Genotypic and haplotypic associations of the DBH gene with plasma dopamine beta-hydroxylase activity in African Americans

Several variants at DBH are significantly associated with plasma DbetaH activity (pDbetaH). However, the overwhelming majority of data on this genotype-phenotype relationship has been gathered in samples from Europeans and European Americans (EAs). In this study, we examined the relationship between DBH polymorphisms and pDbetaH in samples from African-American (AA) subjects. Genotypes were determined at a 19-bp insertion/deletion polymorphism (ins/del) and four single-nucleotide polymorphisms (SNPs) at DBH in 109 samples. Analyses were performed using analyses of variance (ANOVAs) (for individual SNPs) and regression procedures (to assess the joint effects and the specific SNP-based haplotypes). We found: (1) single-variant analysis of all polymorphisms revealed apparent associations to pDbetaH, with rs1611115 accounting for the largest proportion of the variance in pDbetaH (28.7%) and ins/del the smallest (6.5%); (2) modest but significant linkage disequilibrium (LD) existed between ins/del and rs1611115; (3) LD between all other pairs of variants was not observed; (3) stepwise regression showed that a model containing rs1611115, rs2519152 and rs6271 accounted for 37.6% of the variance in pDbetaH, with rs6271 showing additional 7.6% above the effect of rs1611115, and rs2519152 showing additional 2% above rs1611115 and rs6271; (4) two common haplotypes, C-T-C and T-C-C at rs1611115-rs2519152-rs6271 were significantly associated with pDbetaH (P=0.0025 and 0.0036, respectively). The data support the validity of prior reported associations and underscore the importance of analyzing multiple SNPs across DBH in future association studies examining disease and biochemical phenotypes.     

No evidence for allelic association between schizophrenia and a functional variant of the human dopamine beta-hydroxylase gene (DBH).

Dopamine beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinepherine, has been proposed as being involved in the aetiology of schizophrenia. Previous work identified a functional polymorphism at nucleotide 910 of the DBH gene that results in a codon change in the mature protein Ala304Ser, with the mutant allele being associated with a lower enzymatic activity. In this study we performed an RFLP analysis in an association study consisting of 178 unrelated schizophrenic patients and 178 unrelated control subjects, matched for age, sex, and ethnicity. The frequency of the Ser304 DBH allele was 0.10 in the patient group and 0.08 in the control group, with no significant allelic or genotypic association observed. Therefore, we were unable to obtain evidence that this polymorphism contributes directly to susceptibility to schizophrenia.     

No association of a non-synonymous PLAU polymorphism with Alzheimer's disease and disease-related traits.

A 30 cM broad genomic region on the long arm of chromosome 10 at 80 cM shows significant and consistent linkage with AD and with plasma concentration of the beta-amyloid peptide 1-42 (Abeta42). The PLAU gene, which is involved in the production and degradation of Abeta42, maps to that region and is therefore a strong positional candidate for association with sporadic AD. We analyzed the non-synonymous single nucleotide polymorphism (SNP) rs2227564 in two independent case-control series from Switzerland and Greece and investigated the influence of this SNP on cognition in elderly individuals. Because PLAU modulates the cleavage of the amyloid precursor protein (APP) and the degradation of Abeta, we also determined the levels of Abeta in the brain, plasma and in the cerebrospinal fluid (CSF). We found no evidence for association of this SNP with AD or with AD-related traits such as beta-amyloid load in the medial temporal lobe or Abeta42 concentration in the CSF and in plasma. Our findings do not support a major role of PLAU polymorphisms as susceptibility factors for AD and suggest that large-scale association studies which combine genetic information from populations with similar genetic background might prevent the generation of spurious associations. Although PLAU may be pathophysiologially related to AD, the contribution of common genetic variants of this gene to the risk for developing AD is likely to be low.     

