Association of Polymorphisms in the Vitamin D Receptor Promoter with Idiopathic Short Stature

The genetic alterations of vitamin D receptor (VDR) are related with the growth of long bone. There were a lot of reports regarding an association of polymorphisms in the VDR promoter with many disorders, but not with idiopathic short stature (ISS). We investigated the association of them with ISS. A total of 50 subjects, including 29 ISS patients and 21 healthy controls with their heights within the normal range was recruited. We selected two single nucleotide polymorphisms (SNPs) from VDR promoter (rs11568820 at the Cdx-2 binding site upstream of exon 1e and rs4516035 at -1012 upstream of exon 1a) as candidates, respectively. In genotype analysis, the frequency of A/A genotype at the Cdx-2 binding site locus (rs11568820) upstream of exon 1e of VDR was decreased to 6.9% in ISS patients (28.6% in controls) (P = 0.027). The genetic variation at the Cdx-2 binding site of VDR promoter can be a contributing factor of growth of height.     

Analysis on the association of human BLYS (BAFF,TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis

Recent studies indicated a substantial role of BLyS (BAFF, TNFSF13B) in the pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in humans and in animal models. This study was conducted to screen for polymorphisms of human BLYS, and to examine whether they are involved in the genetic susceptibility to human SLE and RA. A systematic polymorphism screening was performed in the coding region, 5' and 3' untranslated regions, and promoter region of human BLYS. Association of the detected polymorphisms with SLE and RA was analyzed in 221 Japanese patients with RA, 156 with SLE, and 227 healthy individuals, using the case-control approach. Four single nucleotide polymorphisms (SNPs) in the promoter, one SNP in intron 1, and one rare nonsynonymous substitution (Ala105Thr) in the coding region were detected. The BLYS SNPs were found to form three common haplotypes. Significant association with the susceptibility to SLE or RA was not observed. However, a tendency for the increase of -871T/T genotype was observed in SLE patients with anti-Sm antibody (P=0.082). BLYS mRNA level was significantly elevated in the monocytes from individuals carrying -871T (P=0.010). In addition, although statistically not significant, 105Thr allele was slightly increased in patients with RA compared with controls (P=0.058). Characterizing the functional and clinical significance of these new SNPs requires further study.     

Molecular modeling of O6-methylguanine-DNA methyltransferase mutant proteins encoded by single nucleotide polymorphisms

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) acts as a chemoprotectant and mediates resistance to alkylating anti-tumor agents. A number of MGMT single nucleotide polymorphisms (SNPs) have been described. We analyzed by molecular modeling the regions likely to be affected in the MGMT mutant proteins encoded by SNPs. Starting from the crystal structure of non-alkylated MGMT, molecular models of mutant proteins encoded by SNPs have been built. Most of the mutations were found to be located either within the DNA binding region (A121E, A121T, G132R, N123V) or in the vicinity of the active Cys145 (I143V, G160R). A further L84F mutant might affect Zn2+ binding. W65C was found to possibly be unstable.     

SCN7A 基因单核苷酸多态性与原发性与原发性高血压的相关研究

目的　检测中国人电压调控钠通道 7型α亚单位基因 (sodium channel,voltage- gated,type ,alpha polypeptide,SCN7A)调控区和编码区的单核苷酸多态性 (single nucleotide polymorphisms,SNPs) ,并探讨其与上海汉族人群原发性高血压的关系。　方法　采用直接测序法检测基因启动子、编码区和部分内含子的序列 ,以确定中国人群中 SCN7A基因 SNPs的位置及类型。采用聚合酶链反应 -限制性片段长度多态性及直接测序法 ,对上海汉族 96例原发性高血压患者和 96名正常血压对照者进行 SNP检测和关联研究。对所发现的 P<0 .0 5的 SNP位点 ,进一步扩大样本 (病例、对照组各 2 88例 )加以验证。结果　在 13132 bp的测序长度中 ,共发现 32个 SNP,包括启动子区 7个 ,编码区 10个 (其中改变氨基酸编码的 6个 ) ,3′非编码区 1个 ,内含子区 14个 ,其中 30个为新发现的 SNP。关联研究结果显示 SNP0 2 1在病例和对照组中的分布差异存在显著性 (P <0 .0 1) ,该 SNP多态可改变氨基酸的编码序列。　结论SCN7A基因变异可能与上海汉族人群原发性高血压相关。     

