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2.
Clin Rheumatol ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31760539

RESUMO

In this study, we aimed to explore the expression levels of JAK2 and PTPRC in peripheral blood mononuclear cells (PBMCs) from SLE patients and controls, detect the effects of SLE activity on genes mRNA expression, and find the association between genes mRNA expression and clinical manifestations of patients. We performed quantitative real-time PCR (qRT-PCR) to test differences in the expression levels of JAK2 and PTPRC in PBMCs extracted from 135 patients with SLE and 130 healthy controls. Furthermore, we detected the regulatory effect of SNPs on gene expression by expression quantitative trait loci (eQTL). We also tested whether the genes mRNA expression was affected with the SLE activity and analyzed the relationship between genes mRNA expression and clinical manifestations of patients. The mRNA expression levels of JAK2 in SLE patients were significantly higher than those in healthy controls (P = 0.005), and PTPRC mRNA expression levels were significantly decreased (P < 0.001). However, no other statistical significance was detected. We found that the elevated JAK2 mRNA expression and the decreased PTPRC mRNA expression may play suggestive roles in the pathogenesis of SLE.Key Points• The JAK2 mRNA expression levels in SLE patients were significantly higher than those in healthy controls.• The PTPRC mRNA expression levels in SLE were decreased.• JAK2 and PTPRC mRNA expression may play suggestive roles in the pathogenesis of SLE.

3.
Nature ; 572(7769): 323-328, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31367044

RESUMO

Exome-sequencing studies have generally been underpowered to identify deleterious alleles with a large effect on complex traits as such alleles are mostly rare. Because the population of northern and eastern Finland has expanded considerably and in isolation following a series of bottlenecks, individuals of these populations have numerous deleterious alleles at a relatively high frequency. Here, using exome sequencing of nearly 20,000 individuals from these regions, we investigate the role of rare coding variants in clinically relevant quantitative cardiometabolic traits. Exome-wide association studies for 64 quantitative traits identified 26 newly associated deleterious alleles. Of these 26 alleles, 19 are either unique to or more than 20 times more frequent in Finnish individuals than in other Europeans and show geographical clustering comparable to Mendelian disease mutations that are characteristic of the Finnish population. We estimate that sequencing studies of populations without this unique history would require hundreds of thousands to millions of participants to achieve comparable association power.

4.
Epigenomics ; 11(4): 455-467, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30785334

RESUMO

AIM: A genomic region on 5q33.3 lies between and encompasses the IL12B and PTTG1 genes, and contains many potential psoriasis causal variants. We aimed to further examine the influence of variants in and around this region. MATERIALS & METHODS: We used least absolute shrinkage and selection operator (LASSO)-based regression analysis to assess independent contributions of 2171 variants to psoriasis susceptibility and tested them for association with different clinical psoriasis subtypes. RESULTS: We found that ADRA1B gene variants contribute to psoriasis in Chinese population. ADRA1B gene variants have a stronger association with moderate-to-severe disease group and an earlier age at onset of psoriasis than IL-12B and PTTG1 variants. CONCLUSION: The association of variants in the ADRA1B gene with psoriasis could explain why variants in the IL-12B, ADRA1B and PTTG1 gene regions are associated with psoriasis.

5.
PLoS One ; 13(6): e0199322, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29902262

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0196635.].

6.
Hum Genet ; 137(6-7): 431-436, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29855708

RESUMO

Genotype imputation is now routinely performed in genomic analysis. Reference panel size, that is, the number of haplotypes in the reference panel, has been well established to be one major driving factor of imputation accuracy. For that reason, huge efforts have been made worldwide to provide large reference panels, with the Haplotype Reference Consortium (HRC) being currently the largest available in the public domain. The imputation performance of HRC, whose major samples are Europeans, has been mainly evaluated in Europeans. We conducted whole-genome genotype imputation on two independent genome-wide genotyping datasets, one with 1000 European samples and the other with 1000 Han Chinese samples. We compared the results obtained using HRC with those using Phase III of the 1000 Genomes Project (1000G) reference panel. For the European dataset, using HRC improved imputation quality, especially for rare variants with minor allele-frequency (MAF) < 0.1%. However, 1000G demonstrates better performance in the Han Chinese dataset, in both imputation quality and number of well-imputed variants. We validated the performance of 1000G reference panel in a second, independent cohort of Han Chinese (N = 2402). Our study showcases the limitations of HRC for Han Chinese populations, strongly suggesting the necessity of building population-specific reference panels.