Association of the single nucleotide polymorphism C1858T of the PTPN22 gene with type 1 diabetes

The PTPN22 (protein tyrosine phosphatase N22) gene encodes the protein tyrosine phosphatase Lyp. One function of Lyp is downregulation of T-cell signaling through its interaction with the negative regulatory kinase C-terminal Src tyrosine kinase (Csk). A single nucleotide polymorphism in the PTPN22 gene, C1858T, encodes products with different Csk binding affinities. Disease association of the PTPN22 1858T allele has been reported in case-control studies of three different autoimmune disorders: type 1 diabetes (T1D), rheumatoid arthritis, and systemic lupus erythematosus. In this study, a set of 341 white, multiplex T1D families were genotyped for the C1858T single nucleotide polymorphism of PTPN22, and transmission disequilibrium test analysis revealed significant association (p = 0.005) of the T allele with T1D. No effects of parent of origin, sex of patient, or human leukocyte antigen genotype (high-risk human leukocyte antigen DR3/DR4 vs non-DR3/DR4) were observed. However, transmission of the T allele was significantly increased in the subset of patients who also carried at least one copy of the TCF7 883A allele, another allele that is important in regulating T-cell responses and that is associated with T1D. These results are consistent with the hypothesis that individuals lacking the C allele of PTPN22 may have reduced capacity to downregulate T-cell responses and may therefore be more susceptible to autoimmunity.     

HSP70-hom gene single nucleotide (+2763 G/A and +2437 C/T) polymorphisms in sarcoidosis

In the present study, two coding polymorphisms within the heat shock protein 70‐hom gene (HSP70‐hom) were analysed. One hundred and thirty‐eight individuals were studied, including 42 Polish patients with sarcoidosis, 13 of which presented with Löfgren's syndrome (LS), and 94 control subjects. Dimorphisms at positions +2763 (A/G) and +2437 (C/T) of the HSP70‐hom gene were typed using amplification refractory mutation system and polymerase chain reaction–restriction fragment length polymorphism technique, respectively. A significant prevalence of the HSP(+2437)‐C allele and the HSP(+2437)‐CC homozygous genotype was observed in patients with sarcoidosis and in those presenting with LS as compared to controls (P < 0.001 in all comparisons made). A majority of HLA‐DRB1*03‐positive patients with LS were carrying both HSP(+2437)‐C and (+2763)‐G alleles, and the concomitant presence of these three genetic factors was more frequent among patients with LS as compared to patients without LS (0.54 vs. 0.17, P < 0.05) and controls (0.54 vs. 0.01, P < 0.001). The association of the HSP(+2437)‐C allele with sarcoidosis and LS appeared to be independent of the presence of DRB1*03, although this HLA specificity was associated with LS manifestation. The HSP(+2763)‐G allele was independently associated with neither sarcoidosis nor LS. However, this HSP(+2763)‐G allele was present with either DRB1*03 or HSP(+2437)‐C within the same haplotypes in the patients and this might explain the observed prevalence of DRB1*03, HSP(+2437)‐C and (+2763)‐G in patients with LS. In conclusion, HSP(+2437)‐C allele was found as a factor associating with susceptibility to sarcoidosis and LS.     

FKBP6基因278C/A单核苷酸多态性与原发无精症相关研究

目的对FKBP6基因第3、4外显子进行突变和多态性筛查,研究第3外显子278C/A位点及第2内含子C/T位点(rs7797242)在无精症患者和正常男性中的多态性,初步探讨与原发无精症的相关性。方法采用变性高效液相色谱和聚合酶链反应-限制性片段长度多态性方法,对第3、4外显子进行突变和多态性筛查,对177例无精症患者和231名正常男性的278C/A和C/T(rs7797242)多态性进行基因分型。结果278C和278A等位基因频率符合Hardy-Weinberg平衡。无精症患者278A显著低于正常对照,差异有统计学意义(P<0.05)。C/T多态性在两组中均未检出,第3、4外显子未筛查到新的变异。结论278A等位基因可能与原发无精症相关。C/T(rs7797242)及370G/A,430G/C,467T/C,468G/A在中国人群中非常罕见。     

Lack of association of single nucleotide polymorphism in LRCH1 with knee osteoarthritis susceptibility