ARIX and PHOX2B polymorphisms in patients with congenital superior oblique muscle palsy

To identify ARIX gene and PHOX2B gene polymorphisms in patients with congenital superior oblique muscle palsy, 3 exons of the ARIX gene and PHOX2B gene were sequenced by genomic DNA amplification with polymerase chain reaction (PCR) and direct sequencing in 31 patients with congenital superior oblique muscle palsy and in 54 normal individuals. A family with a father and one daughter each having congenital superior oblique muscle palsy was also included in this study. Eleven patients with congenital superior oblique muscle palsy had heterozygous nucleotide changes in the ARIX gene, including 4 patients reported on previously. One patient with atrophy of the superior oblique muscle had a new change of T-4G in the promoter region of the ARIX gene. The other 6 patients had a heterozygous nucleotide change of G153A in the 5'-untranslated region (UTR) of the exon 1 of the ARIX gene. These nucleotide changes of the ARIX gene, taken together, had a significant association with congenital superior oblique muscle palsy(P = 0.0022). One patient and 5 patients had heterozygous nucleotide changes of A1106 C and A1121 C in exon 3 of the PHOX2B gene, respectively, while these changes were absent in the normal individuals. Two patients had both the G153A change in the 5'-UTR of exon 1 of the ARIX gene and the A1121 C change in exon 3 of the PHOX2B gene. In conclusion, the polymorphisms of the ARIX gene and PHOX2B gene may be genetic risk factors for the development of congenital superior oblique muscle palsy.     

The absence of disease-specific polymorphisms within the HLA-B51 gene that is the susceptible locus for Behçet''s disease

Beh?et's disease is known to be associated with HLA-B51 in many different populations. Genetic evidence supports that the susceptible gene for Beh?et's disease is the HLA-B51 allele at the HLA-B locus. This study was aimed to determine the HLA-B51 nucleotide sequence variation in three Beh?et's disease patients and three healthy controls in order to elucidate if any disease specific mutations or polymorphisms may exist in the HLA-B51 gene of patients. Long-range polymerase chain reaction (PCR) was first carried out to give a PCR-amplified product of 9.5 kb which was then used as a template for nested PCR to give a final amplified product of 4.2 kb. This final product containing the 1.3-kb promoter/enhancer region and the entire HLA-B gene except for a 363-bp 3' terminal end segment encoding the 3' untranslated region was subcloned by the BP cloning technique and sequenced. The sequencing results showed that all the patients possessed the HLA-B*51011 allele, and there were no differences in the exonic nucleotide sequences between the three Beh?et's disease patients and the three healthy controls. The HLA-B*51011 intronic and promoter/enhancer nucleotide sequences from the three patients had 22 single nucleotide polymorphisms (SNPs), a single insertion of 6 bp and a single deletion of 2 bp. On the other hand, the three healthy controls had 24 SNPs in their intronic and promoter/enhancer regions. However, none of these polymorphisms in the patients were specific for the disease. Therefore, these results clearly demonstrate that the HLA-B exonic sequence that encodes the HLA-B51 allele is the real pathogenic factor in Beh?et's disease.     

Identification of four novel polymorphisms in the calcitonin/alpha-CGRP (CALCA) gene and an investigation of their possible associations with Parkinson disease, schizophrenia, and manic depression

We identified novel polymorphisms in the calcitonin/CGRPalpha (CALCA) gene by direct sequencing of genomic DNA and subsequent genotyping by RFLP (restriction fragment length polymorphism) detection and investigated association with neurological or psychiatric disease. Four novel polymorphic alleles were found: two (g.979G>A and g.4218T>C) represented single nucleotide polymorphisms (SNPs), one consisted of two coupled SNPs in close vicinity to each other (g.1210T>C and g.1214C>G), and one was an intronic 16-bp microdeletion (2919-2934del16). One of the SNPs (g.4218T>C) causes a non-synonymous amino acid change (Leu66Pro) in the third exon, an exon common to both procalcitonin and pro-alpha-CGRP. In a subsequent association study, frequencies of the identified polymorphisms in Parkinson and schizophrenia patients were compared with frequencies in the normal population. No statistically significant association was found in our material. The 16-bp microdeletion polymorphism was present in a family with multiple cases of unipolar or bipolar depressive disorder. Using this polymorphism as marker, cosegregation with the phenotype was observed in the majority of individuals.     

