Association of HLA-DR and type II collagen autoimmunity with Meniere's disease

To investigate HLA-associated genetic susceptibility to Meniere's disease in relation to type II collagen (CII) autoimmunity status, HLA-DRB1 genotyping and ELISA measurement of anti-CII antibody were performed in 41 Korean patients with Meniere's disease. In the anti-CII positive subgroup (20%) of patients, the frequency of HLA-DRB1*0405 was significantly increased (uncorrected) compared with both controls (63% vs 16%) and anti-CII negative patients (63% vs 12%). In the anti-CII negative subgroup, HLA-DRB1*1201 was significantly increased (uncorrected) (27% vs 10%) and DRB1*13 was decreased (6% vs 24%) compared with controls; these alleles appeared to confer susceptibility and resistance to the development of the disease. Association of HLA-DRB1*0405 with anti-CII positive Meniere's disease in this study suggests that it shares a specific HLA-DR sequence, QRRAA, as a genetic susceptibility factor with the anti-CII positive rheumatoid arthritis. In conclusion, whilst type II collagen autoimmunity may have a partial role in Meniere's disease, different HLA-DR alleles may also be associated with either susceptibility or resistance to the development of the disease in relation to anti-CII antibody status.     

多巴胺突触前膜转运载体基因多态性与帕金森病

目的 研究多巴胺突触前膜转运载体（dopamine transporter,DAT)的基因多态性与帕金森病（Parkinson's disease,PD)的关系。方法 比较了85名健康对照和128例PD患者（包含发病年龄小于或等于50岁的早发型PD亚组和发病年龄大于50岁的晚发型PD亚组）的DAT基因串联重复可变数（variable number of tandem repeat,VNTR)多态性分布。结果 该多态性位点的基因型和等位基因分布,在对照组和PD患者之间差异有显著性;晚发型PD与7拷贝等位基因强相关,与11拷贝等位基因弱相关,早发型PD主要与9拷贝等位基因相关。结论 该结果不仅支持DAT与PD相关的假说,而且提示了DAT基因VNTR多态性与PD发病年龄的可能关系。     

Association between adult-onset Still's disease and interleukin-18 gene polymorphisms

Recently, we reported that serum concentration of IL-18 is strikingly high in patients with adult-onset Still's disease (AOSD). The aim of the present study was to screen for genetic polymorphisms in the human IL-18 (hIL-18) gene and to determine the association of polymorphisms with susceptibility to AOSD. We investigated the 6.7 kb region upstream of exon 2 of hIL-18 gene, in which a promoter activity had been reported. Sixteen AOSD patients, 144 rheumatoid arthritis (RA) patients and 92 healthy control individuals were studied. We found seven single nucleotide polymorphisms and a single 9 bp insertion which were frequently present in the AOSD patients. Three haplotypes including a unique combination of these polymorphisms were also determined. Of them, haplotype S01 contained all eight of these polymorphisms. The frequency of individuals carrying a diplotype configuration, ie a combination of two haplotypes, of S01/S01 was significantly higher in the AOSD patients than in the healthy controls (P=0.00059, Fischer's exact probability test, odds ratio [OR]=7.81, 95% confidence interval [95% CI]=2.48-24.65) and the RA patients (P=0.015, Fischer's exact probability test, OR=4.0, 95% CI=1.39-11.54). We therefore conclude that possession of the diplotype configuration of S01/S01 is a major genetic risk factor for susceptibility to AOSD.     

A Meniere's disease gene linked to chromosome 12p12.3.

Meniere's disease (MD) is characterized by spontaneous attacks of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. The majority of patients with MD appear sporadic but 5%-13% of the cases have a family history for the disease. The cause of both the sporadic and inherited forms of MD remains unclear despite a number of candidate genes defined from their association with hearing loss. We have performed a genome wide linkage scan on a large Swedish family segregating MD in five generations. Five candidate regions with a lod score of >1 were identified. Two additional families with autosomal dominant MD were analyzed for linkage to these regions and a cumulative Z(max) of 3.46 was obtained for a single region on chromosome 12p. In two of the three families, a shared haplotype was found to extend over 1.7 Mb which suggests a common ancestral origin. Within this region, a single recombination event restricts the candidate region to 463 kb.     

Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease

Parkinson's disease (PD) is characterized by major alterations of neurotransmitter activity due to damage of the substantia nigra. Changes in neuropeptide concentration within the basal ganglia may play an important role in the putative dopaminergic-peptidergic interactions associated with the disease. Cholecystokinin (CCK) modulates the release of dopamine in the mesolimbic pathway and affects dopamine-related behavior. We analyzed genetic variations in the CCK gene, in both the coding and promoter region, in order to investigate the role of polymorphism in idiopathic PD. Four polymorphic sites of the CCK gene (-196G/A, -45C/T, 1270C/G, 6662C/T) were found in PD patients and controls. Complete linkage disequilibrium was observed between the -45 locus and the 1270 locus, and also a possible linkage disequilibrium was found between the -45 and -196 loci. A significant difference was found in the distributions of three identified genotypes at the -45 locus between 116 PD patients and 95 age-matched control subjects (chi2 = 7.95, p = 0.018, Bonferroni correction; p = 0.054). In addition, a significant difference was obtained amongst the three genotypic groups at the -45 locus when compared between PD patients who experienced hallucinations (n = 23) and those (n = 93) who did not (chi2 = 8.08, p = 0.018, Bonferroni correction, p = 0.126). Our data suggested that mutations at the -45 locus in the promoter region of the CCK gene may influence vulnerability to hallucinations in PD patients treated with L-dopa.     

Association between early-onset Parkinson's disease and mutations in the parkin gene

BACKGROUND: Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. METHODS: We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. RESULTS: Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. CONCLUSIONS: Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.     

Association between a variation in the phosphodiesterase 4D gene and bone mineral density

Background  

Fragility fractures caused by osteoporosis are a major cause of morbidity and mortality in aging populations. Bone mineral density (BMD) is a useful surrogate marker for risk of fracture and is a highly heritable trait. The genetic variants underlying this genetic contribution are largely unknown.     

Association between genetic variation at the APO AI-CIII-AIV gene cluster and familial combined hyperlipidaemia

By using chemical cleavage mismatch analysis and the single strand conformation polymorphism technique, DNA fragments of the apo CIII gene, including the 5′ flanking region and all the exons, were screened for sequence changes underlying the observed association between familial combined hyperlipidaemia (FCHL) and the apo AI-CIII-AIV gene cluster in affected individuals from eight FCHL families. A C₁₁₀₀-T transition in the wobble position of codon 14 in exon 3 and a T₃₂₀₆-G transversion in the non-translated region of exon 4 were identified, occurring in four and all probands, respectively. Using these variants and the G_{_75}-A transition in the apo AI promoter, co-segregation of the gene cluster with hyperlipidaemia could be excluded in all eight families (lod score -∞ at θ=0). No support for co-segregation was obtained using the affected pedigree member method of linkage analysis (overall T=–0.77 for f (p)=1√p). The frequencies of T₁₁₀₀ and G₃₂₀₆ in a group of 55 patients with combined hyperlipidaemia were 0.35 and 0.52, respectively, which were significantly higher compared to 360 controls (0.21, p<0.01 and 0.35 p<0.005 respectively). In patients homozygous for the T₁₁₀₀ allele, levels of plasma triglyceride were 2.5-fold higher (868 mg/dl) than those homozygous for the C₁₁₀₀ allele (337 mg/dl), while patients heterozygous for the polymorphism had intermediate values (443 mg/dl) (p<0.01). A similar association was seen in controls (p<0.04). The three polymorphisms studied were in strong linkage disequilibrium in both the group of CHL patients and the unrelated individuals. This study confirms the association between common variation in the gene cluster and differences in plasma lipid levels in the general population and in patients with combined hyperlipidaemia, but fails to confirm co-segregation with FCHL, suggesting the role of other genetic or environmental factors in the aetiology of FCHL.     

