Correlation of tau gene polymorphism with age at onset of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disease and its prevalence increases with age. The microtubule-associated protein tau (MAPT) is thought to be implicated in the pathogenesis of PD. Association of the MAPT H1 haplotype with PD in Caucasians has been extensively studied, however, the results were inconsistent. In this study, we investigated whether MAPT gene variants contribute to the pathogenesis process including the age at onset in Japanese PD. Promoter region of MAPT gene was analyzed to find polymorphisms in Japanese population. Two single nucleotide polymorphisms (SNPs), C-639T and Del-568TIns, in promoter region were found. C-639T was novel. Unlike Caucasians, the −226C and −45A alleles consisting of the H1 haplotype were monomorphic in Japanese population. Association analysis was performed using 240 PD and 191 controls in these SNPs. No significant association was observed between these SNPs and PD. Haplotype analysis also showed no significant association (P = 0.72). However, the age at onset showed significant correlation with the genotypes of Del-568TIns in PD samples when analyzed by Kendall rank correlation test (Kendall tau = −0.098, P = 0.0243). These results suggested that MAPT gene variants may modify the pathogenesis process of PD.     

The role of 5-HTTLPR polymorphism in antidepressant-associated mania in bipolar disorder

BackgroundThe occurrence of mania during antidepressant treatment is a key issue in the clinical management of bipolar disorder (BD). The serotonin transporter gene is a candidate to be associated with antidepressant-associated mania (AAM) in some patients. This gene has a polymorphism within the promoter region (5-HTTLPR) with two allelic forms, the long (L) and the short (S) variants.MethodsWe performed a case–control study to compare 5-HTTLPR genotype and allelic frequencies between 43 patients with a DSM-IV diagnosis of BD, with at least one manic/hypomanic episode associated with treatment with proserotonergic antidepressants (AAM+) and 69 unrelated, matched bipolar patients, who had been exposed to proserotonergic antidepressants without development of manic symptoms (AAM?). Furthermore, we performed this comparison between a subgroup of 23 AAM+ patients that, when they presented AAM, were not using mood stabilizer (AAM+^?) and 25 AAM? patients who used antidepressant without the concomitant use of a mood stabilizer (AAM?^?). 5-HTTLPR genotyping was performed using PCR.ResultsNo significant differences were found between AAM+ and AAM?. Within the subgroups, our results show that S-carriers (LS + SS Genotypes) are more prone to make a manic/hypomanic episode associated with antidepressant (P = 0.017).LimitationsOur study is retrospective.ConclusionsThe 5-HTTLPR polymorphism may be considered a predictor of abnormal response to antidepressant in patients with BP, but this action is influenced by the presence of a mood stabilizer. Such observations reinforce that a correct diagnosis of bipolarity before the beginning of the treatment is essential, mainly for S-carriers patients.     

Association of aggression with a novel microRNA binding site polymorphism in the wolframin gene

Rare mutations in the WFS1 gene lead to Wolfram syndrome, a severe multisystem disorder with progressive neurodegeneration and diabetes mellitus causing life‐threatening complications and premature death. Only a few association studies using small clinical samples tested the possible effects of common WFS1 gene variants on mood disorders and suicide, the non‐clinical spectrum has not been studied yet. Self‐report data on Aggression, Impulsiveness, Anxiety, and Depression were collected from a large (N = 801) non‐psychiatric sample. Single nucleotide polymorphisms (SNPs) were selected to provide an adequate coverage of the entire WFS1 gene, as well as to include putative microRNA binding site polymorphisms. Molecular analysis of the assumed microRNA binding site variant was performed by an in vitro reporter‐gene assay of the cloned 3′ untranslated region with coexpression of miR‐668. Among the 17 WFS1 SNPs, only the rs1046322, a putative microRNA (miR‐668) binding site polymorphism showed significant association with psychological dimensions after correction for multiple testing: those with the homozygous form of the minor allele reported higher aggression on the Buss–Perry Aggression Questionnaire (P = 0.0005). Functional effect of the same SNP was also demonstrated in a luciferase reporter system: the minor A allele showed lower repression compared to the major G allele, if co‐expressed with miR‐668. To our knowledge, this is the first report describing a microRNA binding site polymorphism of the WFS1 gene and its association with human aggression based on a large, non‐clinical sample. © 2013 Wiley Periodicals, Inc.     

Serotonin receptor 1A −1019C/G variant: Impact on antidepressant pharmacoresponse in melancholic depression?