7.
Cell Immunol ; 331: 16-21, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29748001

RESUMO

This study was aimed to investigate whether NFKB1 participates in the pathogenesis of psoriasis by mediating Th1/Th17 cells. In this study, expression of NFKB1 was assessed in skin tissues from psoriasis patients and the healthy controls through Western blot and Immunohistochemistry. Enzyme-linked immunosorbent assay (ELISA) was used to analyze the serum levels of IFN-γ, IL-17 (IL-17A) and IL-17RA. The imiquimod-induced psoriasis mouse model was employed to examine the role of NFKB1 in psoriasis via the assessment of psoriasis area and severity index (PASI), including erythema, thickness and scales. The effects of NFKB1 on Th1/Th17 cells in were examined by flow cytometry. In vitro co-culture of Th1/Th17 cells isolated from different mice with HaCat cells was conducted to elucidate the effect of Th1/Th17 cells-mediated by NFKB1 on HaCat cells by MTT, wound healing and transwell invasion assay, respectively. The results showed that NF-κB p105/p50 expression in skin tissues was significantly increased in psoriasis (n = 21) compared to the healthy controls (n = 16), as well as levels of serum INF-γ and IL-17. Additionally, NF-κB p105/p50 expression in lesional skin tissues was much higher than that in non-lesional skin tissues of the same patients. In the psoriasis mouse model, NFKB1 overexpression significantly elevated the scores of erythema, thickness and scales. Besides, NFKB1 up-regulated the level of NF-κB p105/p50, INF-γ, T-bet, IL-17 and RORγt, as well as Th1/Th17 cells in skin tissues of psoriasis mice. Finally, in vitro assay confirmed that the activation of Th1 and Th17 mediated by NFKB1 in psoriasis promoted the proliferation, migration and invasion of keratinocytes. These findings suggest a critical role for NFKB1 in the regulation of Th1 and Th17 in psoriasis.

8.
PLoS One ; 13(5): e0196635, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29715312

RESUMO

Psoriasis is a common inflammatory skin disease, with considerable genetic contribution. Genome-wide association studies have successfully identified a number of genomic regions for the risk of psoriasis. However, it is challenging to pinpoint the functional causal variants and then further decipher the genetic mechanisms underlying each region. In order to prioritize potential functional causal variants within psoriasis susceptibility regions, we integrated the genetic association findings and functional genomic data publicly available, i.e. histone modifications in relevant immune cells. We characterized a pervasive enrichment pattern of psoriasis variants in five core histone marks across immune cells/tissues. We discovered that genetic alleles within psoriasis association regions might influence gene expression levels through significantly affecting the binding affinities of 17 transcription factors. We established a catalog of 654 potential functional causal variants for psoriasis and suggested that they significantly overlapped with causal variants for autoimmune diseases. We identified potential causal variant rs79824801 overlay with the peaks of five histone marks in primary CD4+ T cells. Its alternative allele affected the binding affinity of transcription factor IKZF1. This study highlights the complex genetic architecture and complicated mechanisms for psoriasis. The findings will inform the functional experiment design for psoriasis.