A genetic association of knee osteoarthritis (OA) and a C/T transition single nucleotide polymorphism (SNP) (rs912428) located in intron 1 of the LRCH1 gene has recently been reported in European Caucasians; however, the results are inconsistent. Our objective was to evaluate the association in different knee OA populations. Three case-control association studies were conducted in Han Chinese, Japanese, and Greek Caucasian populations. The LRCH1 SNP was genotyped in patients who had primary symptomatic knee OA with radiographic confirmation and in matched controls, and the association was examined. We performed a meta-analysis for the studies together with results of two previous papers using the DerSimonian–Laird procedure and calculated the power of the pooled studies by the software R. A total of 1,145 OA patients and 1,266 controls were genotyped. No significant difference was detected in genotype or allele frequencies between knee OA and control groups in the three populations (all P > 0.05). Association was not observed even after stratification by gender and Kellgren/Lawrence (K/L) scores. Meta-analysis also supported the lack of association between LRCH1 and knee OA. The strong heterogeneity between original and replication studies was detected in Caucasian populations. However, a tendency for the increase of TT genotype was observed in the European populations (OR = 1.46, P = 0.06). The powers for European and Asian replication studies were less than 0.8. Our results suggest that there is no association between LRCH1 and knee OA. However, lack of association should be concluded by further replication studies. Qing Jiang and Dongquan Shi contributed equally to this work.     

Analysis of the C/T(-1) single nucleotide polymorphism in the CD40 gene in multiple sclerosis

The costimulatory CD40-CD40L pathway plays a critical role in the generation and maintenance of adaptive immune responses. Genetic interference of CD40-CD40L interactions strongly influences the onset and course in many autoimmune disease models including experimental autoimmune encephalomyelitis. We analysed the association of a single nucleotide polymorphism of the CD40 gene (C/T(-1)) in 287 patients with multiple sclerosis (MS) and 184 matched controls. No significant differences were found in the frequency of the C/T(-1) polymorphism between the patients with MS and the controls (53% vs 49%) or among different MS subtypes. Cell surface expression of CD40 did not differ within the different genotypes, but carriers of the T allele showed a trend for a lower stimulatory index compared with individuals with the CC genotype. Although these subtle differences indicate functional consequences in the immune stimulatory capabilities related to the CD40 C/T(-1) polymorphism, our population-based study found no association with disease susceptibility or disease course in MS.     

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.     

白介素单核苷酸多态性与骨关节炎易感性关系的研究进展

骨性关节炎是骨科常见的致残致畸性疾病,其具体的病因及发病机制目前尚未阐明。年龄、性别、肥胖、既往关节损伤、关节的过度使用及基因因素可能与骨性关节炎发病风险有关。近年来白介素单核苷酸多态性与骨性关节炎发病风险间的研究成为国内外学者关注的热点,希望从基因层面进一步探讨骨性关节炎的发病机制。本文就目前国内外关于白介素单核苷酸多态性与骨性关节炎易感性关系的研究进展作一综述。     

No association of the C677T methylenetetrahydrofolate reductase polymorphism with schizophrenia

Some serological and genetic studies have suggested that alterations in folate metabolism are associated with increased vulnerability to schizophrenia. In particular, these findings are most striking for the role of a putatively functional variant (C677T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To test the hypothesis that the T allele and the TT genotype are risk factors for psychosis, we genotyped the C677T polymorphism in 206 participants with schizophrenia or schizoaffective disorder and 359 participants from a population control sample. Neither the T allele nor the TT genotype was associated with increased risk for schizophrenia. These results do not support a role for the C677T MTHFR variant in schizophrenia.     

Significant association of a single nucleotide polymorphism in the tumor necrosis factor-alpha (TNF-α) gene promoter with human narcolepsy

Narcolepsy is a sleep disorder in which multiple factors, including environmental and genetic factors, are involved. A genetic factor strongly associated with the disorder has been found in the human leukocyte antigen (HLA) class II region: the haplotype, DRB1*1501-DQB1*0602, predisposes to narcolepsy. No susceptibility genes other than the HLA-haplotype have been found. In this paper, we performed an association study of the tumor necrosis factor-alpha (TNF-alpha) gene located in the HLA class III region with human narcolepsy, in which we examined the known single-nucleotide polymorphisms (SNPs) in the promoter region in 49 narcoleptic patients, who were all positive for DRBI*1501, and 111 healthy control individuals. The results indicated that the frequency of the genotype at position -857 (-857SNP) was significantly different between the patients and controls, and the allele frequencies of 857SNP revealed that the frequency of -857T was significantly increased in the patients as compared with that in the controls (P=0.0068). In addition, haplotypes presumed from HLA-DRB1, -857SNP and HLA-B loci suggested that -857T was mainly associated with DRB1 alleles other than DRB1*1501: the significant increase in frequency of -857T in the patients was not caused by allelic association with DRB1*1501. Therefore, it is conceivable that the TNF-alpha with 857T was associated with narcolepsy independently of the strong association of DRB1*1501 with the disorder. Altogether, the data presented here lead us to propose that TNF-alpha could be a new susceptibility gene in human narcolepsy.     