新疆哈萨克族人Furin基因变异与中心性肥胖的相关性研究

目的 研究哈萨克族人弗林蛋白基因(Furin)变异与中心性肥胖的相关性.方法 以哈萨克族自然人群横断面流行病学调查为基础选取478例肥胖者和378名正常个体进行病例-对照研究.从肥胖者中随机选择66例,对其Furin启动子、外显子区测序筛查其代表性变异;并采用TaqMan PCR技术对筛查出的Furin代表性变异在856名哈萨克族个体中进行分型,分析其与哈萨克族人肥胖的相关性.结果 在478例肥胖者中随机选择66例(男女各33例),共筛查出Furin的12个变异,其中rs6226、rs6227、rs2071410、rs4932178是代表性变异;这4个代表性变异均在大样本哈萨克族人中基因型分型成功(成功率≥99％);在总体、男性、女性哈萨克族自然人群中,rs6226、rs6227、rs2071410、rs4932178多态性位点的基因型、等位基因、单倍型频率在肥胖组及对照组分布差异无统计学意义(P＞0.05);不同基因型携带者之间的腰围平均水平差异也无统计学意义(P＞0.05).结论 Furin变异与新疆哈萨克族中心性肥胖不相关,该变异可能不是哈萨克族人中心性肥胖的易感因素.     

Association between interleukin-17 gene polymorphisms and risk of coronary artery disease

We conducted a case-control study to estimate the association between IL-17A rs2275913, rs3819025 and rs3748067 polymorphisms and development of coronary artery disease. A total of 415 patients with coronary artery disease and 448 health controls were recruited during the period of March 2013 and October 2014. Genotyping of IL-17A rs2275913, rs3819025 and rs3748067 were analyzed by polymerase chain reaction coupled with restriction fragment length polymorphism. By logistic regression analysis, we found that individuals with the AA genotype (OR, 2.18; 95% CI, 1.35-3.56) and the GA+AA genotype (OR, 1.39, 95% CI, 1.06-1.84) of rs2275913 were associated with an increased risk of coronary artery disease when compared with the GG genotype. Individuals carrying the GA+AA genotype of rs2275913 were more likely to have a higher risk of coronary artery disease in those with hypertension and smoking habit, and the adjusted ORs (95% CI) were 3.92 (2.13-6.82) and 2.74 (1.71-4.40). In conclusion, we suggest that individuals with the AA genotype and the GA+AA genotype of rs2275913 are associated with an increased risk of coronary artery disease, especially in those with hypertension and smoking habit.     

Association between somatostatin gene polymorphisms and sporadic Alzheimer's disease in Chinese population

Recent evidence has suggested that down-regulation of somatostatin (SST) expression in the human brain during early stages of aging leads to an elevation in the steady-state levels of Aβ and therefore may be involved in Alzheimer's disease (AD) progression. We hypothesized that alterations in the SST gene might alter its expression or function and also play a role in the pathogenesis of sporadic AD (SAD). First, we sequenced the entire SST gene in 25 randomly selected controls and 25 SAD patients and then screened for C/T polymorphisms (rs4988514) in the 3′ un-translated region. We genotyped rs4988514 polymorphisms as well as apolipoprotein ?4 (APOE ?4) status in 309 SAD patients and 276 normal controls with restriction fragment length polymorphism (RFLP) analysis. Results showed that the C allele of the rs4988514 polymorphism had an increased incidence in the SAD group compared to the control group (p = 0.042). In subjects with the APOE ?4 allele, the presence of both the CC genotype and the C allele of this polymorphism were elevated in the SAD group compared to the control group (genotype p = 0.027, allele p = 0.011). In the whole study group, the age, sex, and APOE ?4 adjusted OR for the risk of AD in C allele carriers was 1.313 (95%CI = 1.068–2.234, p = 0.027) whereas within only APOE ?4 allele carriers, the adjusted OR increased to 2.734 (95%CI = 1.236–5.862, p = 0.012). Our results supported the notion that the C allele of the rs4988514 polymorphism may increase the risk for AD in the Chinese population and possibly have additive effect with the APOE ?4 allele.     