Assuntos
Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Psoríase/genética , Alelos , Doenças Autoimunes/genética , Linhagem Celular , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Fatores de Transcrição/genética
10.
Exp Cell Res ; 365(1): 138-144, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29501569

RESUMO

OBJECTIVE: This study was aimed to explore the effect of Bach2 on B cells in systemic lupus erythematosus (SLE), as well as the underlying mechanisms. METHODS: Expression of Bach2, phosphorylated-Bach2 (p-Bach2), Akt, p-Akt and BCR-ABL (p210) in B cells isolated from SLE patients and the healthy persons were assessed by Western blot. Immunofluorescence staining was performed to assess the localization of Bach2 in B cells. Enzyme-linked immunosorbent assay (ELISA) was employed to detect IgG produced by B cells. Cell counting kit-8 (CCK-8) and Annexin-V FITC/PI double staining assay were adopted to evaluate cell proliferation and apoptosis in B cells, respectively. RESULTS: Compared to the healthy controls, Bach2, p-Akt and p210 were significantly decreased, while nuclear translocation of Bach2, IgG, CD40 and CD86 obviously up-regulated in B cells from SLE patients. Bach2 significantly inhibited the proliferation, promoted apoptosis of B cells from SLE patients, whereas BCR-ABL dramatically reversed cell changes induced by Bach2. Besides, BCR-ABL also inhibited nuclear translocation of Bach2 in B cells from SLE patients. Further, LY294002 treatment had no effect on decreased expression of Bach2 induced by BCR-ABL, but significantly eliminated BCR-ABL-induced phosphorylation of Bach2 and restored reduced nuclear translocation of Bach2 induced by BCR-ABL in B cells from SLE. CONCLUSIONS: Bach2 may play a suppressive role in B cells from SLE, and BCR-ABL may inhibit the nuclear translocation of Bach2 via serine phosphorylation through the PI3K pathway.

11.
Hum Mol Genet ; 27(9): 1664-1674, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29481666

RESUMO

Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.

12.
Ann Rheum Dis ; 77(3): 417, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29233832

RESUMO

OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of considerable genetic predisposition. Genome-wide association studies have identified tens of common variants for SLE. However, the majority of them reside in non-coding sequences. The contributions of coding variants have not yet been systematically evaluated. METHODS: We performed a large-scale exome-wide study in 5004 SLE cases and 8179 healthy controls in a Han Chinese population using a custom exome array, and then genotyped 32 variants with suggestive evidence in an independent cohort of 13 246 samples. We further explored the regulatory effect of one novel non-coding single nucleotide polymorphism (SNP) in ex vivo experiments. RESULTS: We discovered four novel SLE gene regions (LCT, TPCN2, AHNAK2 and TNFRSF13B) encompassing three novel missense variants (XP_016859577.1:p.Asn1639Ser, XP_016859577.1:p.Val219Phe and XP_005267356.1:p.Thr4664Ala) and two non-coding variants (rs10750836 and rs4792801) with genome-wide significance (pmeta <5.00×10-8). These variants are enriched in several chromatin states of primary B cells. The novel intergenic variant rs10750836 exhibited an expression quantitative trait locus effect on the TPCN2 gene in immune cells. Clones containing this novel SNP exhibited gene promoter activity for TPCN2 (P=1.38×10-3) whose expression level was reduced significantly in patients with SLE (P<2.53×10-2) and was suggested to be further modulated by rs10750836 in CD19+ B cells (P=7.57×10-5) in ex vivo experiments. CONCLUSIONS: This study identified three novel coding variants and four new susceptibility gene regions for SLE. The results provide insights into the biological mechanism of SLE.

