In June 1999, Huber et al. published in this journal an extensive study in prion protein deficient mice entitled Prion protein: a role in the sleep regulation? (Huber et al. 1999). The interest for prion protein in the sleep field was gathered by the discover that fatal familial insomnia (FFI) segregate with a mutation in the codon 178 of prion protein gene (Medori et al. 1992). The role of the prion protein (PrP) in the pathogenesis of animal and human transmissible spongiform encephalopaties (TSE) is well established. The FFI is the only known human TSE to affect sleep and it is a very severe disease. Its symptomatology is characterized for motor disturbances, loss of circadian rhythmicity and several neurovegetative symptoms as increased perspiration and salivation, tachycardia, systemic hypertension and fever but mainly for a gradual sleep loss, leading to death. Most classically, a mutation at codon 178 (e.g. Asp178Asn) is present in FFI as well as CJD but a cis polymorphism in codon 129 determines familial FFI versus CJD phenotypes. A valine residue at the codon 129 (129V) segregates with CJD and a methionine in the same position (129M) lead to FFI (Goldfarb et al. 1992). Interestingly, the 129 polymorphism, without the mutation at the codon 178 is very common in the general population and does not cause any prion disease, the 129M allele frequency range from 0.62 to 0.68. Whereas much has been learned regarding the role of abnormal prions in the generation of these TSEs, little is known regarding the normal role of the wild type protein. Genetics studies in the sleep field have identified important genes regulating sleep and circadian rhythms and FFI is a potential model for genetics studies of insomnia (Taheri and Mignot 2002). Thus in the present study we explored if the 129V ⁄M polymorphism influences sleep in the general population, with special emphasis on items related to insomnia complaints and sleep disruption. A population based random sample of 884 middle-aged men and woman enrolled in an epidemiological study of natural history of sleep disorders was used in this analysis (Young et al. 1993). All subjects had undergone blood draw as part of an overnight sleep protocol and were asked to complete a 4-item insomnia questionnaire. Mean age ± SD was 50.0 ± 7.9 years. 489 subjects (55.3%) were males. We genotype the 129 V ⁄M polymorphism in the population sample using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) as described in Goldfarb et al. (1992). Subjects were categorized in three groups on the basis of their prion genotype (129M ⁄M, 129M ⁄V and 129 V ⁄V). Linear and logistic regression were used to assess differences between groups for polysomnographic parameters and the insomnia questionnaire responses, respectively. Analysis were adjusted for the potential confounding factors such as age, sex, ethnic heritage, body mass index (BMI) and apnoea–hypoapnoea index (AHI), P-values <0.05 were considered to indicate statistical significance. The SAS statistical package was used for all analysis. Overall allele frequencies for 129M was 0.66 in this mostly Caucasian (90%) sample. Genotype distributions for 129M, 129M ⁄V and 129V were 406 ⁄ 884, 370 ⁄ 884 and 108 ⁄ 884, respectively. These distributions did not deviate from expected Hardy–Weinberg frequencies. Nocturnal polysomnography (Table 1) and insomnia questions did not differ consistently across genotypes. Only two comparisons led to borderline significant differences. In one, 129V negative subjects reported waking up more at night and having more difficulties getting back to sleep [Odds ratio, 95% CI: 0.72 (0.64, 1.01, P 1⁄4 0.05)]. However, 129V positive and negative subjects did not differ with respect to the other three insomnia questions. Furthermore, during the nocturnal
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