Previous studies on the effects of serotonin receptor 1A (5-HT1A) gene variation on treatment response in depression revealed inconsistent results with studies pointing towards a detrimental influence of the 5-HT1A −1019G allele on antidepressant treatment response, while others did not discern any involvement of 5-HT1A variants. In order to further delineate the impact of 5-HT1A gene variation on pharmacoresponse in depression over 6 weeks of antidepressant treatment, the influence of the 5-HT1A −1019C/G (rs6295) polymorphism was investigated in 340 Caucasian patients with a Major Depressive Episode (DSM-IV) with particular attention to the subtype of depression (major depression and melancholic depression). Antidepressant treatment response across 5-HT1A −1019C/G genotype groups showed no differences in either Major Depressive Episode or major depression between genotype groups, whereas stratification for the melancholic subtype of depression revealed a significantly worse treatment response as conferred by the −1019CC genotype (p = 0.02). The poorer treatment response in melancholic depression could first be detected in week 2 (p = 0.03), continuing until week 6 and showing a maximum effect in week 3 (p = 0.01). The present study adds to the clarification of the role of 5-HT1A variation in treatment response in major depression by providing preliminary support for poor treatment response mediated by the 5-HT1A −1019C allele repressing 5-HT1A activity specifically in the melancholic subtype of depression.     

Functional genetic variants of CTLA-4 and risk of tobacco-related oral carcinoma in high-risk North Indian population

Single nucleotide polymorphisms (SNPs) of the CTLA-4 gene have been implicated in susceptibility to different cancer in different ethnic populations. We assessed the association of five SNPs [−1722C/T, −1661A/G and −318C/T in the promoter region49A/G in exon 1 and CT60A/G in the 3′untranslated region (UTR)] with tobacco-related oral squamous cell carcinoma (OSCC) in North Indian subjects. We genotyped 130 OSCC patients and 180 normal subjects by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) using BbvI, MseI, NcoI and BstEII restriction endonucleases. Among these SNPs, −1722CC, −1661AG and CT60AA genotypes were more prevalent in OSCC patients as compared to controls and in the logistic regression analysis with odd ratio (OR) 2.85, 95% CI (0.69–11.68); OR 2.48, 95% CI (1.29–4.78) and OR 3.0, 95% CI (1.43–6.28) respectively, these genotypes showed strong association with OSCC risk. With higher prevalence in controls 49GG genotype and G allele (OR 0.57, 95% CI 0.40–0.81) appeared to be protective. Moreover, TACAG, TACGA and TATAG appeared as susceptible while TACGG and CACGG appeared as protective haplotypes. These results suggest significant risk modifying effects of CTLA-4 −1722C/T, −1661A/G, −318T/C, CT60 A/G and 49A/G SNPs in tobacco-related OSCC in North Indian population.     

Association study between cannabinoid receptor gene (CNR1) and pathogenesis and psychotic symptoms of mood disorders*

Cannabis can induce mood change and sometimes psychotic symptoms in normal persons. In brain, the main active ingredient of cannabis acts via the cannabinoid CB1 receptor (CNR1) which is located on chromosome 6q14‐15. Linkage studies have suggested the presence of a bipolar disorder susceptibility locus on chromosome 6q. In this population based association study, we tested the hypothesis that a microsatellite polymorphism in the promoter region of the CNR1 gene confers susceptibility to mood disorders and psychotic features. We genotyped the CNR1 gene is 154 mood disorder patients and 165 normal controls. The results showed that the triplet repeat polymorphism in the promoter region of the CNR1 gene was not likely to be involved in the pathogenesis or in the psychotic symptoms of mood disorders. © 2001 Wiley‐Liss, Inc.     

Association of single nucleotide polymorphisms on Interleukin 17 receptor A (IL17RA) gene with aspirin hypersensitivity in asthmatics

Aim

To investigate the association of single nucleotide polymorphisms (SNP) on IL17RA gene with Aspirin Exacerbated Respiratory Disease (AERD) and the functional effect of these variants on expression of IL17RA gene products.

Material & methods

15 SNPs of IL17RA gene were analyzed in 825 normal controls and 143 subjects with AERD and 411 with aspirin-tolerant asthma (ATA) and functionally characterized using measurement of protein and m-RNA expression.

Result

Minor alleles frequencies of the three SNPs (−1075 A > G, −947 A > G, −50 C > T) and one haplotype (BL1_ht1) were significantly lower in AERD compared to those in ATA (p^corr = 0.002–0.03). IL17RA protein expression and mRNA amount in CD14⁺ peripheral blood monocytes and mononuclear cells were significantly increased in subjects carrying the common alleles homozygote compared with those carrying the minor alleles.

Conclusions

The minor alleles of the three SNPs may decrease the risk of AERD via attenuation of IL17RA gene expression.     

Interleukin-10 gene promoter polymorphisms in celiac patients from north-eastern Italy

Celiac disease is a complex chronic intestinal disorder driven by an immune response against the gliadin fraction of gluten: many factors are involved in the pathogenesis of the disease, and among these Interleukin-10 could play an important role. In the present study, the −1082A>G, −819T>C and −592A>C IL10 functional polymorphisms were analyzed in 565 celiac patients and 576 healthy controls from north-eastern Italy, stratified for HLA class II celiac disease risk haplotypes. No significant differences were observed for the three IL10 polymorphisms distribution between celiac patients and controls with the exception of a slightly increased risk for the −1082A allele in HLA-DQ8 male individuals. Although our findings suggest that the IL10 genetic variants analyzed do not have a major role in the susceptibility to the development of celiac disease in north-eastern Italian patients, we think that the possible involvement of IL10 gene in CD should deserve further investigation and that large-scale studies are recommended to confirm our findings.