13.
Artigo em Inglês | MEDLINE | ID: mdl-28440896

RESUMO

Nicotine dependence (ND) has a reported heritability of 40-70%. Low-coverage whole-genome sequencing was conducted in 1,889 samples from the UCSF Family study. Linear mixed models were used to conduct genome-wide association (GWA) tests of ND in this and five cohorts obtained from the database of Genotypes and Phenotypes. Fixed-effect meta-analysis was carried out separately for European (n = 14,713) and African (n = 3,369) participants, and then in a combined analysis of both ancestral groups. The meta-analysis of African participants identified a significant and novel susceptibility signal (rs56247223; p = 4.11 × 10-8 ). Data from the Genotype-Tissue Expression (GTEx) study suggested the protective allele is associated with reduced mRNA expression of CACNA2D3 in three human brain tissues (p < 4.94 × 10-2 ). Sequence data from the UCSF Family study suggested that a rare nonsynonymous variant in this gene conferred increased risk for ND (p = 0.01) providing further support for CACNA2D3 involvement in ND. Suggestive associations were observed in six additional regions in both European and merged populations (p < 5.00 × 10-6 ). The top variants were found to regulate mRNA expression levels of genes in human brains using GTEx data (p < 0.05): HAX1 and CHRNB2 (rs1760803), ADAMTSL1 (rs17198023), PEX2 (rs12680810), GLIS3 (rs12348139), non-coding RNA for LINC00476 (rs10759883), and GABBR1 (rs56020557 and rs62392942). A gene-based association test further supported the relation between GABBR1 and ND (p = 6.36 × 10-7 ). These findings will inform the biological mechanisms and development of therapeutic targets for ND.

14.
Asian Pac J Allergy Immunol ; 35(4): 196-202, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28364410

RESUMO

BACKGROUND: Atopic dermatitis (AD) and other atopic diseases often share some common genetic and pathogenic bases. Recent genome-wide association studies (GWAS) have identified several loci associated with atopic diseases, allergic sensitization and asthma in different populations. The aim of this study was to investigate whether these susceptibility loci were related to AD in Chinese Han population. METHODS: Eight single nucleotide polymorphisms (SNPs) from recent atopic diseases and allergic sensitization GWAS were genotyped in 3,013 AD patients and 5,483 healthy controls in Chinese Han population using Sequenom MassArray system. Data was analyzed with PLINK 1.07 software. RESULTS: We identified that the susceptibility loci at 5q31 (RAD50/IL13, rs2158177, P = 1.08×10-3, OR = 1.15) and 5q22.1 (TSLP, rs1837253, P = 2.66×10-3, OR = 0.91) were significantly associated with AD. Genotype-based association testing revealed that the dominant model provided the best fit for both rs2158177 (P = 3.75×10-3) and rs1837253 (P = 5.30×10-3). Pathway analysis conformed that both loci were associated with the JAK-STAT signaling pathway. CONCLUSIONS: We identified two susceptibility loci 5q31 and 5q22.1 for AD that might bear candidate genes conferring susceptibility to AD.

15.
Gene ; 617: 17-23, 2017 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-28351738

RESUMO

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease. The 5q22.1 region was found to have an association with AD in our previous genome-wide association study (GWAS). OBJECTIVE: To identify the AD susceptibility gene in 5q22.1 and observe its expression in AD tissues. METHODS: Suggestive indels from the GWAS data were genotyped in 3013 AD patients and 5075 controls from the Chinese Han population with the SequenomMassArray system. Association, Bayesian and bioinformatics analyses were used to identify possible causal indels and genes in the 5q22.1 region. Immunohistochemistry (IHC) was performed to observe protein expression in the tissues. PLINK 1.07 software was used for all statistical analyses. RESULTS: The genotyping and association analysis showed that six deletions and four SNPs were associated with AD (P<0.005). The rs11357450 (Pcombined=7.79E-04, OR=1.39, logBayes Factor=1.29) deletion located in TMEM232 was identified to be the strongest variant. Analysis of the genetic model revealed that the dominant model best described rs11357450 (P=1.96E-03, OR=1.22; 95% CI=1.07-1.37). IHC showed that the expression of TMEM232 decreased gradually from the granular layer to the basal layer in AD, but in normal tissues, this trend was reversed. Additionally, positive cytoplasm staining was found in lymphocytes around the blood vessels in AD. CONCLUSIONS: The study indicates that TMEM232 in the 5q22.1 region is the causal gene for AD in the Chinese Han population.