Association between AKT1 gene and Parkinson's disease: a protective haplotype

Variation in AKT1 has been associated with schizophrenia, bipolar disease and type II diabetes. The aim of the present study was to investigate the potential role of variability within AKT1 as a risk factor for Parkinson's disease (PD). We performed a case-control association analysis of AKT1 in a Greek cohort of PD using four tagging SNPs and five constructed haplotypes. To assess the structure of this locus in different populations we have performed linkage disequilibrium (LD) analysis using these variants [dunning]. In multilocus analysis, the frequency of a four-SNP1/2/3/4 haplotype was significantly higher in controls in comparison with PD patients (chi(2)=19.76, p=0.00009, OR=0.11 C.I.=0.03-0.35). The association remained significant even after Bonferroni correction for the number of haplotypes (p=0.0002). So, this certain haplotype was significantly associated with reduced risk of the disease. The data presented here suggest the involvement of AKT1 in protection of PD through many possible mechanisms involving different signaling pathways that could be potential therapeutic targets in the future.     

Association between the interleukin-1alpha gene and Alzheimer's disease: a meta-analysis

Inflammatory processes are involved in the pathogenesis of Alzheimer's disease (AD). Several studies have addressed the effects of interleukin-1 (IL-1) genes polymorphisms on the risk of developing AD. The results are not in full agreement on whether these polymorphisms are associated with the disease. To clarify this issue, we performed a meta-analysis of all the association studies between IL-1 genes and AD. Due to the relatively small number of published articles, the meta-analysis was restricted to the association of the IL-1alpha -889 C/T gene polymorphism and AD. Under a random effects model, the risk for the disease was significantly higher in subjects with the T/T genotype in comparison with both C/T (OR: 1.51; 95% C.I.: 1.15-1.99) and C/C (OR: 1.49; 95% C.I.: 1.09-2.03) subjects. There was modest heterogeneity for these effect estimates. Analysis of subgroups showed a significant association in patients with early-onset AD but not in late-onset AD. Our data support a significant but modest association between the T/T genotype of the IL-1alpha gene and AD.     

Association between a variant of the sigma-1 receptor gene and Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex etiology and strong genetic predisposition. A number of investigations support the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathophysiology of AD. We aimed to investigate the association between SIGMAR1 polymorphisms and late-onset AD, therefore we genotyped rs1799729 (GC-241-240TT) and rs1800866 (Q2P) in 322 Hungarian late-onset AD patients and 250 ethnically matched, elderly control individuals. The investigated polymorphisms were in nearly complete linkage disequilibrium resulting in the GC-Q and TT-P predominant haplotypes that were subjected to the statistical analyses. Our data demonstrates an association between the SIGMAR1 TT-P variant and the risk for developing AD (p=0.019), and a potential modest interaction effect (p=0.058) of the co-presence of the TT-P haplotype with apolipoprotein E4 allele on the risk for AD. Based on this mild significance, we could not fully support the hypothesis that TT-P haplotype in interaction with APOE E4 allele confers risk for developing AD.     

Familial clustering and genetic heterogeneity in Meniere's disease

The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology‐Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λ_s) and offspring (λ_o) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λ_s and λ_o were 16–48 and 4–12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.     

Association between TSHR gene polymorphism and the risk of Graves' disease: a meta-analysis

