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Sökning: WFRF:(Nikitina Zake Liene)

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  • Tidskriftsartikel (refereegranskat)
  • Gupta, Manu, et al. (författare)
  • Association between the transmembrane region polymorphism of MHC class I chain related gene-A and type 1 diabetes mellitus in Sweden
  • 2003
  • Ingår i: Human Immunology. - : Elsevier. - 0198-8859. ; 64:5, s. 553-561
  • Tidskriftsartikel (refereegranskat)abstract
    • Major histocompatibility complex (MHC) class I chain related gene-A (MIC-A) is associated with type 1 diabetes mellitus (T1DM) in other populations. We tested the association of MIC-A gene polymorphism with T1DM in Swedish Caucasians; if it has an age-dependent association; and if the association has an effect on gender. We studied 635 T1DM patients and 503 matched controls in the age group of 0-35 years old. MIC-A5 was significantly increased in T1DM compared with controls (odds ratio [OR] =1.81, p(c) < 0.0005). Logistic regression analysis revealed MIC-A5 association was independent of HLA. MIC-A5 with DR4-DQ8 or MIC-A5 with DR3-DQ2 gave higher OR than the OR obtained with either of them alone (OR = 1.81, 7.1, and 3.6, respectively). MIC-A5 was positively (OR = 2.48, p(c) < 0.0005) and MIC-A6 negatively associated (OR = 0.61, p(c) = 0.035) with the disease in less than or equal to 20 years of age. The negative association of MIC-A6 in young onset was confirmed by logistic regression analysis. MIC-A5 was associated with the disease in males (OR = 2.05, p(c) = 0.0005). MIC-A6 conferred protection (OR = 0.098, p(c) = 0.032) in females heterozygous for DR3/DR4. In conclusion, MIC-A5 is associated with T1DM; the association was higher in individuals less than or equal to 20 years old; and negative association of MIC-A6 was stronger in younger onset patients than in older onset patients.
  • Huckins, Laura M., et al. (författare)
  • Gene expression imputation across multiple brain regions provides insights into schizophrenia risk
  • 2019
  • Ingår i: ; 51:4, s. 659-
  • Tidskriftsartikel (refereegranskat)abstract
    • Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
  • Lu, Yingchang, et al. (författare)
  • A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.
  • 2018
  • Ingår i: ; 78:18, s. 5419-5430
  • Tidskriftsartikel (refereegranskat)abstract
    • .AbstractLarge-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10−6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10−7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10−3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419–30. ©2018 AACR.
  • Ripke, Stephan, et al. (författare)
  • Biological insights from 108 schizophrenia-associated genetic loci
  • 2014
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 511:7510, s. 421-427
  • Tidskriftsartikel (refereegranskat)abstract
    • Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
  • Ciganoka, Darja, et al. (författare)
  • Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly
  • 2011
  • Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 165:4, s. 517-525
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics. Design and methods: The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls. Results: In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR) = 3.38; 95% confidence interval (CI), 1.78-6.42; P=0.00016 and OR=2.41; 95% CI, 1.41-4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P=0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient beta=-10.4; P=0.002), increased body mass index (beta=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014). Conclusions: Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.
  • Kalnina, Ineta, et al. (författare)
  • Polymorphisms in FTO and near TMEM18 associate with type 2 diabetes and predispose to younger age at diagnosis of diabetes
  • 2013
  • Ingår i: Gene. - 0378-1119 .- 1879-0038. ; 527:2, s. 462-468
  • Tidskriftsartikel (refereegranskat)abstract
    • Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.
  • Nikitina-Zake, Liene (författare)
  • Immunogenetic markers in immune mediated diseases
  • 2003
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The aim of this thesis was to study HLA class II markers, as well as other - MHC and non MHC genes in different immune - mediated diseases, namely, cervical intraepithelial neoplasia (CIN), cervical cancer, juvenile idiopathic arthritis (JIA), mixed connective tissue disease (MCTD) and type I diabetes mellitus (T1 DM). HLA class II genes are located on the short arm of chromosome 6 and are known to be important for pathogenesis of immune - mediated diseases due to the function of the molecules these genes encode. The HLA molecules present self and foreign peptides to the T cells thus playing major role in activation of pathogenetically important cells. MICA gene in the MHC class I encodes for molecules that are ligands for NKG2D receptor on NK, (gamma)(delta)T cells, CD8+ T cells, CD28 negative (alpha)(beta)T cells and macrophages. Engagement of NKG2D by MICA leads to activation of the cells bearing this receptor. It has been shown that polymorphisms of the gene sequence can generate molecules with different affinities for NKG2D receptor and thus modulate the strength of activating signal. TNF is a cluster of genes and microsatellites in the MHC class III. Many studies have reported associations of polymorphisms in this region with TNFalpha production. Furthermore, the microsatellites in this region are sometimes used as additional markers for association. KIR genes encode for inhibitory and activating receptors expressed on NK cells and some subset of T cells. These receptors interact with classical HLA class I molecules and depending on the interaction can either inhibit or stimulate KIR bearing cells. Our studies on cervical lesions showed that TNFa microsatellite polymorphisms in CIN and cervical cancer could not be considered as single markers for either CIN or cervical cancer. However, as a part of extended MHC haplotypes, these polymorphisms can contribute to susceptibility to infection with HPV virus. HLA DR15-DQ6 is the most attributable locus for development of HPV induced cervical lesions. We did not find any association of MICA microsatellite polymorphism with either CIN or cervical cancer. The study of MICA and TNFa polymorphisms in JIA showed that MICA4 and TNFa2 are significantly positively associated with the disease in patients group. TNFa7 is significantly negatively associated with JIA. This suggests that MICA as well as TNFa genetically contribute to the disease pathogenesis, protection and susceptibility. Our association study of the markers in HLA loci in Swedish MCTD patients demonstrated that susceptibility to MCTD may be linked to the MICA allele 5.1 and 4, and HLA-DRB1*04, and that all these markers in combination are necessary to confer increased genetic risk for MCTD. The study of MICA gene microsatellite polymorphism in HBDI families revealed that allele 5.1 of this polymorphism was transmitted more frequently from healthy parents to affected offspring. This allele was transmitted more frequently together with high-risk HLA genes than alone. MICA 6 was transmitted less frequently. The study on KIR genes in T1DM showed some genes associated with the disease. KIR 2DL2 and 2DS2 showed the strongest association. We found also that two specific genotypes were either positively or negatively associated with the disease. These two genotypes differed only by presence of 2DL2 in the genotype found more frequently in patients. The conclusion we can draw from this study is that KIR genes are probably important in T1DM, although the functional importance of the cells bearing these receptors, as well as expression of these genes in subsets of cells important in pathogenesis of T1DM has to be ruled out still.
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