Assuntos
Dermatite Atópica/genética , Mutação INDEL , Proteínas de Membrana/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Lactente , Masculino , Proteínas de Membrana/metabolismo , Polimorfismo de Nucleotídeo Único
16.
J Gene Med ; 19(1-2)2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27976820

RESUMO

BACKGROUND: Psoriasis is a common inflammatory skin disease, whereas schizophrenia is a psychiatric disorder with substantial comorbidity. Although these two disorders manifest with apparently unrelated phenotypes, there is some evidence suggesting that they share common genetic factors. METHODS: We implemented a genetic analysis incorporating pleiotropy and annotation to genome-wide association summary statistics data for approximately 120 000 psoriasis and schizophrenia samples, as well as whole blood expression quantitative trait loci in 5311 samples. RESULTS: We observed a significant pleiotropic effect between psoriasis and schizophrenia (p = 5.92 × 10-43 ). We characterized an enrichment of whole blood expression quantitative trait loci in genome-wide association data for psoriasis and schizophrenia (q1 /q0  > 1.5, p < 10-77 ) and we revealed that common variants for both diseases were more likely to confer expression quantitative trait loci effects (q1 /q0  = 4.197, SE = 0.183). Through joint analysis of the associations in the combined psoriasis and schizophrenia data set, we identified a potential susceptibility PTPN1 gene for psoriasis, which may affect the risk of psoriasis through modulation of the function of TYK2 kinase. CONCLUSIONS: The results of the present study highlight the expression quantitative trait loci enrichment and pleiotropy in psoriasis and schizophrenia, and also suggest a possible key role of the PTPN1 gene in the etiology of psoriasis.


Assuntos
Expressão Gênica , Estudos de Associação Genética , Pleiotropia Genética/genética , Predisposição Genética para Doença , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Psoríase/genética , Locos de Características Quantitativas , Alelos , Biologia Computacional/métodos , Estudo de Associação Genômica Ampla , Genômica , Genótipo , Antígenos HLA/genética , Humanos , Polimorfismo de Nucleotídeo Único , Mapeamento de Interação de Proteínas , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Psoríase/diagnóstico , Psoríase/metabolismo , Esquizofrenia/genética , Transdução de Sinais
17.
Clin Epigenetics ; 8: 131, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27980695

RESUMO

BACKGROUND: Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and altered keratinocyte differentiation and inflammation and is caused by the interplay of genetic and environmental factors. Previous studies have revealed that DNA methylation (DNAm) and genetic makers are closely associated with psoriasis, and strong evidences have shown that DNAm can be controlled by genetic factors, which attracted us to evaluate the relationship among DNAm, genetic makers, and disease status. METHODS: We utilized the genome-wide methylation data of psoriatic skin (PP, N = 114) and unaffected control skin (NN, N = 62) tissue samples in our previous study, and we performed whole-genome genotyping with peripheral blood of the same samples to evaluate the underlying genetic effect on skin DNA methylation. Causal inference test (CIT) was used to assess whether DNAm regulate genetic variation and gain a better understanding of the epigenetic basis of psoriasis susceptibility. RESULTS: We identified 129 SNP-CpG pairs achieving the significant association threshold, which constituted 28 unique methylation quantitative trait loci (MethQTL) and 34 unique CpGs. There are 18 SNPs were associated with psoriasis at a Bonferoni-corrected P < 0.05, and these 18 SNPs formed 93 SNP-CpG pairs with 17 unique CpG sites. We found that 11 of 93 SNP-CpG pairs, composed of 5 unique SNPs and 3 CpG sites, presented a methylation-mediated relationship between SNPs and psoriasis. The 3 CpG sites were located on the body of C1orf106, the TSS1500 promoter region of DMBX1 and the body of SIK3. CONCLUSIONS: This study revealed that DNAm of some genes can be controlled by genetic factors and also mediate risk variation for psoriasis in Chinese Han population and provided novel molecular insights into the pathogenesis of psoriasis.


