Estrogen receptor alpha gene variants are associated with Alzheimer's disease

The present research is aimed at assessing the role of 3 estrogen receptor alpha (ESR1) gene variants in late onset Alzheimer's disease (AD) susceptibility. One thousand one hundred thirteen unrelated late onset sporadic AD patients, 1109 healthy controls and 121 neurologically healthy elderly controls were used to carry out case-control genetic association studies with ESR1 rs3844508, rs2234693, and ESR1 noncoding deletion 1 (ESR1-NCD1) polymorphisms. Thirty-five healthy male samples were used for molecular analyses. The rs2234693 polymorphism is associated with AD in our population (odds ratio [OR], 1.29; p = 0.008). The rs3844508 marker confers protection against AD in males (OR, 0.57; p = 0.001) and the deletion ESR1-NCD1 is a risk factor for AD in women (OR, 1.67; p < 0.001). Molecular analyses on ESR1-NCD1 indicate that this deletion confers a higher response to estradiol activity on ESR1 receptor and it is also associated with differential expression of ESR1 isoforms. Our results support the involvement of ESR1 gene in AD and point to the existence of sexual dimorphism for ESR1 markers. In addition, carriers of ESR1-NCD1 deletion could overrespond to estradiol action.     

No replication of genetic association between candidate polymorphisms and Alzheimer's disease

Alzheimer's disease is a genetically complex disorder, for which new putative susceptibility genes are constantly proposed in the literature. We selected 16 candidate genes involved in biological pathways closely related to the pathology, and for which a genetic association with Alzheimer's disease was previously detected: ACE, BACE1, BDNF, ECE1, HSPG2, IDE, IL1a, IL6, IL10, MAPT, PLAU, PrnP, PSEN1, SORL1, TFCP2 and TGFb1. The variants originally associated with the disease were genotyped in a French Caucasian sample including 428 cases and 475 controls and tested for association in order to replicate the initial results. Despite a careful replication study design, we failed to validate the initial findings for any of these variants, with the possible exception of MAPT, SORL1 and TFCP2 for which some nominal but inconsistent evidence of association was observed.     

Association of TLR4 and TLR5 gene polymorphisms with Graves’ disease in Chinese Cantonese population

Graves’ disease (GD) is postulated to be caused by the combined effects of susceptibility genes and environmental triggers. Toll like receptors (TLRs) play a role in the activation of innate and adaptive immune responses in mammalians. The aim of this study was to evaluate the potential association of TLR4 and TLR5 gene polymorphisms with GD in Chinese Cantonese population. Four single nucleotide polymorphisms (SNPs), rs11536889 and rs7873784 in TLR4, rs2072493 and rs5744174 in TLR5, were evaluated in 332 GD patients and 351 unrelated controls from Chinese Cantonese population. The minor allele C of TLR5 rs5744174 decreased the risk to GD in females (OR_{C vs. T} = 0.63; p = 0.003; p_trend = 0.003). Under a dominant model, rs5744174 conferred a protective effect in all cases (OR_{CC/CT vs. TT} = 0.65; p = 0.009) or female subset (OR_{CC/CT vs. TT} = 0.57; p = 0.002). Under a co-dominant model, rs5744174 also conferred a protective effect in all cases (OR_{TC vs. TT} = 0.64; p = 0.008) and females (OR_{TC vs. TT} = 0.57; p = 0.002). The haplotype A-C of TLR5 (rs2072493–rs5744174) decreased the risk of GD in females (OR = 0.62; p = 0.002). The other three SNPs were not found associated with GD. This study provided evidence that polymorphisms in TLR5 might be associated with decreased susceptibility of GD in females.     

Association between neprilysin polymorphisms and sporadic Alzheimer's disease

The deposition of amyloid beta peptide (Abeta) in the form of plaques in the brain is a hallmark of Alzheimer's disease (AD). Neprilysin is the major Abeta-degradating enzyme and reduction in neprilysin activity could contribute to Alzheimer's by increasing the steady-state level of Abeta. To provide further evidence for the role of neprilysin in AD we genotyped 22 polymorphisms, 21 SNPs and the GT repeat in the promoter region, across the neprilysin gene in 298 Caucasian sporadic Alzheimer's patients and 298 age-matched controls. Several SNPs showed genotypic and allelic association to AD. SNP rs1836915, in linkage disequilibrium block 2, showed the greatest extent of genotypic association with AD (p=0.0076). We were unable to replicate any of the SNPs that were previously reported as putatively associated with AD. However, these novel findings add to the weight of evidence supporting the involvement of neprilysin in the aetiology of Alzheimer's disease.     