Thyroid stimulating hormone receptor (TSHR) is thought to be a significant candidate for genetic susceptibility to Graves' disease (GD). However, the association between TSHR gene polymorphism and the risk of GD remains controversial. In this study, we investigated the relationship between the two conditions by meta-analysis. We searched all relevant case-control studies in PubMed, Web of Science, CNKI and Wanfang for literature available until May 2015, and chose studies on two single nucleotide polymorphisms (SNPs): rs179247 and rs12101255, within TSHR intron-1. Bias of heterogeneity test among studies was determined by the fixed or random effect pooled measure, and publication bias was examined by modified Begg's and Egger's test. Eight eligible studies with 15 outcomes were involved in this meta-analysis, including 6,976 GD cases and 7,089 controls from China, Japan, Poland, UK and Brazil. Pooled odds ratios (ORs) for allelic comparisons showed that both TSHR rs179247A/G and rs12101255T/C polymorphism had significant association with GD (OR=1.422, 95%CI=1.353–1.495, P<0.001, P heterogeneity=0.448; OR=1.502, 95%CI: 1.410–1.600, P<0.001, P heterogeneity=0.642), and the associations were the same under dominant, recessive and co-dominant models. In subgroup analyses, the conclusions are also consistent with all those in Asian, European and South America subgroups (P<0.001). Our meta-analysis revealed a significant association between TSHR rs179247A/G and rs12101255T/C polymorphism with GD in five different populations from Asia, Europe and South America. Further studies are needed in other ethnic backgrounds to independently confirm our findings.     

冠心病患者焦虑情绪与APOE基因多态性

目的:探讨冠心病(coronary heart disease,CHD)患者焦虑情绪与载脂蛋白E(ApoE)基因多态性的关系。方法:对符合1979年世界卫生组织CHD诊断标准的107例冠心病患者,进行汉密顿焦虑量表(Hamilton Anxiety Scale,HAMA)、焦虑自评量表(Self-Rating Anxiety Scale,SAS)测评,依焦虑评分情况将患者分为CHD伴焦虑组(焦虑组)、CHD不伴焦虑组(无焦虑组),选择53例健康人为对照组。于入院2日内留存血样,以Hhal限制性内切酶酶切及琼脂糖凝胶电泳确定ApoE基因多态性,采用生物化学方法测定血清血脂。结果:焦虑组ε4等位基因频率高于无焦虑组和对照组(26.0%vs.10.4%,26.0%vs.13.6%;P=0.021,0.004)。焦虑组E4/4基因型频数高于无焦虑组(4vs.0,P=0.032)。焦虑组E3/4基因型频数高于对照组(17vs.8,P=0.018)。无焦虑组ε4等位基因频率高于对照组,但差异无统计学意义(13.6%vs.10.4%,P=0.802)。CHD组携带ε4等位基因患者HAMA[(13.2±5.2)vs.(9.2±6.5)]、SAS评分[(42.3±7.7)vs.(37.1±8.3)]及总胆固醇[(5.4±1.1)mmol/Lvs.(4.8±1.3)mmol/L]、低密度脂蛋白水平[(3.6±1.0)mmol/Lvs.(3.1±1.1)mmol/L]均高于非携带ε4等位基因者(P0.05)。结论:冠心病患者的焦虑情绪可能与ApoE基因多态性具有一定关系。ApoEε4等位基因可能是CHD患者焦虑情绪的危险因素。     

Association of serotonin transporter gene variation with smoking, chronic obstructive pulmonary disease, and its depressive symptoms

A serotonin transporter gene, SLC6A4, is thought to be related to nicotine dependence and depression, one of the comorbidities of chronic obstructive pulmonary disease (COPD). To investigate the association between SLC6A4 variation and tobacco consumption, susceptibility to COPD, and depression status. In all, 247 patients with COPD and 119 control subjects were genotyped for 5 tag single-nucleotide polymorphisms (SNPs) of SLC6A4. We analyzed the correlation between these genotypes and COPD, using the results of a pulmonary function test or chest computed tomography; data on tobacco consumption (pack-years); and the depression score based on the hospital anxiety and depression scale (HADS) after adjusting for age, gender, and smoking status (and pack-years, when appropriate). The rare allele rs2020936 was significantly associated with COPD incidence in the trend model (P = 0.003; odds ratio, 2.20; 95% confidence interval, 1.31-3.74). This allele was also associated with the number of pack-years (P = 0.026). The major allele of another SNP of SLC6A4, namely rs3794808, correlated with the HADS depression score (P = 0.016). We conclude that SLC6A4 variation affects COPD pathogenesis, and this effect depends partly on tobacco consumption. SLC6A4 variation also affects depressive symptoms. SLC6A4 could be modified to prevent COPD and treat the depressive symptoms of COPD.