Novel polymorphisms of the human cholecystokinin a receptor gene: An association analysis with schizophrenia

The cholecystokinin A receptor (CCK‐AR) modulates CCK‐stimulated dopamine release in the posterior nucleus accumbens, and its gene is mapped to 4p15.2‐15.1 with the dopamine receptor 5 (DR5) gene. We speculated that alterations in the CCK‐AR lead to an increase in dopamine release, which may in turn constitute a predisposition in schizophrenia. We investigated genetic variations in the promoter region and the coding region of the CCK‐AR gene. An association analysis was conducted between 83 unrelated schizophrenic patients and 80 healthy controls. Novel polymorphisms (201A→G, 246G→A in the promoter region, 1260T→A, 1266T→C in intron 1 within the 3′ mRNA splice acceptor site consensus sequence, and Leu306Leu in exon 5) were found in addition to the variants (608G→A in intron 1, 3849C→T [Ile296Ile] in exon 5) reported previously. Significant differences were found in the allele frequencies of the 201A→G nucleotide substitution in the promoter region between patients and controls (P = 0.0181, odds ratio: 1.972, after Bonferroni correction: P = 0.0543). These differences were also found between the patients with paranoid type and controls (P = 0.0274, odds ratio = 3.667, after Bonferroni correction: P = 0.0822). Our analyses suggest that the 201A allele frequency was higher in the schizophrenic group, especially in the paranoid type, than in the control group at a rate that was not quite significant after Bonferroni correction. Am J. Med Genet. (Neuropsychiatr. Genet.) 96:141–145, 2000. © 2000 Wiley‐Liss, Inc.     

Sequenom质谱法分析细胞毒性T淋巴细胞相关分子4基因多态性与宫颈癌易感性的关系

目的 探索细胞毒性T淋巴细胞相关分子4(cytotoxic T-lymphocyte-associated protein 4,CTLA4)基因单核苷酸多态性(single nucleotide polymorphism,SNPs)与宫颈癌易感性的关系.方法 应用sequenom MassARRAY时间飞行质谱系统对100例宫颈癌及100名健康对照者 CTLA4基因20个多态位点(CTLA4_1～CTLA4_20)进行基因型分型,统计分析基因型频率和肿瘤易感性的关系.结果 与正常人群中最常见的 CTLA4基因单倍型-1576A、-318C和1402G相比,带有单倍型-1576G、-318T或1402A的个体均显著增加宫颈癌的风险(P<0.05),相对风险度的比值比及其95%可信区间分别为2.87(1.75～4.76),4.02(1.72～9.09)和4.51(1.46～13.88),而其余基因型与宫颈癌发病风险没有显著的相关性;其中rs5742909易感位点与先前的报道相一致.而双荧光素酶报告基因实验进一步证明,位于基因启动子区域的rs11571316多态位点能显著影响报告基因的表达活性.结论 CTLA4基因启动子区域的SNP可能通过影响 CTLA4基因的表达水平来影响个体对宫颈癌的易感性.

Abstract：

Objective To evaluate the association between single nucleotide polymorphisms (SNPs) of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene and susceptibility to cervical cancer. Methods One hundred patients and 100 healthy controls from Hubei province were genotyped for 20 polymorphic loci using Sequenom. Results The frequency of rs11571316 G allele and rs5742909 T allele, which are localized in the promoter region, and rs11571319 A allele, which is downstream of the gene, were significantly higher in patients than in controls. Luciferase assay showed that, as the previously reported rs5742909 T allele, rs11571316 G allele could significantly increase the expression of the reporter gene. Conclusion SNPs in the promoter region of CTLA4 gene might increase the susceptibility to cervical cancer by increasing CTLA4 gene expression.     

