Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures

Research Center for Ageing and Osteoporosis, Department of Clinical Biochemistry, Glostrup University Hospital, Glostrup, Denmark.
European journal of human genetics: EJHG (Impact Factor: 4.35). 01/2012; 20(6):675-81. DOI: 10.1038/ejhg.2011.253
Source: PubMed


The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45-58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.

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Available from: Jens-Erik Beck Jensen
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    • "Some P2X7 SNPs eg Glu496Ala, have been associated with a higher prevalence of osteoporosis in Dutch women [38]. Conversely, other SNPs, eg A348 were reported to be link to less bone resorption and potentially be protective against the development of osteoporosis, in Danish women [39,40]. At the preclinical level, P2X7 KO mice have been shown to express a gender-dependent phenotype when exocrine secretion [41] or bone remodelling [42] have been evaluated. "
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    ABSTRACT: Background Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. Results The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. Conclusions Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.
    Full-text · Article · Jun 2014 · Molecular Pain
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    • "Non-synonymous SNPs in the P2RX7 gene have been identified in patients with an increasing number and variety of conditions, including chronic lymphocytic leukemia (CLL) (Thunberg et al., 2002; Wiley et al., 2002; Starczynski et al., 2003; Zhang et al., 2003; Dao-Ung et al., 2004; Nückel et al., 2004; Chong et al., 2010), bipolar disorder (BP), major depressive disorder (MDD), and anxiety disorders (Barden et al., 2006; Lucae et al., 2006; Erhardt et al., 2007; Green et al., 2009; Grigoroiu-Serbanescu et al., 2009; Hejjas et al., 2009; McQuillin et al., 2009), pulmonary tuberculosis (Franco-Martinez et al., 2006; Nino-Moreno et al., 2007), osteoporosis in post-menopausal women (Ohlendorff et al., 2007; Gartland et al., 2012; Jørgensen et al., 2012) and fracture patients (Husted et al., 2013; Wesselius et al., 2013), multiple sclerosis (MS) (Oyanguren-Desez et al., 2011), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) (Portales-Cervantes et al., 2012), ischemic stroke (IS) and ischemic heart disease (IHD) in smokers (Gidlof et al., 2012), chronic inflammatory and neuropathic pain (Sorge et al., 2012). More importantly, genetic linkage studies have gathered evidence to support an association of NS-SNPs with altered disease susceptibility, including A76V with MS (Oyanguren-Desez et al., 2011); G150R with osteoporosis in fracture patients (Husted et al., 2013; Wesselius et al., 2013); H155Y and R270H with chronic inflammatory pain (Sorge et al., 2012); R307Q with osteoporosis in post-menopausal women (Gartland et al., 2012; Jørgensen et al., 2012); A348T with anxiety disorders (Erhardt et al., 2007) and osteoporosis in post-menopausal women (Jørgensen et al., 2012) and fracture patients (Husted et al., 2013); R460Q with BP and MDD (Barden et al., 2006; Lucae et al., 2006; Erhardt et al., 2007; Hejjas et al., 2009; McQuillin et al., 2009; but, see Green et al., 2009; Grigoroiu-Serbanescu et al., 2009) and osteoporosis in post-menopausal women (Jørgensen et al., 2012) and fracture patients (Husted et al., 2013; Wesselius et al., 2013); E496A with CLL (Thunberg et al., 2002; Wiley et al., 2002; but, see Starczynski et al., 2003; Zhang et al., 2003; Nückel et al., 2004), tuberculosis (Nino-Moreno et al., 2007), IS, IHD (Gidlof et al., 2012) and osteoporosis in post-menopausal women (Ohlendorff et al., 2007; Jørgensen et al., 2012) and fracture patients (Husted et al., 2013; Wesselius et al., 2013); I568N with osteoporosis in post-menopausal women (Ohlendorff et al., 2007; Jørgensen et al., 2012). The P451L NS-SNP in the mouse p2rx7 gene is associated with neuropathic pain (Sorge et al., 2012) and also with osteoporosis (Syberg et al., 2012). "
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    ABSTRACT: The mammalian P2X7 receptors (P2X7Rs), a member of the ionotropic P2X receptor family with distinctive functional properties, play an important part in mediating extracellular ATP signaling in health and disease. A clear delineation of the molecular mechanisms underlying the key receptor properties, such as ATP-binding, ion permeation, and large pore formation of the mammalian P2X7Rs, is still lacking, but such knowledge is crucial for a better understanding of their physiological functions and contributions in diseases and for development of therapeutics. The recent breakthroughs in determining the atomic structures of the zebrafish P2X4.1R in the closed and ATP-bound open states have provided the long-awaited structural information. The human P2RX7 gene is abundant with non-synonymous single nucleotide polymorphisms (NS-SNPs), which generate a repertoire of human P2X7Rs with point mutations. Characterizations of the NS-SNPs identified in patients of various disease conditions and the resulting mutations have informed previously unknown molecular mechanisms determining the mammalian P2X7R functions and diseases. In this review, we will discuss the new insights into such mechanisms provided by structural modeling and recent functional and genetic linkage studies of NS-SNPs.
    Full-text · Article · May 2013 · Frontiers in Pharmacology
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    • "As we observed increased levels of both IL-1β and TNF-α in P2X7MUT subjects relative to P2X7WT subjects, it might be suggested that P2X7MUT subjects have an increased risk to develop osteoporosis. This hypothesis is consistent with previous reports showing that the Glu496Ala polymorphism, leading to a non-functional P2X7 receptor, is associated with decreased BMD values, i.e. increased osteoporosis risk [37-39]. "
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    ABSTRACT: Background The P2X7 receptor plays an important role in cytokine release during the inflammatory response in vivo. Polymorphisms within the P2X7 receptor gene that lead to loss of receptor function may contribute to impaired cytokine release by immune cells. Therefore, we investigated whether a known loss-of-function polymorphism (Glu496Ala) in the P2X7 receptor gene leads to alterations in cytokine release in response to ATP. Results An ex vivo whole blood model was used to induce an inflammatory reaction with the pro-inflammatory stimuli LPS and PHA (phytohemagglutinin). Blood from n=9 subjects with the Glu496Ala P2X7 SNP (P2X7MUT) and n=7 ‘wild-type’ subjects (no P2X7 SNP; P2X7WT) was used. Addition of ATP (0.9-3 mM) to LPS/PHA-stimulated whole blood induced an increase in IL-1β release in P2X7MUT subjects, whereas decreased release was observed in P2X7WT subjects. Decreased levels of IL-6 and TNF-α in response to ATP were shown in both P2X7MUT and P2X7WT subjects, which was less pronounced in P2X7MUT subjects. ATP at 3 mM also significantly decreased levels of lactate dehydrogenase (LDH) in P2X7MUT subjects compared to P2X7WT subjects. Conclusions The presence of the non-synonymous Glu496Ala loss-of-function polymorphism within the P2X7 receptor gene is likely to be of importance in the release of cytokines during inflammation. Furthermore, this study suggests that carriers of the Glu496Ala loss-of-function polymorphism are protected against the cytotoxic effects of high ATP-levels.
    Full-text · Article · Dec 2012 · BMC Immunology
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