Lack of an association between Paraoxonase 1 gene polymorphisms (Q192R, L55M) and Alzheimer's disease: a meta-analysis

The association between Paraoxonase 1 (PON1) gene polymorphisms (Q192R, L55M) and Alzheimer's disease (AD) risk has been reported inconsistent results. To assess the association between PON1 polymorphisms and AD risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Web of Science, Weipu, and CBM databases, a total of 10 studies including 3081 AD cases and 3054 controls were identified. The pooled odds ratio (OR) with 95% confidence interval (95% CI) were performed. There was no significant association between PON1 Q192R polymorphism and AD risk in all comparison models (R vs. Q, OR=0.89, 95% CI=0.82-0.96; RR vs. QQ, OR=0.83, 95% CI=0.68-1.01; RR+RQ vs. QQ, OR=0.86, 95% CI=0.75-0.97; and RR vs. QR+QQ, OR=0.94, 95% CI=0.81-1.11). For the PON1 L55M polymorphism, lack of an association was also found (L vs. M, OR=0.95, 95% CI=0.86-1.05; LL vs. MM, OR=0.67, 95% CI=0.51-0.88; LL vs. ML+MM, OR=0.82, 95% CI=0.69-0.98; and LL+ML vs. MM, OR=0.75, 95% CI=0.58-0.96). On subgroup analysis by ethnicity, similar results were found. Conclusively, the present meta-analysis revealed that PON1 gene polymorphisms (Q192R, L55M) were unlikely to contribute to AD susceptibility.     

Association between Q192R paraoxonase 1 polymorphism and serumadipocyte-fatty acid binding protein (FABP4) levels in Mexican women

Aim: This study aimed to evaluate the genetic effects of PON1 Q192R polymorphism on serum FABP4 levels in Mexican women.

Methods: PON1 Q192R polymorphism was genotyped using a TaqMan allelic discrimination assay and serum FABP4 concentration was measured using an enzyme-linked immunosorbent assay.

Results: The distribution of genotype frequencies in the assessed women (PON1 Q192R polymorphism) was QQ?=?20%, QR?=?48% and RR?=?32%. Significantly higher serum FABP4 levels were found in women with genotype QR/RR (20.6?±?2.20?ng/mL), when compared with the levels found in the QQ group (12.8?±?1.70?ng/mL) (p?=?.004). After, the odds ratio (OR) was calculated by binomial logistic regression analysis and a significantly higher OR was found in the QR/RR group when compared with the QQ group (OR?=?3.45; 95% CI?=?1.80–16.50; p?Conclusion: The results support an association between 192R-allele of the PON1 polymorphism (Q192R) and increased serum FABP4 levels (suggested as an early biomarker of CVDs risk) in assessed Mexican women.     

Effects of intronic and exonic polymorphisms of paraoxonase 1 (PON1) gene on serum PON1 activity in a Korean population

Paraoxonase 1 (PON1) hydrolyzes a number of toxic organophosphorous compounds and reduces lipid peroxide accumulation, and PON1 genetic polymorphisms in the coding region modulate serum PON1 activity. In this study, we investigated the association between 3 polymorphisms of PON1 located in intron 5 (17899insdelTT and 17974CT) and exon 6 (192QR) and serum PON1 activity. The genetic polymorphisms and serum activity of PON1 were analyzed in 153 healthy Koreans by using a direct sequencing assay and spectrophotometric method, respectively. A significant linkage disequilibrium (LD) was observed between all tested single nucleotide polymorphisms, with the strongest LD observed between 17899insdelTT and 192QR (D' = 0.984). The 17899insdelTT, 17974CT and 192QR genetic polymorphisms were associated with significant differences in serum paraoxonase activity. In multiple regression analyses, smoking, triglyceride level, high-density lipoprotein (HDL) level, and the 17899insdelTT and 192QR genetic polymorphisms were significant determinants of serum paraoxonase activity, while age, smoking, triglyceride level, HDL level, and the 192QR genetic polymorphism were significant determinants of serum arylesterase activity. These results suggest that although the 192QR genetic polymorphism in the coding region of PON1 is primarily associated with serum PON1 activity, the intronic polymorphisms are also involved in serum PON1 activity, and this association may be mediated by LD.     

Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease

Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case–control material. We found a significant association (p = 0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD.     

Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease

Intracellular second messengers play an important role in capsaicin- and analogous-induced sensitization and desensitization in pain. Fluorescence Ca²⁺ imaging, enzyme immunoassay and PKC assay kit were used to determine a novel mechanism of different Ca²⁺ dependency in the signal transduction of capsaicin-induced desensitization. On the average, capsaicin increased cAMP, cGMP concentration and SP release in bell-shaped concentration-dependent manner, with the maximal responses at concentrations around 1 μM, suggesting acute desensitization of TRPV1 receptor activation. Capsaicin-induced intracellular Ca²⁺ concentration ([Ca²⁺]_i) increase depended on extracellular Ca²⁺ influx as an initial trigger. The Ca²⁺ influx by capsaicin increased PKC activation and SP release. These increases were completely abolished in Ca²⁺-free solution, suggesting that the modulation of capsaicin on PKC and SP are Ca²⁺-dependent. Interestingly, the maximal cAMP increase by TRPV1 activation was not blocked Ca²⁺ removal, suggesting at least in part a Ca²⁺-independent pathway is involved. Further study showed that cAMP increase was totally abolished by G-protein and adenylate cyclase (AC) antagonist, suggesting a G-protein-dependent pathway in cAMP increase. However, SP release was blocked by inhibiting PKC, but not G-protein or AC, suggesting a G-protein independent pathway in SP release. These results suggest that both Ca²⁺-dependent and independent mechanisms are involved in the regulation of capsaicin on second messengers systems, which could be a novel mechanism underlying distinct desensitization of capsaicin and might provide additional opportunities in the development of effective analgesics in pain treatment.     

Effect of 5-haplotype of dysbindin gene (DTNBP1) polymorphisms for the susceptibility to bipolar I disorder.

We investigated a possible association between dysbindin gene (DTNBP1) variants and bipolar I disorder (BID). Five SNPs within DTNBP1 (rs3213207, rs1011313, rs2005976, rs760761, and rs2619522) were genotyped for 151 patients with BID and 478 controls. We observed a significant protective association of the haplotype A-C-G-T-A (all SNPs, P = 0.00016) and particularly G-T-A (the last three SNP, P = 0.00007) within DTNBP1 variants investigated. Single marker and subgroup (e.g., psychotic features, age at onset, family history, etc.) analyses showed no significant association. Although the association was due to a small number of subjects, specific DTNBP1 haplotypes, previously associated with schizophrenia, may be also associated with BID. Adequately powered studies from different ethnicities will be necessary to confirm our findings.     

Association study between the Down syndrome cell adhesion molecule (DSCAM) gene and bipolar disorder

OBJECTIVES: Defects of neurodevelopmental processes are suggested to underlie the pathogenesis of bipolar disorder. Down syndrome cell adhesion molecule (DSCAM), a member of neural immunoglobulin superfamily playing a diverse role for neural development, is mapped to chromosome 21q22, a linkage locus for bipolar disorder, and is, therefore, an interesting candidate for the disease. METHODS: We performed a variation screening of the gene and association studies in 22 multiplex bipolar pedigrees of Caucasian descent and 119 Japanese patients with bipolar disorder and 140 controls. Expression levels of DSCAM were also examined in postmortem brains from the Stanley Medical Research Institute. RESULTS: We found 27 single nucleotide polymorphisms in DSCAM. Possible associations of SNP DC141 (IVS27-15A>G; P=0.042) and DC142 (IVS29+328C>A; P=0.036) were observed in pedigree samples, and G allele of DC141 was correlated with increased expression levels of DSCAM (P=0.038) in postmortem brains. Possible association of DC136 (4749C>T), which is in the same haplotype block with DC141 and DC142, was detected in Japanese populations (P=0.049). CONCLUSIONS: These results suggest the possible contribution of DSCAM gene in bipolar disorder, and warrant further investigations.     