幼年特发性关节炎患儿甘露糖结合凝集素基因启动子区SNP研究

目的探讨甘露糖结合凝集素(MBL)基因启动子区单核苷酸多态性(SNP)与幼年特发性关节炎(JIA)易感性的关系。方法对50例JIA患儿和48名正常健康儿童MBL基因启动子区SNP位点-550(G/C,称H/L等位基因)和-221(G/C,称X/Y等位基因)采用等位基因特异性PCR法(PCR-SSP)检测,并分析其单元型及基因型频率。结果共检出HY、LY和LX三种单元型,在JIA患儿中的频率依次为0.540、0.270和0.190,而在正常儿童中频率分别为0.594、0.292和0.114;两组间各单元型比较均无显著性差异。结论MBL基因启动子区单核苷酸多态性与JIA无相关性。     

SLC22A12基因第8外显子和第8内含子多态与中国汉族人原发性高尿酸血症关联研究

目的 研究原发性高尿酸血症患者SLC22AI2基因第8内含子和第8外显子单核苷酸多态(single nucleotide polymorphism,SNP)位点与原发性高尿酸血症遗传易感性的关系.方法 选择山东沿海地区原发性高尿酸血症患者215例,正常对照人群323名.提取基因组DNA,PCR扩增SLC22A12基因第8内含子和第8外显子,对PCR扩增产物进行测序.结果 序列分析发现:(1)SLC22AI2基因第8外显子存在T1309C单核苷酸多态,第8内含子存在-103A＞G单核苷酸多态,这2个多态位点完全连锁.(2)高尿酸血症组-103A＞G G等位基因频率和T1309C C等位基因频率明显高于正常对照组(均为51.9%vs.42.4%,P＜0.01);(3)高尿酸血症组GG+GA基因型频率和CC+CT基因型频率显著高于正常对照组(均为80.0%vs.69.0%,P＜0.01).(4)-103 A＞G和T1309C基因多态中,含有等位基因G的基因型GG+GA及含有等位基因C的基因型CC+CT均使高尿酸血症的发病危险性上升了1.79倍(OR=1.79,95%CI:1.19～2.70).结论 SLC22A12基因第8外显子T130gC及第8内含子-103A＞G SNP与原发性高尿酸血症密切相关.     

Novel and previously reported single‐nucleotide polymorphisms in the human 5‐HT1B receptor gene: No association with cocaine or alcohol abuse or dependence

Evidence from animal self‐administration and human genetics studies suggests that the serotonin_1B (5‐HT_1B) receptor may be involved in modulating responses to cocaine or alcohol. We hypothesize that polymorphisms, including single‐nucleotide polymorphisms (SNPs), in the human 5‐HT_1B receptor gene, may be associated with individual differences in vulnerability to cocaine or alcohol abuse or dependence. A total of 210 subjects were studied, including individuals with a primary diagnosis (DSM‐IV criteria) of cocaine abuse or dependence, alcohol abuse or dependence, and controls with no history of previous or current illicit drug or alcohol abuse or dependence. Genomic DNA samples were isolated from each individual. For 157 of the subjects, polymerase chain reaction (PCR) was used to amplify the entire coding region of the 5‐HT_1B receptor gene as well as parts of the 5′ and 3′ untranslated regions. PCR products were sequenced in forward and reverse directions on an automated sequencer. Amplified DNA from an additional 53 subjects was sequenced in the 5′ untranslated region to gain additional data on the frequency of one identified SNP. Seven polymorphisms were identified: one novel SNP in the 5′ untranslated region (UTR) of the gene (A‐161T); one SNP not reported in any published scientific communication (but found to be recorded in GenBank) in the 3′ UTR (A1180G); two novel dinucleotide deletions at positions ? 184/? 183 and ? 182/? 181; and three previously identified SNPs (T‐261G, C129T, G861C). Data were stratified by ethnicity and pooled Relative Risk was calculated for combined alcohol abuse and dependence cases and controls, and also for combined cocaine abuse and dependence cases and controls. No significant differences between cases and controls were found. © 2001 Wiley‐Liss, Inc.     

