© 2004 American Thoracic Society
Linkage to Apnea–Hypopnea Index Across the Life-SpanIs this a Viable Strategy?To the Editor:Palmer and colleagues (1) are to be congratulated on using a genome-wide scan to identify genes conferring risk for obstructive sleep apnea. However, the logarithm of the odds (LOD) score for the linkage for the quantitative trait assessed "apnea–hypopnea index" is only 1.09 after controlling for body mass index (BMI) as a covariate (1.29 before including BMI as a covariate). On the basis of standard criteria for interpreting linkage results for complex traits (2), this LOD score is not even in the suggestive range for linkage (suggestive LOD > 2.2; significant LOD > 3.6) (2). Thus, as the authors indicate, the study is underpowered and the report seems premature. It is also premature to discuss candidate genes in the region of linkage before additional microsatellite markers to narrow the region have been used. This is particularly important because the area covered by the reported linkage extends from 125.8 to 128.5 Mb, containing over 1,600 poorly characterized expressed sequence tags (ESTs). An important issue is whether performing linkage analysis to apnea–hypopnea index as a quantitative trait in subjects over a wide age range is an appropriate strategy. Apnea–hypopnea index is an age-dependent phenotype (3, 4), and it is unclear if one can deal with this simply by including age as a covariate. It seems, for example, that the children of probands who were studied and who had a mean age of 22.2 years (n = 64), and the other relatives (n = 53) (mean age 25.0 years), will not contribute anything to this study. Indeed, they will likely confuse the picture. These groups together make up 42% of the 277 subjects studied. At this age, apnea–hypopnea index will be low as is shown in Table 1 of the article by Palmer and colleagues (1). This will be so even in individuals with high genetic risk, who may develop the disorder later in life. Thus, the apnea–hypopnea indices used in the linkage analysis will be much lower than would have been included if the same individuals had been studied later in life. Moreover, we know that premenopausal women are very protected from sleep apnea (5, 6). Thus, premenopausal women will also have a lower apnea–hypopnea index even if they have genetic risk. Thus, one questions whether the strategy being used in this study of investigating linkage to apnea–hypopnea index, including subjects over a wide age range (including young people), as well as premenopausal women, can lead to identification of genes conferring risk for obstructive sleep apnea.
a University of Pennsylvania Philadelphia, Pennsylvania FOOTNOTES Conflict of Interest Statement:A.P. has a grant from ResMed, Inc. to study the relative role of ambulatory recording of sleep-disordered breathing as it compares to full sleep study and also receives royalties from Marcel Dekker for a book he edited entitled "Sleep Apnea: Pathogenesis, Diagnosis and Treatment" and has a patent pending related to the use of serotonin agonists to treat sleep apnea in mammals; T.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter; H.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this letter. REFERENCES
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