Association between the macrophage inflammatory protein-l alpha gene polymorphism and Alzheimer's disease in the Chinese population

Genetic polymorphisms in chemokine receptor and their natural ligand genes have been shown to modify the disease progression of Alzheimer's disease (AD). Human macrophage inflammatory protein-1 alpha (MIP-1alpha) is a chemotactic cytokine which plays a considerable role in AD pathogenesis, but its genetic contribution to AD has never been investigated. Recently, a biallelic dinucleotide microsatellite repeat (TA repeat) polymorphism has been found in the MIP-1alpha gene promoter region at position -906. We investigated whether this promoter polymorphism of MIP-1alpha gene might be responsible for susceptibility to AD in a Chinese population, utilizing a clinically well-defined group of 138 sporadic AD patients and 180 age-matched controls. We also examined the combined gene effects between the MIP-1alpha and apolipoprotein E (APOE) genes. The overall distribution of MIP-1alpha-906 alleles and genotypes was significantly different between AD cases and controls (P<0.05). The odds ratio for AD associated with the (TA)(6)/(TA)(6) versus non-(TA)(6)/(TA)(6) genotype was 1.893 (95% CI=1.208-2.967), while that for APOE varepsilon4 and MIP-1alpha (TA)(6)/(TA)(6) carriers was 7.140 (95% CI=3.222-15.823). In addition, we found that serum MIP-1alpha levels in patients with (TA)(6)/(TA)(6) genotype were increased significantly when compared with non-(TA)(6)/(TA)(6) genotype. The results indicate that the MIP-1alpha-906 (TA)(6)/(TA)(6) genotype, either by itself or interacting with the APOE varepsilon4 gene seems to be a genetic risk factor for AD. This genotype is associated with elevated serum MIP-1alpha levels in patients, which can contribute to increase the inflammatory process occurring in AD.     

ABCA1 polymorphisms and Alzheimer's disease

In our search for genetic factors related to the development of Alzheimer's disease, we have genotyped 332 pedigrees for three coding polymorphisms in the ABCA1 gene, two of which are known to alter plasma cholesterol levels, as well as a non-coding polymorphism within the promoter. We show an apparent weak association of rs2230806 (p-value=0.01) with the disease in a sibpair series of Alzheimer's disease that had shown previously evidence for linkage to the chromosome 9 locus where ABCA1 maps.     

Androgen receptor gene and sex-specific Alzheimer's disease

Women are at a 2-fold risk of developing late-onset Alzheimer's disease (AD) (onset at 65 years of age or older) compared with men. During perimenopausal years, women undergo hormonal changes that are accompanied by metabolic, cardiovascular, and inflammatory changes. These all together have been suggested as risk factors for late-onset AD. However, not all perimenopausal women develop AD; we hypothesize that certain genetic factors might underlie the increased susceptibility for developing AD in postmenopausal women. We investigated the Androgen Receptor gene (AR) in a clinical cohort of male and female AD patients and normal control subjects by sequencing all coding exons and evaluating the length and distribution of the CAG repeat in exon 1. We could not establish a correlation between the repeat length, sex, and the disease status, nor did we identify possible pathogenic variants. AR is located on the X chromosome; to assess its role in AD, X-inactivation patterns will need to be studied to directly correlate the actual expressed repeat length to a possible sex-specific phenotypic effect.     

己烯雌酚对促甲状腺激素受体在小鼠淋巴结内表达的影响 

目的 了解生后不同时期BALB/c小鼠淋巴结内促甲状腺激素受体（TSHR）的表达状况及给予新生期BALB/c小鼠己烯雌酚（DES）后对该表达所产生的影响,并借此探讨生后不同时期小鼠淋巴结内促甲状腺激素（TSH）的可能来源及DES对TSH表达所产生影响的可能机制。方法 选取同窝及体重差异小于5%的新生BALB/c小鼠,随机分为DES组与对照组,雌、雄各选30对,即共取小鼠120只,在生后24h内,DES组小鼠颈背部皮下注射DES,每隔24h注射1次,共连续注射5次;对照组小鼠平行注射等量无菌豆油。分别在生后第7、14、21、35、49和第63天将小鼠处死,每个时间点雌、雄各取5对小鼠,取其颈深淋巴结进行常规石蜡包埋、切片及TSHR的免疫组织化学检测。结果 无论是对照组还是DES组,小鼠从生后第7天到第63天,淋巴结内均可见到TSHR阳性细胞,阳性表达在雌性和雄性小鼠     

