjects was 212.1 microm (range 165-277). CRT was statistically related to refractive error, with increasing myopia associated with a thinner CRT. CRT was more highly correlated within MZ twin pairs (r = 0.88) than with DZ twin pairs (r = 0.58), suggesting a genetic role. A model combining additive genetic and unique environmental factors provided the best fitting model and gave a heritability estimate of 0.90. CONCLUSION: Genetic factors appear to play an important role in CRT, with a heritability estimate of 0.90.

Central corneal thickness is highly heritable: the twin eye studies.

PURPOSE: A classic twin study was performed to determine the heritability of central corneal thickness (CCT), an important parameter in glaucoma assessment. METHODS: The concordance of CCT between monozygotic (MZ) and dizygotic (DZ) twins was compared. A total of 256 twin pairs (131 MZ and 125 DZ) were recruited from three centers: the Twin Eye Study in Tasmania, the Brisbane Adolescent Twin Study, and the Twins U.K. Adult Registry held at St. Thomas' Hospital in London. As part of an extensive ophthalmic evaluation, CCT was measured by ultrasound pachymetry. Structural equation modeling with the Mx program (Department of Psychiatry, Medical College of Virginia, Richmond, VA) was used to determine the heritability of CCT. RESULTS: The mean age of subjects was 38 years (range, 8-81). The mean CCT of all eyes examined was 544.5 +/- 37.3 mum (SD). The CCT measurements correlated more highly in MZ twins than in DZ twins, with intraclass correlation coefficients of 0.95 and 0.52, respectively, suggesting a strong genetic influence. A model of additive genetic and unique environmental effects provided the best fit, yielding a heritability of 0.95 (95% confidence interval [CI], 0.93-0.96) with the remaining variation being attributable to unique environmental factors. CONCLUSIONS: In this study of Australian and U.K. twins, genetic factors were shown to be of major importance in CCT, with a heritability of 0.95.

The heritability of the ring-like distribution of macular pigment assessed in a twin study.

PURPOSE: It has been suggested that ring-like patterns of macular pigment, as measured with dual wavelength autofluorescence, are observed less frequently in subjects with age-related maculopathy. We explored relative contributions of genetic and environmental factors in macular pigment optical density (MPOD) distributions using a classic twin study. METHODS: As part of a previous nutritional study, 322 healthy Caucasian female twins, aged 16 to 50 (mean 40) years, underwent measurement of MPOD optical density by two-wavelength fundus autofluorescence. In the present study, the right eye MPOD profile was assessed for the presence of a ring-like pattern by two graders independently, using common criteria, with a third grader arbitrating in cases of disagreement. Concordance was calculated as 2C/(2C + D), where C is the number of twin pairs concordant, and D the number discordant, for the ring-like pattern. Also, heritability was calculated using maximum-likelihood structural equation modeling. RESULTS: Images and zygosity data were available for 314 twins (88 monozygotic [MZ] and 69 dizygotic [DZ] pairs). The overall prevalence of the ring pattern was 25.8%. Respective concordances for MZ and DZ twins were 0.75 and 0.22. Additive genetic factors were estimated to contribute to 84.0% of the total variance (95% confidence intervals, 63.7%-94.6%). CONCLUSIONS: Concordance for MZ twins was over three times that for DZ twins, with heritability estimated at 84%, indicating that genetic factors contribute to the development of the ring structure. Studies have suggested that ring-like patterns of macular pigment can affect risk for age-related maculopathy. In a classic twin study, we found that the presence of such a pattern was highly heritable.

The heritability of macular response to supplemental lutein and zeaxanthin: a classic twin study.

PURPOSE: Antioxidant supplements may reduce age-related macular degeneration (AMD) progression. The macular carotenoids are of particular interest because of their biochemical, optical, and anatomic properties. This classic twin study was designed to determine the heritability of macular pigment (MP) augmentation in response to supplemental lutein (L) and zeaxanthin (Z). METHODS: A total of 322 healthy female twin volunteers, aged 16-50 years (mean 40 ± 8.7) was enrolled in a prospective, nonrandomized supplement study. Macular pigment optical density (MPOD) measurements using two techniques (2-wavelength fundus autofluorescence [AF] and heterochromatic flicker photometry [HFP]), and serum concentrations of L and Z, were recorded at baseline, and at 3 and 6 months following daily supplementation with 18 mg L and 2.4 mg Z for a study period of 6 months. RESULTS: At baseline, mean MPOD was 0.44 density units (SD 0.21, range 0.04-1.25) using HFP, and 0.41 density units (SD 0.15) using AF. Serum L and Z levels were raised significantly from baseline following 3 months' supplementation (mean increase 223% and 633%, respectively, P < 0.0001 for both), with no MPOD increase. After 6 months' supplementation, a small increase in MPOD was seen (mean increase 0.025 ± 0.16, P = 0.02, using HFP). Subdivision of baseline MPOD into quartiles revealed that baseline levels made no difference to the treatment effect. Genetic factors explained 27% (95% confidence interval [CI] 7-45) of the variation in MPOD response. Distribution profiles of macular pigment did not change in response to supplementation. CONCLUSIONS: MPOD response to supplemental L and Z for a period of 6 months was small (an increase over baseline of 5.7% and 3.7%, measured using HFP and AF, respectively), and was moderately heritable. Further study is indicated to investigate the functional and clinical impact of supplementation with the macular carotenoids.

Central retinal thickness is positively correlated with macular pigment optical density.

Macular pigment (MP) has been suggested to have a protective role in age-related macular degeneration by reducing the amount of oxidative stress on the retina. MP levels peak at the foveal center, where it is found predominantly in the receptor axon and inner plexiform layers of the retina. The purpose of this study was to investigate the relationship between central retinal thickness and macular pigment optical density in a group of healthy subjects. We report that macular pigment optical density (MPOD) has a significant and positive relationship with central retinal thickness as measured by optical coherence tomography. The strength of the observed relationship (r approximately 0.30) was independent of the technique used to measure MPOD, whether heterochromatic flicker photometry (HFP) or 2-wavelength autofluorescence (AF). Of note, there was no statistically demonstrable relationship between MPOD at an eccentricity of 1- or 2-degrees and central retinal thickness. This finding has important implications for future studies investigating MPOD, and its response to dietary modification/supplementation.