Affiliations: Cincinnati Children’s Hospital,
Center for Genome Information, University of Cincinnati, Cincinnati, OH,
Shinshu University School of Medicine, Matsumoto, Japan
Correspondence to: Maninder Kalra, MD, MS, Cincinnati Children’s Hospital, Pulmonary Medicine, 3333 Burnet Ave, Cincinnati, OH 45229; e-mail: firstname.lastname@example.org
We read with great interest the article entitled “Leptin and Leptin Receptor Gene Polymorphisms in Obstructive Sleep Apnea Syndrome” published recently in CHEST (January 2008).1 This work investigated the relation between polymorphisms of the leptin and leptin receptor (LEPR) genes and obstructive sleep apnea syndrome (OSAS). The authors concluded that there was no association between OSAS and the tetranucleotide repeat polymorphism of the leptin gene and two of the three single-nucleotide polymorphisms examined in the LEPR. The 14 alleles of the leptin gene site were classified into two groups (short and long) by their repeat size. The minor allele (short repeats) frequency was 20.4% in control subjects (Table 2 in the article by Hanaoka et al1). The odds ratio for the leptin allele using data from Table 2 in the article by Hanaoka et al1 is calculated as 1.05, and that for LEPR single-nucleotide polymorphisms using data from Table 5 in the article by Hanaoka et al1 was calculated as ranging from 1.03 to 1.17. We performed power calculations using a sample of 50 control subjects and 125 case patients for allele frequencies observed for the leptin and LEPR genes keeping the type 1 error at 0.05 and the mode of inheritance assumptions the same as that used by Hanaoka et al.1 The results are displayed in Table 1
These computations demonstrate that the study conducted by Hanaoka et al1was underpowered to detect an effect size below an odds ratio of 2.0 for the leptin gene and an odds ratio of 2.5 for the LEPR gene. Their results should therefore be interpreted with caution. Although association studies using unrelated control subjects have been highly successful in unraveling the genetic determinants of complex phenotypes such as OSAS, the replication of the results from such studies has been difficult, with lack of power being a major contributor to this problem.2Leptin has been proposed as a candidate gene for OSAS.3–4 Knowledge of leptin genetic variants associated with OSAS not only can empower the clinician screening for this disorder but also holds promise as a therapeutic option.5 Given the potential implications for morbidity due to OSAS, future studies with adequate power are needed.
The authors have no conflicts of interest to disclose.
Values are given as %, referring to power computations for the dominant model (power computations for the additive model).
The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
We thank Drs. Kalra and Chakraborty for their comments on our recent article in CHEST (January 2008),1 in which they pointed out the underpowered statistical analysis in detecting the associations of leptin and leptin receptor (LEPR) gene polymorphisms with obstructive sleep apnea syndrome (OSAS) in a Japanese population.
We agree with the comments that the statistical analysis in a sample of 50 control subjects and 125 case patients for 20% minor allele frequency was underpowered. In the statistical analysis, we did not calculate the odds ratio because the p value was > 0.05. We did not calculate the statistical power because the results were all negative and the Fisher exact test was used when a cell value was < 5.
The leptin gene has been proposed as a candidate gene for states of energy deficiency, including obesity and OSAS2–; however, genetic diversity in different racial populations causes inconsistent results in studies regarding the associations of the leptin and LEPR polymorphisms with OSAS.3 In this study, we analyzed the associations of the polymorphisms of leptin and LEPR genes not only with OSAS patients, but also with obese OSAS patients (ie, OSAS patients with a body mass index of ≥ 27 kg/m2) and the severity of OSAS in a Japanese population. Our results were consistent with previously reported studies4 regarding the association of the leptin gene with obesity in a Japanese population. We believe that the current leptin and LEPR genetic information provides a reference for future replications as well as recommends a method for the specific analysis of obese OSAS patients and the severity of OSAS. We completely agree that the study should be replicated when enough samples are collected at our institute and the study can be powered appropriately.
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