Lack of genetic association between PPARG gene polymorphisms and Finnish late-onset Alzheimer's disease

Single nucleotide polymorphisms (SNPs) in diabetes related peroxisome proliferator-activated receptor gamma (PPARG) gene were investigated with a case-control approach. To examine the genetic association of this gene with Alzheimer's disease (AD) risk, we used the TaqMan technique to genotype eight SNP sites for PPARG gene, in 538 Finnish AD cases and 672 controls and conducted a single allele and genotypic distribution comparison as well as estimated haplotype frequencies between cases and controls. No significant differences in AD risk were found in single SNP and haplotype analyses for PPARG gene between the study groups. We conclude that PPARG gene does not play a major role in the genetic predisposition to AD in the Finnish population.     

Association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and nontuberculous mycobacterial lung disease in a Korean population

This study evaluated the association between the guanine-thymine (GT) repeat polymorphism in intron II of the Toll-like receptor 2 (TLR2) gene and lung disease caused by nontuberculous mycobacteria (NTM). Polymerase chain reaction and gene scans were used to determine the numbers of GT repeats for 193 patients with the nodular bronchiectatic form of NTM lung disease, including 110 patients with Mycobacterium avium-intracellulare (MAC) infection, 82 patients with Mycobacterium abscessus infection, and 1 patient with co-infection of both organisms. These values were compared with the results for 191 controls. Genotypes with shorter GT repeats were more common among patients with NTM lung disease (50.8 vs 37.7%, p = 0.01). In the subgroup analysis, genotypes that included S alleles were more common in the patients with MAC lung disease (53.6%, p = 0.01, OR, 1.91; 95% CI, 1.16, 3.16) than in healthy controls, whereas this difference was not statistically significant in patients with M. abscessus lung disease (47.6%, p = 0.13). In conclusion, these results suggest that the GT repeat microsatellite polymorphisms in intron II of the human TLR2 gene contribute to the development of NTM lung disease, especially MAC lung disease, in a Korean population.     

Association study of the PIN1 gene with Alzheimer's disease

Genetic linkage studies indicate evidence for one or more Alzheimer's disease (AD) genes on chromosome 19 independently of the apolipoprotein E gene, a well-characterized AD-risk factor. Recently, the PIN1 gene on chromosome 19p13.2 has been proposed as a candidate gene for AD. Here, we have investigated the potential impact of two promoter polymorphisms (rs2233678 and rs2233679) within this gene on the risk of developing AD. No association of these polymorphisms or haplotypes with the disease was observed in a large French case-control population. Our data suggest that these genetic variants in PIN1 do not make a significant contribution to AD risk.     

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese

Toll-like receptor 2 (TLR2) represents a reasonable functional and positional candidate gene for Alzheimer's disease (AD) as it is located under the linkage region of AD on chromosome 4q, and is functionally involved in the microglia-mediated inflammatory response and amyloid β (Aβ) clearance. In the current study, 7 single nucleotide polymorphisms (SNPs) that span the TLR2 were selected and their associations with late-onset AD (LOAD) risk were assessed in a case-control sample comprising 785 individuals in a Han Chinese population. No significant differences in the frequency of TLR2 alleles, genotypes, and haplotypes in the AD cases were detected compared with the controls. TLR2 gene might not play a major role in the genetic predisposition to late-onset Alzheimer's disease in this population.     

Alzheimer's disease risk factor complement receptor 1 is associated with depression

Variation in the complement receptor 1 gene (CR1) has been identified in recent genome-wide association studies as a risk factor for Alzheimer's disease. Here, we show that two Alzheimer's disease-associated CR1 variants, rs6656401 and rs3818361, are associated with major recurrent depression in females in a population-based cohort using individuals from the Generation Scotland: Scottish Family Health Study.     