A new PCR-SSP typing method for six single-nucleotide polymorphisms impairing the blood-clotting cascade as well as T-cell stimulation

Single-nucleotide polymorphisms (SNPs) within the genes of factor V (FV) (G1691A; exon 10), prothrombin (FII) (G20210A; 3'untranslated - region) and methylenetetrahydrofolate reductase (MTHFR) (C677T; exon 4) are associated with hypercoagulability, and systematic screening of individuals being at higher risk of thrombosis has been suggested. SNPs in the 2q33 region within the genes of CD28 (+17T/C; intron 3) and CTLA4 (-318C/T; promoter and +49A/G; exon 1) are likely to affect T-cell proliferation and antigen presentation signaling, which may lead to altered sensitivity of allograft or self-tissue recognition and affect the incidence of autoimmune diseases. We developed primers that allow specific amplification of these six SNPs at test conditions identical with those used for HLA typing with the CTS PCR-SSP reagents. One hundred ninety-six healthy German Caucasian individuals were tested for the six SNPs. The genotype frequencies for all SNPs were in Hardy-Weinberg equilibrium. There was no significant difference in the distribution of genotypes when compared to other published studies in which these SNPs were tested. The described PCR-SSP method can be used to screen large numbers of patients for these SNPs.     

广东地区汉族人群TLR1 基因多态性的测序研究

目的: 人类Toll样受体1(TLR1)在先天性免疫中起着重要作用。本文将着重研究广东地区汉族正常人群中TLR1 基因功能区的单核苷酸多态性(SNPs)图谱和频率分布。方法: 随机收集50例健康、无亲缘关系的中国广东地区汉族人外周血液,对TLR1 基因的启动子区、5'和3'非翻译区、4个外显子区的序列进行PCR扩增和直接测序,找出多态性位点及其频率分布规律。在此基础上对多态性位点进行Hardy-Weinberg平衡分析、中性进化分析和连锁不平衡分析。结果: 共发现17个SNPs以及2个插入/缺失多态位点,其中2个是首次发现的新多态性位点。位于编码区的新SNP位点+1 378 A/G为非同义突变位点,能导致460位丝氨酸(Ser)残基替换为甘氨酸(Gly)残基,并且这个氨基酸残基的替换处于TLR1胞外区的LRR结构域中,从而有可能影响蛋白的识别功能。另外,频率最高的SNPs是+743 A/G和+1 518 A/G,其次要等位基因频率均达到48%。所有多态性位点均符合Hardy-Weinberg平衡。中性检验显示广东汉族人群 TLR1 基因不符合中性进化假说,很可能是其调控区受到平衡选择作用的原因。连锁不平衡分析显示多态性位点-6 912 C/TA、-6 876 C/T、-6 399 C/T和-6 375 C/T之间,-6 847 A/G和-6 737 A/T之间,以及-5 984 -/CT、-5 531 A/G和-5 490 C/G之间完全连锁。结论: 本研究首次报道了汉族正常人群TLR1 基因的功能性多态性图谱,发现了一些种族特异性的多态性位点及频率分布规律,为今后开展汉族人基因多态性与疾病相关性研究打下一定的基础。     

Functional SNP in 3′‐UTR MicroRNA‐Binding Site of ZNF350 Confers Risk for Age‐Related Cataract

Many studies have suggested that individual susceptibility to age‐related cataract (ARC) may be associated with DNA sequence polymorphisms affecting gene regulation. As DNA repair is implicated in ARC pathogenesis and single‐nucleotide polymorphisms (SNPs) in the 3′‐terminal untranslated region (3′‐UTR) targeted by microRNAs (miRNAs) can alter the gene function, we hypothesize that the miRNA‐binding SNPs (miRSNPs) in DNA double‐strand break repair (DSBR) and nucleotide excision repair (NER) pathways might associate with ARC risk. We genotyped nine miRSNPs of eight genes in DSBR and NER pathways in Chinese population and found that ZNF350‐ rs2278414:G>A was significantly associated with ARC risk. Even though the Comet assay of cellular DNA damage indicated that all the subtypes of ARC patients had more DNA breaks in peripheral lymphocytes than the controls independent of rs2278414 genotypes, individuals carrying the variant A allele (AA and AG) had lower ZNF350 mRNA levels compared with individuals with GG genotype. Moreover, the in vitro experiment indicated that miR‐21‐3p and miR‐150‐5p specifically downregulated luciferase reporter expression in the cell lines transfected with rs2278414 A allele compared with rs2278414 G. These results suggested that the association of SNP rs2278414 with ARC might involve an altered miRNA regulation of ZNF350.     

