This is the first study that specifically explored the heritability of ACD in a population-based twin cohort in a large group of Chinese people. The concept of rACD, a ratio of ACD and AL, was introduced to adjust the effect of AL, and to de-emphasize the influence of myopia on the ACD trait. Our study confirmed that a large proportion of ACD variance was attributable to genetic effects; the heritability remained high, even after adjustment for myopic effects.
This twin cohort was enrolled from a population-based twin registry and therefore the concordance-dependent bias in this study should have been minimized.
24 Although comparable ACD data in a young population are not available in the literature, the refractive error (spherical equivalent) distribution in our twin cohort was found to be comparable to a general population sample.
25 This further suggests that our twin cohort is representative and that the results should be generalizable to the entire population.
Two published twin studies reported the heritability of refractive error as well as the that of ocular biometry parameters, including ACD.
26 27 The study in Danish twins used handheld ultrasound for the ACD measurement, which may be subject to significant measurement error, particularly for the ACD measurement, due to the inadvertent indentation of the cornea.
27 We used noncontact laser interferometry for ACD measurement in this study, a method that has been widely used and found to have good diagnostic efficacy in the detection of angle closure.
28 The study by Lyhne et al.
27 in 53 MZ and 61 DZ Danish twin pairs (age, 20–45 years) identified 88% heritability of ACD,
27 a study with larger sample size and wider age range found 51% heritability in male and 78% in females in Australia twins (345 MZ and 267 DZ, age 18–88 years).
26 Our data identified a slightly higher level of heritability (90.1%, 95% CI: 88.2%–91.7%) for ACD in a Chinese sample, although the rate of myopia was much higher in this Chinese cohort. When reporting heritability separately for the boys and girls, we did not identify differences in heritability between genders (boys: 90.6%, 95% CI: 87.9%–92.7%; girls: 89.7%, 95% CI:86.9%–91.9%, χ
2 test,
P = 0.142). Looking further into the ICCs reported in Australia twins and our twin cohort, the ICCs in the Australian (0.46–0.62 for MZ, 0.26–0.37 for DZ) are lower than that in our Chinese twins (0.92 for MZ, 0.50 for DZ) although the ratios between the MZ and DZ twin pairs are quite similar between the Australia and Chinese samples. The twin studies in Denmark and Australia recruited twins in adulthood, and the environmental effect should therefore be greater than that on younger twins and tends to be diversified between twins in a pair. Nevertheless, it is intriguing to find that our heritability findings are compatible with those in a family study (involving the siblings and children of a PAC proband) in Eskimos where heritability of ACD was estimated as approximately 70% with additive polygenic inheritance when the effects from age and gender variations were adjusted by a lineal regression model.
29
It is interesting to find that ICCs and heritability remained high when rACD was considered as the parameter of interest, and the effect of myopia was de-emphasized. The high heritability of rACD appears to suggest the genetic determinant of anterior positioning of the iridolenticular diaphragm in addition to the ACD variation secondary to AL changes. The concept of rACD is similar but not the same as the relative lens position (RLP) proposed by Lowe, where RLP = (ACD + ½ lens thickness)/axial length.
30
The results of the present study must be taken within the context of limitations. First, the impact of environmental exposures on observed phenotypes in different populations vary according their relative exposures. However, the similarity of our findings with those from Australia and Denmark suggest that this is not a major impediment to the use of twin data. Second, ACD and rACD data were treated as intermediate phenotypes for angle closure, given that their anatomic characteristics are associated with established disease. The continuous distribution of ACD (quantitative trait) was used to estimate the importance of genes and environment. However, our study participants were healthy young people in whom angle-closure is extremely uncommon. As far as we are aware, there were no cases of angle-closure among our participants. Consequently, the results are only applicable to Chinese children. Our inference that our findings are relevant to future risk of angle-closure depends on the assumption that shallow ACD in childhood indicates a propensity to a shallow ACD in later life. On the other hand, limited data suggest that PAC develops over a 5- to 10-year period in only a fraction (between 10% and 20%) of people with narrow angles.
31 32 This suggests that, while there may be strong genetic control over the anatomic characteristics associated with angle-closure, there may well be other factors (either genetic or environmental) that determine individual predisposition to angle-closure glaucoma in which iridotrabecular contact causes elevated intraocular pressure leading to loss of vision.
We believe our findings have relevance for the understanding of the mechanisms controlling ocular development and particularly that of the anterior segment. In addition, it helps to clarify the factors that determine the risk of angle-closure glaucoma in a population with high rates of this disease in adulthood. It remains possible but unproven that identification of genetic factors may have a role in risk profiling for angle-closure glaucoma.
The authors thank Yoon-Mi Hur, Seoul National University, for her comments and suggestions on the manuscript.