Distribution of paraoxonase PON1 gene polymorphisms in Mexican populations. Its role in the lipid profile

Paraoxonase gene polymorphisms (PON1-55 and PON1-192) were determined in four Mexican populations (Mestizos, Nahuas, Teenek and Mayos) belonging to different ethnic groups. The role of these polymorphisms in the lipid profile in the Mestizo group was also analyzed. PON1 polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. Comparison among Mexican populations showed increased frequencies of PON1-55 L allele and LL genotype and decreased frequencies of M allele and LM genotype in the three Amerindian populations when compared to Mestizos (P < 0.05). Mexicans together with Asian populations (from Japan and China) presented the highest frequencies of PON1-55 L allele (P < 0.05 when compared to Caucasian populations). Heterogeneous data were noted when PON1-192 polymorphism comparison was made. In summary, distribution frequencies of PON1 showed that Mexican populations are more related to Asians than Caucasians. This confirms previous studies with other genetic markers indicating that Native Americans have stronger genetic affinities to the Paleolithic people of North-East Asia than to other major world populations. In Mexican Mestizos, lack of correlation between PON1 polymorphisms and lipid profile was found, corroborating previous data in other populations. The present data could be helpful to understand the distribution of these polymorphisms and its role as genetic and evolutive markers in the Amerindian populations.     

Association between OPCRIT dimensions and polymorphisms of HPA axis genes in bipolar disorder

The aim of the study was to investigate the possible association between polymorphisms of HPA axis genes-CRHR₁ (corticotrophin-releasing hormone receptor), NR3C1 (glucocorticoid receptor) and AVPR1B (arginine vasopressin receptor) and dimensions of bipolar disorder assessed by OPCRIT.     

Association between a polymorphism in the pseudoautosomal X-linked gene SYBL1 and bipolar affective disorder

In the past decade, several chromosomal regions have been analyzed for linkage with bipolar affective disorder (BPAD). There have been conflicting results regarding the involvement of X-chromosomal regions in harboring susceptibility genes for BPAD. Recently, a new candidate gene (SYBL1) for BPAD has been described on Xq28. SYBL1, which maps to the Xq pseudoautosomal region (PAR), encodes a member of the synaptobrevin family of proteins involved in synaptic vesicle docking, exocytosis, and membrane transport. A subsequent case-control association study, including 110 US-American patients with BPAD and 119 unrelated controls, investigated a potential etiological role of a novel polymorphism (G-->C transversion) in a regulatory region of the SYBL1 gene. In this analysis, the C allele showed a statistical trend to be more frequent in males with BPAD than in respective controls (P=0.06). This finding prompted us to verify whether a similar effect was also present in a larger German sample of 164 unrelated patients with BPAD (148 patients with BP I disorder, 16 patients with BP II disorder) and 267 controls. We observed a significantly increased frequency of genotypes homozygous for the C allele in females with BPAD in comparison with controls (P=0.017). Thus, our data strengthen the role of the SYBL1 gene as a candidate gene for BPAD.     

Paraoxonase 1 (PON1) gene polymorphisms and Parkinson's disease in a Finnish population

Paraoxonase 1 (PON1) is involved in the metabolism and detoxification of insecticides and pesticides. Two polymorphisms within the gene affect the enzyme activity. One is a methionine to leucine change at position 54 (M54L) and the other is a glutamine to arginine variant at position 192 (Q192R). There are contrasting reports assessing the role of these variants in Parkinson's disease (PD). We performed a case--control association study in order to elucidate the possible contribution of variability within PON1 to the risk of sporadic PD in a Finnish population. There was no statistically significant association of the allele, genotype or haplotype distribution with PD (all P values > 0.75). Our results suggest that the M54L and Q192R polymorphisms are not major risk factors for PD in the Finnish population.     