Single nucleotide polymorphisms of the very low density lipoprotein receptor (VLDLR) gene

The very low density lipoprotein receptor (VLDLR) has a potentially important role in lipoprotein metabolism and Alzheimer's disease. We developed amplification primers for most of the coding region and 3′-untranslated region of VLDLR and used sequencing of genomic DNA to examine these regions of VLDLR in subjects with familial combined hyperlipidemia and in normal controls. We identified ten novel single nucleotide polymorphisms (SNPs) for VLDLR. We also found one rare coding sequence variant, S>R153, in a subject with familial combined hyperlipidemia, which was absent from 2360 normal alleles. The identification of intron–exon boundaries, amplification primers, and SNPs provides tools to investigate VLDLR for genetic association and linkage studies. Received: April 30, 2001 / Accepted: May 1, 2001     

A comprehensive survey for polymorphisms in the bovine IFN-gamma gene reveals a highly polymorphic intronic DNA sequence allowing improved genotyping of Bovinae.

This study aimed to identify interferon-gamma (IFN-gamma) gene variants in cattle for diagnostic purposes. Therefore, the entire bovine IFN-gamma gene (BoIFNG) and 2605 bp of its promoter DNA were sequenced. The BoIFNG DNA sequence conforms to the published part of Bo-IFN-gamma cDNA. Primer extension experiments show the presence of a 5' extension of exon 1 by 42 nucleotides (nt). One SINE element (Bov-A2) is located in the 5'-region, and two SINE elements (Bov-tA, Bov-B) are contained in the 3'-region of BoIFNG. The variants were detected by comparative sequence analysis of PCR amplicons from different bovine species. Four polymorphic mononucleotide repeats are situated in the promoter and in intron 1. Four distinct series of single nucleotide polymorphisms (SNP) were found in functionally important regions of BoIFNG. The region between the two intron 1 microsatellites contains the highest density of SNPs in Bos taurus breeds. One G-T transversion in the coding region of exon 1 causes a Gly(14) to Val(14) exchange in the BoIFNG signal peptide of different bovine species. A G-A transition in exon 2 encodes a Ser(19) to Asn(19) change in the mature protein of the Tibetan yak. Genotyping of randomly sampled Holstein Friesian cows at selected SNPs and of both intron 1 microsatellites revealed two dominant BoIFNG microhaplotypes. The detected SNPs improve the recently reported genotyping system of cattle.     

SIP1基因编码区点突变及多态性在先天性巨结肠症中的检测与分析

目的 检测先天性巨结肠症(Hirschsprung disease,HSCR)患者SIP1(Smad-interacting protein 1)基因编码区点突变及单核苷酸多态性特点,探讨SIP1基因与HSCR的关系.方法 应用聚合酶链反应.单链构像多态性(polymerase chain reaction-single strand conformation polymorphism,PCR-SSCP)和DNA直接测序技术,对50例HSCR、30名正常对照外周血SIP1基因编码区的10个外显子,进行点突变与单核苷酸多态性的检测与分析.结果 HSCR与正常对照突变图谱比较,有1例病例在第7外显子出现杂合性缺失,密码子157位点GTG→GTA置换,引起亮氨酸的同义突变,属于单核苷酸多态性,突变率为2%(1/50).有4例患者在第8外显子出现突变,突变率为8%(4/50).PCR-SSCP银染分析,第2外显子2例出现相同类型泳动变位;第7外显子3例出现相同类型泳动变位;第8外显子7例出现相同类型泳动变位.结论 HSCR有SIP1基因突变,提示SIPI基因与HSCR的发病存在一定程度的关联.     

Association analysis of delta-opioid receptor gene polymorphisms in methamphetamine dependence/psychosis.

The role of the delta-opioid receptor (OPRD1) in methamphetamine (MAP) addiction was investigated using association analysis between OPRD1 gene polymorphisms and MAP dependence/psychosis. DNA samples from Japanese patients with MAP dependence/psychosis were analyzed to find polymorphisms in OPRD1 gene exons and exon-intron boundaries. One novel single nucleotide polymorphism (SNP) in intron 1 and two SNPs in exon 3 were identified. The two SNPs in exon 3 were in linkage disequilibrium. No significant difference was observed in either genotypic or allelic frequencies of these SNPs between controls (n = 260) and MAP dependent/psychotic patients (n = 170). Global analyses using the three SNPs and subcategory analyses on clinical parameters also showed no significant differences. These results suggest that the OPRD1 gene variants may not be a factor in vulnerability to MAP dependence/psychosis.