rs2230912

Association study of P2RX7 gene polymorphisms in a Chinese Han male population revealed that rs2230911 is associated with primary gout risk, with allele G conferring increased susceptibility (OR=1.755, 95% CI 1.278-2.410, P<0.001). The study examined 293 primary gout patients, 187 hyperuricemia patients, and 269 healthy controls using SNaPshot genotyping of seven P2RX7 SNPs, finding that rs2230911-G variant carriers also showed higher blood glucose and uric acid levels.

This international doctoral thesis examined gene-physical activity interactions in fibromyalgia through six studies analyzing 64 SNPs across 34 candidate genes in Spanish women. The case-control study (314 fibromyalgia cases vs. 112 controls) identified associations of rs841 (GCH1), rs1799971 (OPRM1), and rs2097903 (COMT) with fibromyalgia susceptibility (p=0.04, p=0.02, and p=0.04 respectively). Cross-sectional studies (n=274-276 fibromyalgia patients) found that SCN9A rs4453709 and other genetic polymorphisms interacted with physical activity to influence pain, fatigue, and resilience outcomes.

Association study of 15 non-synonymous P2X7 receptor polymorphisms in 921 Dutch fracture patients (690 women, 231 men) found that the Ala348Thr gain-of-function variant was associated with increased lumbar spine BMD (p=0.012), while loss-of-function variants Glu496Ala and Gly150Arg were associated with decreased hip and lumbar spine BMD (p=0.018, p=0.011 respectively), and in men, Gln460Arg was associated with 40% decreased osteoporosis risk (OR=0.58 [95%CI, 0.33-1.00]).

This review examines purinergic signaling, particularly P2X7 receptors, in major depressive disorder (MDD) and bipolar disorder (BPD). The SNP rs2230912 (Glu460Arg) in P2RX7 is associated with MDD with gain-of-function effects. Genetic studies show mixed but accumulating evidence for P2RX7 variants in mood disorder susceptibility, while animal studies consistently demonstrate that P2X7 deficiency or antagonism produces antidepressant and mood-stabilizing phenotypes with altered stress reactivity.

This dissertation characterizes transgenic mouse models targeting the P2X7 receptor (P2X7R) to study its role in anxiety and depression. A humanized P2X7R knockout (hKO) mouse, a microglia-specific P2X7R knockout, and P2X7R overexpressing reporter lines (P2X7-EGFP and sEGFP) were behaviorally tested under baseline and stress conditions. P2X7R inactivation did not produce significant effects on anxiety, anhedonia, or coping behaviors, and P2X7R overexpression similarly showed no significant alterations in depressive or anxiety-related phenotypes compared to controls.

This review examines the role of P2X7, a purinergic ion channel expressed on microglia, in affective disorders including depression and bipolar disorder. P2X7 knockout mice show resilience to depressive-like behavior, and a functional variant in the human P2RX7 gene (rs2230912-G) is a gain-of-function allele associated with increased IL-1β secretion in immune cells, though conflicting association studies exist. The authors propose that altered P2X7 signaling and resulting inflammatory changes in the brain, particularly through microglial activation, may contribute to mood disorder pathophysiology.

This dissertation characterizes multiple transgenic P2X7 receptor (P2X7R) mouse models to investigate the role of P2X7R in anxiety- and depression-related behaviors. Humanized P2X7R knockout mice and a microglia-specific P2X7R-KO showed no significant alterations in anxiety, anhedonia, or coping behaviors under baseline or chronic stress conditions, contrary to some prior animal studies. Two reporter lines (P2X7-EGFP and sEGFP) both displayed P2X7R overexpression but exhibited differential expression patterns. A third CreERT2 inducible line lacked functionality due to aberrant targeting construct insertion. Neither P2X7R overexpressing line showed significant behavioral phenotypes compared to controls, highlighting both the utility and limitations of transgenic approaches for studying P2X7R in neuropsychiatric disease models.

This doctoral thesis conducted multiple candidate gene association studies in 274-426 southern Spanish women with fibromyalgia to investigate gene-physical activity/sedentary behavior interactions with pain, fatigue, and resilience. Study III identified rs841 (GCH1) GG genotype (OR=0.61, p=0.04) and rs2097903 (COMT) AT/TT genotypes (OR=1.66, p=0.04) associated with fibromyalgia susceptibility, and confirmed rs1799971 (OPRM1) GG genotype (OR=0.58, p=0.02) confers genetic risk. Study IV found rs6311/rs6313 (HTR2A) polymorphisms individually associated with algometer pain score, and gene-sedentary behavior interactions involving rs4680/rs165599 (COMT), rs1383914 (ADRA1A), rs12994338/rs4453709 (SCN9A), and rs6860 (CHMP1A) significantly associated with pain outcomes. SCN9A emerged as most robust gene for fibromyalgia phenotype.