Circadian Rhythms 55.qxp

IN RECENT YEARS, THERE HAS BEEN A RAPID AND SIGNIFICANT PROGRESS IN UNDERSTANDING THE MOLECULAR BASIS OF THE CIRCADIAN RHYTHMICITY, AS SEVERAL CLOCK GENES HAVE BEEN CLONED IN MAMMALS. Studies with these genes focusing on loss of function have demonstrated abnormal sleep/wake length periods, disturbed entrainment, and loss of persistence of circadian rhythms. Current findings clearly indicate that the core components of the pacemaker work on the basis of feedback loops of gene expression and repression.1-5 The same genes found in rodents remain well preserved in humans and the same mechanisms that underlie endogenous circadian rhythmicity in these animals are likely to play an important role in regulating human circadian rhythms.6 The wake/sleep cycle is regulated in a circadian fashion, in addition to its homeostatic regulation. Since mutations in rodent clock genes are related to circadian abnormal regulation of the rest/activity cycle, it is likely that mutations in the same genes may give rise to circadian rhythm-related syndromes in humans. Alternatively, less drastic changes in these genes, such as natural polymorphisms, could be related to subtle differences in circadian phenotypes, as seen in the so-called “morning” and “evening” persons, ie, individuals who reportedly function better during specific parts of the day. Since the first publication7 reporting an association of a polymorphism in the Clock gene with diurnal preference, there has been a steady increase in the number of studies assessing possible correlations between polymorphisms or mutations and circadian phenotypes in humans. Katzenberg et al8 and Pedrazzoli et al9 did not find any association of the human Per1 and Timeless polymorphisms with diurnal preference. Toh et al10 reported a familial case of advanced sleep phase syndrome with a mutation in the hPer2 gene. Ebisawa et al11 reported an association of polymorphisms in the human Per3 gene (hPer3) with the delayed sleep phase syndrome (DSPS) in Japan, and Archer et al12 reported an association of a length polymorphism in the same hPer3 gene with evening preference and DSPS in England. These last results were obtained in developed countries located in the northern hemisphere, where there is considerable seasonal variation in day length along the year. A pertinent question is whether these effects of the hPer3 length polymorphism would also be observed in populations living in the southern hemisphere. In order to verify this possibility, we have genotyped this polymorphism in a population selected for diurnal preference in the cities of São Paulo and Curitiba, Brazil, and also in a group of patients with DSPS living in the city of São Paulo.