## 3 Discussion
Since our study showed that _CLOCK_ rs1801260 polymorphism accounts mainly for the differences in MEG, it may help to explain why no differences in serum lipids are found in studies relying only on morning measurements [61]. Remarkably, as far as morning values are concerned, our study reaches similar conclusions as those of a recent metanalysis, which reported considerably higher mean TC and lower mean HDL-C values in patients diagnosed with glaucoma than in patients without glaucoma, but no statistically significant difference in mean LDL-C values [37]. Common clinical practice consists of assessing lipids in the morning. Unlike other lipids, however, LDL-C is more predictive of impairment in the evening than in the morning, as shown herein. Not only in glaucoma, but also in other common pathologies affecting retinal light perception, such as in diabetic retinopathy, a lower HDL-C/LDL-C ratio was found to correlate with disease severity, assuming that light perception can be involved [63]. Furthermore, in a transgenic mouse model of neurodegenerative pathology (Alzheimer's disease), the diminished amplitude of circadian light signaling was associated with a higher amyloid load, whilst strong robust signaling correlated with a reduced amyloid load [64]. These results suggest that altered light perception and circadian disruption can facilitate a vicious cycle in the progression of neurodegenerative pathology that may include glaucoma [21]. Note that _CLOCK_ gene rs1801260 polymorphism, yet again, can be involved [65]. Alterations to biotic signaling and transduction cause disruption of circadian rhythms, the severity of which depends on impairment of ipRGCs, and melatonin production can also be affected by its receptor gene polymorphisms [19; 21]. The fact that when visual function is lost, photic signaling is still transferred to the central clock prompted the discovery of ipRGCs [66; 67; 68]. Studies in totally blind people revealed that circadian rhythms of melatonin and cortisol were not equally compromised when light perception was not possible. [PERSON] and al. [69] described that 23% of individuals with no light perception remained entrained, and even more (37%) in another study [70], while the majority was non-entrained or had abnormal phase positions [69; 70]. Individual differences may be either due to genetic polymorphisms in clock, clock-controlled, or melatonin receptors' genes, or to differences in non-photic cues that likely include food consumption. Since loss of light perception affects pineal and pituitary functions, down-streaming hormones are also compromised [71; 72], leading to the occurrence of complex metabolic consequences. No statistically significant associations between lipids and parameters of salivary melatonin were found in our study. This result is likely due to the modest number of patients involved and the lack of lipid determinations during the nocturnal phase of the 24 h cycle. This study did not specifically address damage to ipRGCs, which is its limitation. Our findings of pronounced alterations that occur simultaneously in lipid metabolism, circadian rhythms, and sleep, specifically in patients with advanced glaucoma, however, are in good agreement with findings of [PERSON] et al. [42] showing that specific damage to ipRGCs appears in advanced but not in mild stages of glaucoma. This study was primarily observational in design. Therefore, patients were free to follow their habitual sleep-wake schedules, a design feature that could affect results. However, the meal regimen was standardized in this study, suggesting that MEG differences are not derived from individual differences in diet or meal timing. Implementing circadian research for applied clinical purposes is important for translational circadian medicine [73; 74]. This study is just one of this kind. Since light and feeding contribute to circadian alignment, further in-depth studies are needed to assess their roles. Light, being a principal synchronizer, can also modulate mealtimes.