Reduction of REM sleep latency associated with HLA-DQB1*0602 in normal adults
Authors: Emmanuel Mignot, Terry Young, Ling Lin, Laurel Finn, Mari Palta
Journal: The Lancet (1998)

Genetic factors involved in sleep and its disorders are only starting to be isolated.1Mignot E Genetics of narcolepsy and other sleep disorders.Am J Hum Genet. 1997; 60: 1289-1307Summary Full Text PDF PubMed Scopus (45) Google Scholar A relevant model is the neurological disorder narcolepsy. Narcolepsy is characterised by sleepiness, very short REM latency, and symptoms of abnormal REM sleep. It affects 0·05% of the general population in Europe and the USA. The disorder is frequently familial and strongly associated with HLA DR2 and DQB1*0602. These alleles are almost always found in narcoleptic patients but also occur in 25% of the normal population.1Mignot E Genetics of narcolepsy and other sleep disorders.Am J Hum Genet. 1997; 60: 1289-1307Summary Full Text PDF PubMed Scopus (45) Google Scholar In 1986, a report by Schultz in this journal2Schulz H Geisler P Pollmacher T et al.HLA-DR2 correlates with rapid-eye-movement sleep latencies in normal human subjects.Lancet. 1986; ii: 803Abstract Scopus (9) Google Scholar found a reduced REM sleep latency in DR2-positive normal volunteers, a result they were not able to replicate in a second sample.3Schulz H Geisler P Pollmacher T et al.HLA-DR2 and Rapid-Eye-Movement sleep latency: failure to replicate.Lancet. 1987; i: 627Abstract Scopus (6) Google Scholar We retested this hypothesis in a large population-based sample of polygraphically recorded adults.4Young T Palta M Dempsey J et al.The occurrence of sleep disordered breathing among middle-aged adults.N Engl J Med. 1993; 29: 1230-1235Crossref Scopus (8509) Google Scholar The sample included 509 normal adults enrolled in the Wisconsin Sleep Cohort Study4Young T Palta M Dempsey J et al.The occurrence of sleep disordered breathing among middle-aged adults.N Engl J Med. 1993; 29: 1230-1235Crossref Scopus (8509) Google Scholar (209 women and 280 men, 50 [8] years of age; 98% white). Informed consent was obtained for all volunteers. The presence or absence of DQB1*0602 was determined with established sequence specific primer and oligotyping techniques. Polysomnographic variables (table) were then compared by DQB1*0602 status by linear regression analysis with adjustment for possible confounding factors including sex, age, body-mass index, amount of sleep the night before polysomnography, and severity of sleep apnoea (apnoea hypopnoea index).TableSleep variables in DQB1*0602 positive and negative volunteersSleep variableDQB1*0602 positive (n=127)DQB1*0602 negative (n=363)pTime in bed (min)440 (4)445 (3)0·38Total sleep time (min)383 (5)378 (3)0·40Sleep efficiency (%)87·1 (0·8)85·0 (0·5)0·03Sleep onset latency (min)8·5 (1·2)10·9 (0·7)0·11REM sleep latency (min)104 (6)122 (3)0·008% wake after sleep onset13·5 (1·1)16·0 (0·7)0·06% stage 17·8 (0·4)9·2 (0·3)0·007% stage 256·8 (0·9)56·3 (0·5)0·66% stage 312·1 (0·6)12·2 (0·3)0·91% stage 44·2 (0·5)4·5 (0·3)0·69% REM sleep19·0 (0·6)17·7 (0·3)0·05Data are means (SE) adjusted for age, sex, body-mass index, apnoea-hypopnoea index, and amount of sleep the night before nocturnal polysomnography. Open table in a new tab Data are means (SE) adjusted for age, sex, body-mass index, apnoea-hypopnoea index, and amount of sleep the night before nocturnal polysomnography. A highly statistically significant 18 min reduction in REM latency was observed in DQB1*0602 positive volunteers. This effect was associated with an increase in percent REM sleep and with changes indicative of greater sleep continuity, such as less stage one, less percent wake after sleep onset, and better sleep efficiency. This finding demonstrates for the first time with a large sample and proper control of confounding factors that the genetic background at the level of HLA influences normal sleep, with special emphasis on REM sleep. Notably, the difference in REM latency obtained in our sample was similar to that estimated when both Schultz samples were combined (101 [7] min, n=39 vs 121 [7] min, n=63, for positive and negative, respectively, p=0·05). Narcolepsy is well known to be associated with abnormal REM tendencies. Our result could thus be explained by unsuspected narcolepsy phenotypes with very short REM latencies in the DQB1*0602 positive group. However, less than one narcoleptic patient would be expected in this sample based on prevalence data. Furthermore, a comparison of the distribution of REM sleep latencies in both groups did not substantiate this hypothesis; there was no evidence for bimodality in the DQB1*0602 positive group (data not shown). Rather, the data suggest a direct effect of the DQB1*0602 genotype that results in a shifted distribution. HLA DQ might thus be the first genetic factor identified that influences normal sleep patterns in the general population. The work was supported by NIH grants"NS23274, HL42242, RR03186. We thank Anna Voros, Linda Evans, and the University of Wisconsin Sleep and Respiration Research group for assistance.