Association between late-onset Alzheimer's disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene

The amyloid beta protein (Aβ) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 2 (TLR2) is thought to contribute to Aβ clearance. Studies have reported the presence and functional implications of guanine-thymine (GT) repeat microsatellite polymorphisms in intron II of the human TLR2 gene. The present study evaluated the association of the microsatellite polymorphism and sporadic late-onset AD (LOAD) in the Han Chinese population. The numbers of (GT) repeats were counted in 137 AD patients and in 137 non-AD control subjects, using polymerase chain reaction and genescan analysis. The alleles were divided into three subclasses: (GT)16 or less as the S allele, (GT)17 to (GT)22 as the M allele, and (GT)23 or more as the L allele. Patients with AD had more S alleles (P < 0.001; odds ratio (OR) = 2.32; 95% confidence interval (CI) = 1.57–3.42) and fewer L alleles (P = 0.02; OR = 0.66; 95% CI = 0.46–0.93) than did healthy controls. Genotypes SS and SM were more common, whereas ML and SL were less common in patients with AD. In subgroup analyses, the genotypes including S alleles were associated with an increased risk of LOAD (OR = 2.05, 95% CI = 1.26–3.34), and this association was influenced by the presence of APOE ?4 alleles. This study demonstrates an association of microsatellite polymorphisms in intron II of the human TLR2 gene with risk for LOAD in Han Chinese.     

Association of the estrogen receptor alpha gene polymorphisms with osteoporosis in the Mexican population

The estrogen receptor gene (ER alpha) has been implicated in the development of osteoporosis. In this study, the association of two ER alpha gene polymorphic markers (a TA dinucleotide repeat and a single nucleotide polymorphism, G2014A) with osteoporosis was tested in 70 osteoporotic women, 70 non-osteoporotic women and 500 subjects from the Mexican population. According to the genetic analysis of the Mexican population using eight unlinked polymorphic markers, we found that our population is structured into three subpopulations; therefore, the allele-phenotype relationship was analyzed with a statistical method that considered population stratification. We found that the G2014A polymorphism is associated with the presence of osteoporosis while the TA dinucleotide repeat is not. The G allele and the GG genotype frequencies of the G2014A marker were significantly higher in osteoporotic than in non-osteoporotic women. Likewise, subjects bearing the G allele in heterozygous or homozygous displayed lower values for lumbar bone mineral density and T score than those who did not present any G allele. The effect of confounders for osteoporosis on the association of G allele-osteoporosis was ruled out. In summary, we conclude that the G2014 polymorphism may become a useful marker for genetic studies of osteoporosis in the Mexican population.     

维生素D受体基因ApaⅠ和TaqⅠ位点多态性与帕金森病的相关性研究

目的 探讨维生素D受体(vitamin D receptor,VDR)基因ApaⅠ和Taq Ⅰ位点多态性与帕金森病(Parkinson's disease,PD)遗传易感性的相关性.方法 采用聚合酶链反应-限制性片段长度多态性技术和基因测序方法,检测285例中国北方汉族散发PD患者与285名正常对照VDR基因ApaⅠ和TaqⅠ位点多态性,并比较两组基因型和等位基因频率的差异.结果 ApaⅠ和Taq Ⅰ位点基因型和等位基因频率在PD组和对照组之间差异均无统计学意义(P＞0.05).将样本按性别及发病年龄分组后比较,ApaⅠ位点各亚组间基因型频率和等位基因频率差异亦无统计学意义(P＞0.05),而TaqⅠ位点的基因型分布在男性PD组(168例)与男性对照组(1 60名)之间差异有统计学意义(x2=4.187,P=0.032,OR=2.149,95％CI:1.011～4.567),男性PD组T等位基因频率较男性对照组显著增高(x2=3.867,P=0.036,OR=2.064,95％CI:0.989～4.307).结论 VDR基因ApaⅠ位点多态性与PD风险间无相关性,但TaqⅠ可能是男性PD的风险因素.     

Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche

BACKGROUND: The age of menarche may be subject to hereditary influences, but the specific genetic determinants are largely unknown. We evaluated whether the XbaI and PvuII polymorphisms of the estrogen receptor alpha gene are associated with the age of menarche. METHODS: We performed genotyping for XbaI and PvuII in a cohort of 145 adolescent females from a closed community in North-Western Greece. RESULTS: There was strong linkage disequilibrium between the two polymorphisms. Menarche occurred later in girls with the XX genotype than in girls with the Xx or xx genotype (mean +/- SD: 13.36 +/- 1.24 versus 12.80 +/- 1.14 and 12.75 +/- 1.35 years respectively; P = 0.017). Menarche also tended to occur later in PP homozygotes than in Pp and pp subjects, but the difference was not significant (mean +/- SD: 13.09 +/- 1.29 versus 12.80 +/- 1.19 and 12.85 +/- 1.33 years respectively). The strongest effect was seen when the PX haplotype was considered [mean +/- SD: 13.43 +/- 1.18 years for homozygotes versus 12.76 +/- 1.25 years in heterozygotes and in subjects without the PX allele, P = 0.006]. CONCLUSIONS: We document that the XbaI polymorphism, and possibly PvuII, may be genetic determinants of the age of menarche.     

Lack of interaction between LRP1 and A2M polymorphisms for the risk of Alzheimer disease

Alzheimer disease (AD) has a heterogeneous aetiology, involving genetic and environmental factors. Low-density lipoprotein receptor-related protein 1 (LRP1), alpha-2-macroglobulin (A2M) and apolipoprotein E (APOE) are involved in molecular pathways leading to beta-amyloid deposition. Three polymorphic sites in these genes (APOE-?2/?3/?4, A2M-Ile/Val and LRP1-C/T) have been associated with AD, but the results were not univocal. We carried out a case-control study to investigate the association between these polymorphisms and the risk of developing AD and their possible interaction. We recruited 125 AD patients who fulfilled the diagnostic criteria proposed by NINCDS-ADRDA for probable or possible AD and 310 controls subjects. PCR was used to detect the polymorphisms. ORs and 95% CIs were estimated using logistic regression analysis. The OR for subjects carrying at least one allele Val (A2M-Val+) in their genotypes was 1.52 (95% CI 1.00–2.31; p = 0.05); for subjects carrying at least one allele C (LRP1-C+), 1.58 (95% CI 1.00–2.50; p = 0.05); for subjects carrying at least one allele ?4 (APOE-?4+), 3.1 (95%CI 1.87–5.00; p < 0.001). The coexistence of at least one allele Val (A2M-Val+) and one allele C (LRP1-C+) increased up two times the risk of AD (OR 2.32; 95% CI 1.23–4.35; p < 0.009). No evidence of significant interaction has been found between the studied polymorphisms (p > 0.05). In conclusion our study suggests that LRP1-C/T, A2M-Ile/Val and APOE-?2/?3/?4 polymorphisms are associated with AD.     

白细胞介素-4受体基因多态性与RSV毛细支气管炎相关性的病例对照研究

目的检测白细胞介素-4(IL-4)受体α链(IL-4Rα)I50V和Q576R基因多态性与呼吸道合胞病毒(RSV)毛细支气管炎的相关性。方法采用聚合酶链-限制性片段长度多态法检测130例RSV毛细支气管炎患儿和108例健康儿童IL-4Rα/I50V、Q576R基因多态性,应用化学发光法和酶联免疫吸附法检测血清总IgE和鼻咽分泌物(NPS)IL-4R水平。结果病例组II、IV和VV基因型频率为24.6%、51.5%和23.9%,对照组为27.8%、40.7%和31.5%,差异无统计学意义(χ2=2.960,P0.05);病例组I、V等位基因频率为50.4%、49.6%,对照组为48.1%、51.9%,差异无统计学意义(χ2=0.236,P0.05),II基因型NPS中IL-4R高于IV和VV基因型(Z=2.031,2.034,P0.05)。病例组QQ和QR基因型频率为72.3%、27.7%,对照组为64.8%、35.2%,差异无统计学意义(χ2=0.521,P0.05);病例组Q、R等位基因频率为86.2%、13.8%,对照组为82.4%、17.6%,差异无统计学意义(χ2=1.261,P0.05),R等位基因携带者NPSIL-4R高于Q等位基因携带者(Z=2.205,P0.05)。两个位点基因型间血清总IgE差异无统计学意义(F=1.021,t=0.452,P0.05);基因型频率与病情间亦无关联(χ2=0.322,1.393,P0.05)。结论 IL-4Rα/50II基因型及576R等位基因携带者与RSV毛细支气管炎NPSIL-4R水平增高相关。