We extended our genetic identification within the leptin cascade to the associations of three common exonic polymorphisms of the LEPR gene, the Lys109Arg, Gln223Arg, and Lys656Asn SNPs, with OSAS in a Japanese population. All three polymorphisms are associated with amino acid substitutions in the extracellular region of the leptin receptor and have potential functional consequences.21 One polymorphism causes a conservative change (lysine [K] to arginine [R] at codon 109), whereas the other two result in change (glutamine [Q] to arginine [R] at codon 223 and lysine [K] to asparagine [N] at codon 656) and therefore are the most likely to have functional consequences.30 There were no associations, however, of allelic frequency or genetic distribution with OSAS. In addition, it is difficult to conclude that the wild-type alleles of Gln223Arg and Lys656Asn SNPs in the LEPR gene are associated with mild OSAS (AHI ≥ 10 to < 20) in a dominant model because both p values were marginally significant. Similar negative results concerning the associations of these polymorphisms in the LEPR gene with obesity were obtained in studies of different racial populations including Japanese,,21 whites,31and Pima Indians,32 although another study19 reported that the Gln223Arg SNP is positively associated with obesity in a Mediterranean population. According to the protein structure, leptin receptor is composed of extracellular, transmembrane, and intracellular regions. The LEPR gene contains several functionally important domains. The extracellular region contains two cytokine motifs (GXWSXWS) that are implicated in ligand binding. The intracellular region contains box 1, box 2, and box 3 consensus sequences, which are involved in interactions with Janus-activated kinase and activators of the transcription system in the hypothalamus.,21,32 None of the three candidate SNPs were located in these functionally defined domains. Taken together, therefore, it is unlikely that these three candidate SNPs of the human LEPR gene are associated with the OSAS phenotype in the Japanese.