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Letter to the editor in response to Dr. Kapoor's comments “systemic and psychiatric disorders associated with polymorphisms of the P2RX7 gene”

I would like to reflect on the letter of Dr. Kapoor about the importance of P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) gene in psychiatric disorders. Non-synonymous single nucleotide polymorphisms (SNPs) of this gene have only recently been indicated as candidate polymorphisms in mood disorders. Our initial results showed an association of the 460Arg variant (G-allele of rs2230912) with increased anxiety and depression scores assessed by the Hospital Anxiety and Depression Scale [HADS, Zigmond and Snaith, 1983] among patients with major depressive or bipolar disorder [Hejjas et al., 2008]. This association has been supported by our second study conducted among nonpsychiatric patients at risk for depression. We chose patients with diabetes mellitus, because the prevalence of major depression is two times higher among diabetic patients compared to controls [Anderson et al., 2001]. Although the average anxiety and depression scores were in the normal range in this clinical group, patients with at least one G-allele had significantly higher HADS anxiety and depressive scores compared to the AA homozygotes [Nagy et al., 2008]. These findings highlight the importance of dimensional approach in complex-inheritance disorders, for example, using severity scales in the phenotypic characterization. In this regard, the Hospital Anxiety and Depression Scale is a reliable and practical tool for researchers in the quantification of the two most common forms of emotional disturbances. It is interesting to note, that the Gln460Arg (A1405G SNP, rs2230912) substitution resulted in a gain-of-function, enhancing P2X7 pore activity measured in monocytes [Denlinger et al., 2006]. Other polymorphisms in the C-terminal region of the receptor had negative effect on P2X7 pore activity: Thr348Ala (A1068G SNP, rs1718119) and Thr357Ser (C1096G SNP, rs2230911) heterozygotes were enriched in the low pore-activity group [Denlinger et al., 2006]. The Glu496Ala (A1513C SNP, rs3751143) and Ile568Asn (T1729A SNP, rs1653624) have been shown to impede optimal receptor assembly and trafficking [Gu et al., 2001; Wiley et al., 2003]. On the other hand, the 460Arg variant suppressed the negative effect of amino acids 496Ala or 568Asn and therefore might overrule the defects in receptor expression caused by these substitutions [Denlinger et al., 2006]. Consequently, future association analyses should take into account these functional polymorphisms jointly. REFERENCES