Several studies have shown that mutations and polymorphisms in clock genes are associated with abnormal circadian parameters in humans and also with more subtle non-pathological phenotypes like chronotypes. However, there have been conflicting results, and none of these studies analyzed the combined effects of more than one clock gene. Up to date, association studies in humans have focused on the analysis of only one clock gene per study. Since these genes encode proteins that physically interact with each other, combinations of polymorphisms in different clock genes could have a synergistic or an inhibitory effect upon circadian phenotypes. In the present study, we analyzed the combined effects of four polymorphisms in four clock genes (Per2, Per3, Clock and Bmal1) in people with extreme diurnal preferences (morning or evening). We found that a specific combination of polymorphisms in these genes is more frequent in people who have a morning preference for activity and there is a different combination in individuals with an evening preference for activity. Taken together, these results show that it is possible to detect clock gene interactions associated with human circadian phenotypes and bring an innovative idea of building a clock gene variation map that may be applied to human circadian biology.

OBJETIVO: Revisar resumidamente a literatura dos últimos 36 anos de pesquisa em cronobiologia molecular a fim de informar aos profissionais de saúde os avanços obtidos nesta área e os potenciais para aplicação na clínica médica. MÉTODO: Buscas na literatura foram realizadas utilizando as bases de dados PubMed e Scopus usando como palavras-chave "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSÃO: Atualmente, o mecanismo molecular da regulação da ritmicidade circadiana é compreendido em grande detalhe. Muitos estudos publicados mostram associações de polimorfismos nos genes relógio com transtornos do ritmo circadiano e com transtornos do humor. CONCLUSÕES: De maneira geral, o progresso obtido na área de cronobiologia molecular traz um melhor entendimento da regulação do sistema de temporização biológico. O desenvolvimento de estudos nesta área tem o potencial de ser aplicável ao tratamento dos transtornos dos ritmos circadianos e certos transtornos do humor, além de prevenir riscos à saúde causados por viagens intercontinentais (Jet Lag) e por trabalhos noturnos e por turnos.

OBJECTIVE: The aim of this study was to review the molecular chronobiology studies in the last 36 years in order Eto point out the advances in this area to health professionals. METHOD: We searched in the PubMed and Scopus data banks for articles related with human molecular chronobiology. The keywords used were "clock genes, circadian rhythms, diurnal preference, delayed sleep phase syndrome, advanced sleep phase syndrome, photoperiod and mood disorder". DISCUSSION: The knowledge about molecular mechanism of circadian rhythms increased a lot in the last years and now we are able to better understand the details of molecular processes involved in circadian and sleep regulation. Studies show that polymorphisms in clock genes are associated with sleep and mood disorders. These studies will be helpful to further elucidate the regulation of molecular mechanisms of circadian rhythms. CONCLUSIONS: The development of these studies in molecular chronobiology can be helpful to treat circadian and mood disorders and to prevent health risks caused by intercontinental flights (Jet Lag), nocturnal or shift work schedule.