Association study of tryptophan hydroxylase 2 gene polymorphisms in bipolar disorder patients with panic disorder comorbidity

Frequent comorbidity between panic disorder (PD) and mood disorders has been widely reported in clinical and epidemiological studies and, recently, an increasing attention has been paid to the cooccurrence of PD and bipolar disorder (BD). Several studies have shown that an imbalance of serotonin activity could be related to panic symptoms. Tryptophan hydroxylase 2 (TPH2) are plausible candidates for the association with PD. The aim of this study is to investigate a possible association between TPH2 gene polymorphisms and the PD comorbidity susceptibility.Our sample consisted of 515 patients; 274 patients with BD (subtypes I and II), including 45 patients with lifetime panic disorder comorbidity and 241 controls. These patients were genotyped for eight tagging single nucleotide polymorphisms of the gene of human TPH2. We found significant differences between patients with BD, with panic disorder comorbidity, and controls in the allelic analysis (rs4448731, P=0.0069; rs4565946, P=0.0359; rs4760820, P=0.0079; rs1487275, P=0.0439) and genotypic analysis (rs4448731, P=0.011; rs4760820, P=0.0259). We also identified significant differences between patients with BD, with and without panic disorder comorbidity in the allelic analysis (rs4448731, P=0.004; rs4565946, P=0.011; rs11179000, P=0.031; rs4760820, P=0.018; rs1487275, P=0.038; rs10879357, P=0.023) and genotypic analysis (rs4448731, P=0.004; rs4565946, P=0.010; rs4760820, P=0.023; rs10879357, P=0.052). The haplotype analysis in the group of patients with BD, with and without panic disorder comorbidity, was also significant (rs4448731-rs4565946, P=0.0190; rs4448731-rs4565946, P=0.0220; rs10506645-rs4760820, P=0.0360). Further studies are needed to replicate the positive association that we observed.     

Association between the GABAA receptor α5 subunit gene locus (GABRA5) and bipolar affective disorder

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA_A receptor α5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:73–80, 1998. © 1998 Wiley-Liss, Inc.     

Association analysis of the proneurotensin gene and bipolar disorder

Neurotensin (NT) localizes within dopaminergic neurones in the mesocortical, mesolimbic and nigrostriatal systems, and it is now clear that NT can selectively modulate dopaminergic neurotransmission. It has therefore been proposed that altered NT function might contribute to the pathogenesis of neuropsychiatric disorders in which disordered dopaminergic neurotransmission is suspected. We have previously screened the gene encoding NT in a sample of schizophrenic and bipolar subjects, and identified three sequence variants. These have now been tested for association with bipolar disorder using a case-control sample of unrelated bipolar subjects and matched controls. No evidence for association was found, and our data therefore suggest that sequence variation in this gene does not make an important contribution to susceptibility to bipolar disorder.     