Assuntos
Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Fatores de Transcrição Otx/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Quinases/genética , Proteínas/genética , Psoríase/genética , Adolescente , Adulto , Idoso , Criança , China/etnologia , Epigenômica/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/etnologia , Adulto Jovem
18.
J Genet Genomics ; 43(9): 549-554, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27614704

RESUMO

Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies (GWASs) have identified that COL11A1 is an important susceptibility gene for human height. To determine whether the variants of COL11A1 are associated with adult and children height, we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was Chr1_103380393 with P value of 4.8 × 10(-7). Chr1_103380393 also showed nominal significance in the validation stage (P = 1.21 × 10(-6)). Combined analysis of 16,738 samples strengthened the original association of chr1_103380393 with adult height (Pcombined = 3.1 × 10(-8)), with an increased height of 0.292sd (standard deviation) per G allele (95% CI: 0.19-0.40). There was no evidence (P = 0.843) showing that chr1_103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258. This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.


Assuntos
Estatura/genética , Colágeno Tipo XI/genética , Grupos Étnicos/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Criança , Pré-Escolar , China/etnologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
19.
Nat Genet ; 48(8): 940-946, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399966

RESUMO

Systemic lupus erythematosus (SLE; OMIM 152700) is a genetically complex autoimmune disease. Genome-wide association studies (GWASs) have identified more than 50 loci as robustly associated with the disease in single ancestries, but genome-wide transancestral studies have not been conducted. We combined three GWAS data sets from Chinese (1,659 cases and 3,398 controls) and European (4,036 cases and 6,959 controls) populations. A meta-analysis of these studies showed that over half of the published SLE genetic associations are present in both populations. A replication study in Chinese (3,043 cases and 5,074 controls) and European (2,643 cases and 9,032 controls) subjects found ten previously unreported SLE loci. Our study provides further evidence that the majority of genetic risk polymorphisms for SLE are contained within the same regions across both populations. Furthermore, a comparison of risk allele frequencies and genetic risk scores suggested that the increased prevalence of SLE in non-Europeans (including Asians) has a genetic basis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Humanos
20.
G3 (Bethesda) ; 6(6): 1503-11, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27172182

RESUMO

We aimed to elucidate the cell types, tissues, and pathways influenced by common variants in systemic lupus erythematosus (SLE). We applied a nonparameter enrichment statistical approach, termed SNPsea, in 181 single nucleotide polymorphisms (SNPs) that have been identified to be associated with the risk of SLE through genome-wide association studies (GWAS) in Eastern Asian and Caucasian populations, to manipulate the critical cell types, tissues, and pathways. In the two most significant cells' findings (B lymphocytes and CD14+ monocytes), we subjected the GWAS association evidence in the Han Chinese population to an enrichment test of expression quantitative trait locus (QTL) sites and DNase I hypersensitivity, respectively. In both Eastern Asian and Caucasian populations, we observed that the expression level of SLE GWAS implicated genes was significantly elevated in xeroderma pigentosum B cells (P ≤ 1.00 × 10(-6)), CD14+ monocytes (P ≤ 2.74 × 10(-4)) and CD19+ B cells (P ≤ 2.00 × 10(-6)), and plasmacytoid dendritic cells (pDCs) (P ≤ 9.00 × 10(-6)). We revealed that the SLE GWAS-associated variants were more likely to reside in expression QTL in B lymphocytes (q1/q0 = 2.15, P = 1.23 × 10(-44)) and DNase I hypersensitivity sites (DHSs) in CD14+ monocytes (q1/q0 = 1.41, P = 0.08). We observed the common variants affected the risk of SLE mostly through by regulating multiple immune system processes and immune response signaling. This study sheds light on several immune cells and responses, as well as the regulatory effect of common variants in the pathogenesis of SLE.


Assuntos
Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/metabolismo , Transdução de Sinais , Análise por Conglomerados , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Variação Genética , Genômica/métodos , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
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