Identification of a significant association of a single nucleotide polymorphism in TNXB with systemic lupus erythematosus in a Japanese population

Systemic lupus erythematosus (SLE) is one of the common autoimmune diseases, with complex genetic components. Here, we report on a case–control association study of 178 SLE patients and 899 control subjects, using genome-wide gene-based single nucleotide polymorphism (SNP) markers. An SNP, rs3130342, in a 5’ flanking region of the TNXB gene revealed a significant association with SLE [P = 0.000000930, odds ratio (OR) 3.11, with 95% confidence interval (95%CI) of 1.89–5.28] in a Japanese population. This association was replicated independently with 203 cases and 294 controls (P = 0.0440, OR 1.52, with 95%CI of 1.01–2.78). Although a copy number variation (CNV) of the C4 gene adjacent to the TNXB gene was reported to be associated with SLE, our analysis on this CNV revealed that the association of CNV of the C4 gene was weaker than the SNP in the TNXB gene and likely to reflect the linkage disequilibrium between C4 CNV and this particular SNP. Stratified analysis also revealed that the association of SNP rs3130342 with SLE was independent of the HLA-DRB1*1501 allele that has been shown to be associated with SLE. Our findings strongly imply that the TNXB gene is a candidate gene susceptible to SLE in the Japanese population. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

RANTES基因-28C／G单核苷酸多态性与子宫内膜异位症遗传易感性的研究

目的探讨调节正常T细胞表达和分泌活性因子（regulated on activation, normal T cell expressed and secreted,RANTES）基因启动子区-28C／G单核苷酸的多态性与广东籍汉族患者子宫内膜异位症的关系。方法应用聚合酶链反应-限制性酶切片段长度多态性技术（PCR—RFLP）并进行基因测序的方法检测广东籍汉族子宫内膜异位症患者59例（内异症组）,非子宫内膜异位症患者49例（对照组）,比较分析各组间基因型频率和等位基因频率。结果RANTES基因启动子区-28C／C基因型在子宫内膜异症组及对照组分布频率分别为81．36％、81．63％,C／G基因型分布频率分别为18．64％、18．37％;两组间的基因型分布频率比较差异无显著性（P〉0．05）。RANTES基因启动子区-28位点C等位基因型在内异症组及对照组中的分布频率分别为90．68％、90．82％,G等位基因型分布频率分别为9．32％、9．18％,两组间等位基因型频率比较差异无统计学意义（P〉0．05）。结论在广东籍汉族妇女中,RANTES基因启动子区-28C／G单核苷酸多态性与子宫内膜异位症遗传易感性可能无关联。     

Investigations into the molecular effects of single nucleotide polymorphism.

OBJECTIVES: DNA sequences are very rich in short repeats and their pattern can be altered by point mutations. We wanted to investigate the effect of single nucleotide polymorphism (SNP) on the pattern of short DNA repeats and its biological consequences. METHODS: Analysis of the pattern of short DNA repeats of the Thy-1 sequence with and without SNP. Searching for DNA-binding factors in any region of significance. RESULTS: Comparing the pattern of short repeats in the Thy-1 gene sequences of Turkish patients with ataxia telangiectasia (AT) with the "wild type" sequence from the DNA database, we identified a missing 8-bp repeat element due to an SNP in position 1271 (intron II) in AT-DNA sequences. Only the mutated sequence had the potential for the formation of a stem loop in DNA or pre-mRNA. In super-shift experiments we found that DNA oligomers covering the area of this SNP formed a complex with proteins amongst which we identified the proliferating cell nuclear antigen (PCNA) protein. CONCLUSION: SNPs have the potential to alter DNA or pre-mRNA conformation. Although no SNP-depeding formation of the DNA-protein complex was evident, future investigations could reveal differential molecular mechanisms of cellular regulation.