对氧磷酶1 55 Met/Leu、对氧磷酶2 148 Ala/Gly基因多态性与冠状动脉粥样硬化性心脏病的关系

目的探讨对氧磷酶1 55Met/Leu(paraoxonase 1, PON1 55Met/Leu)、对氧磷酶2 148 Ala/Gly(PON2148 Ala/Gly)基因多态性与冠状动脉粥样硬化性心脏病(简称冠心病)、血浆对氧磷酶(paraoxonase,PON)、总超氧化物歧化酶(total superoxide dismutase, T-SOD)活性以及丙二醛(maleic dialdehyde, MDA)浓度的关系.方法采用聚合酶链反应-限制性片段长度多态性方法检测262例冠心病患者和100名对照的PON1 55Met/Leu、PON2 148 Ala/Gly基因多态性,采用比色法测定血浆PON、T-SOD活性以及MDA浓度.结果与对照比较,冠心病患者的血浆PON[(349.27±138.36) nmol/min· mL vs. (454.75±166.00) nmol/min*mL, P<0.01]、T-SOD[(23.61±16.51) U/mL vs. (44.01±22.68) U/mL, P<0.01]活性明显降低,MDA浓度显著增高[(2.47±0.73) nmol/mL vs. (2.15±0.55) nmol/mL, P<0.01];冠心病患者的PON1 55 LM杂合子基因型(24.8% vs. 1.4%, P<0.01)、M等位基因频率(12.4% vs. 0.5%,P=0.001),PON2148 GG纯合子基因型和AG 杂合子基因型(11.8% vs. 5.0%和48.1% vs. 24.0%, P<0.01)、G等位基因频率(36.0% vs. 17.0%, P<0.01)较对照组明显增高;PON1 55 LM杂合子基因型的PON和T-SOD活性较LL纯合子基因型明显降低(P<0.01和P<0.05);PON2148 GG基因型和AG基因型的PON活性较AA基因型明显降低(P<0.01);Logistic回归分析显示PON1 55 LM杂合子基因型、M等位基因、PON2 148GG/AG基因型、G等位基因是冠心病的危险因子.结论冠心病患者的血浆PON和T-SOD活性明显降低,MDA浓度显著增高;PON1 55Met/Leu的LM基因型和M等位基因、PON2148 Ala/Gly的GG/AG基因型和G等位基因是冠心病的危险因子,并且与其他基因型相比,这些基因型患者的血浆PON活性降低.     

Paraoxonase-1 (PON1) promoter region polymorphisms,serum PON1 status and coronary heart disease

Introduction

Serum paraoxonase-1 (PON1) retards the oxidation of low-density lipoprotein and cell membranes and is atheroprotective. Polymorphisms in the promoter region of the PON1 gene have been shown to affect serum PON1 levels and have been related to the presence of coronary heart disease (CHD) in some studies. However, contradictory results have been reported with regard to promoter region polymorphisms and CHD presence; therefore we have re-examined the effects of the C-108T and G-909C promoter polymorphisms on PON1 levels and the presence of CHD in a large case-control study.

Material and methods

Paraoxonase-1 activity, concentration and the C-108T and G-909C polymorphisms were measured in 417 people with CHD and 282 healthy controls, in a case control study.

Results

Paraoxonase-1 activity and concentration were significantly lower in the CHD population compared to controls regardless of their C-108T and G-909C genotype (p < 0.001). Paraoxonase-1 activity was significantly different in the C-108T genotypes in both the control and CHD groups in the order TT < TC < CC (p < 0.01). Paraoxonase-1 concentration was significantly different in the CHD group only in the G-909C genotype in the order GG > GC > CC (p < 0.01). Haplotype analysis revealed no consistent patterns of PON1 activity in the CHD population; however, in the controls PON1 activity differed between haplotypes GGCC > GGTC > GGTT (p < 0.05) and GCCC > GCTC > GCTT (p < 0.02). Neither promoter polymorphism was associated with CHD presence.

Conclusions

Paraoxonase-1 status was significantly lower in people with CHD and was affected by the promoter region polymorphisms.     

No evidence for allelic association between bipolar disorder and monoamine oxidase a gene polymorphisms

We have tested the hypothesis that DNA markers in the MAOA gene show allelic association with bipolar affective disorder. Eighty-four unrelated Caucasian patients with DSM III-R bipolar disorder and 84 Caucasian controls were typed for three markers in MAOA: a dinucleotide repeat in intron 2, a VNTR in intron 1, and an Fnu4HI RFLP in exon 8. No evidence for allelic association was observed between any of the markers and bipolar disorder. © 1995 Wiley-Liss, Inc.