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  • 1
    Online Resource
    Online Resource
    Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus
    BMJ ; 2021
    In:  Annals of the Rheumatic Diseases Vol. 80, No. 5 ( 2021-05), p. 632-640
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 80, No. 5 ( 2021-05), p. 632-640
    Abstract: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. Methods We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. Results We identified 113 genetic regions including 46 novel loci at genome-wide significance (p 〈 5×10 −8 ). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r g =−0.242) and non-albumin protein (r g =0.238). Conclusion This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-219209
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 1481557-6
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  • 2
    Online Resource
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    Clinicopathological features of fast eGFR decliners among patients with diabetic nephropathy
    BMJ ; 2020
    In:  BMJ Open Diabetes Research & Care Vol. 8, No. 1 ( 2020-06), p. e001157-
    Details
    In: BMJ Open Diabetes Research & Care, BMJ, Vol. 8, No. 1 ( 2020-06), p. e001157-
    Abstract: The speed of declining kidney function differs among patients with diabetic nephropathy. This study was undertaken to clarify clinical and pathological features that affect the speed of declining kidney function in patients with diabetic nephropathy. Research design and methods This study was design as multicenter retrospective study. The subjects (377 patients with diabetic nephropathy diagnosed by kidney biopsy at 13 centers in Japan) were classified into three groups based on the estimated glomerular filtration rate (eGFR) declining speed. The eGFR increasing group, the control group, and the eGFR declining group were divided at 0 and 5 mL/min/1.73 m 2 /year, respectively. Characteristics of clinicopathological findings of declining kidney function were evaluated. Results The mean observation period of this study was 6.9 years. The control group, the eGFR increasing group, and the eGFR declining group included 81, 66, and 230 patients, respectively. The incidences of composite kidney events represented by 100 persons/year were 25.8 in the eGFR declining group and 2.0 in the eGFR increasing group. After adjustment for age, sex, systolic blood pressure, hemoglobin, and urinary albumin levels, three clinicopathological findings (urinary albumin levels, presence of nodular lesion, and mesangiolysis) were risk factors for inclusion in the eGFR declining group (the ORs were 1.49, 2.18, and 2.08, respectively). In contrast, the presence of subendothelial space widening and polar vasculosis were characteristic findings for inclusion in the eGFR increasing group (the ORs were 0.53 and 0.41, respectively). Conclusions As well as urinary albumin elevation, nodular lesion and mesangiolysis were characteristic pathological features of patients with fast declining kidney function.
    Type of Medium: Online Resource
    ISSN: 2052-4897
    URL: Article
    DOI: 10.1136/bmjdrc-2019-001157
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 2732918-5
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  • 3
    Online Resource
    Online Resource
    Two-year longitudinal trajectory patterns of albuminuria and subsequent rates of end-stage kidney disease and all-cause death: a nationwide cohort study of biopsy-proven diabetic kidney disease
    BMJ ; 2021
    In:  BMJ Open Diabetes Research & Care Vol. 9, No. 1 ( 2021-08), p. e002241-
    Details
    In: BMJ Open Diabetes Research & Care, BMJ, Vol. 9, No. 1 ( 2021-08), p. e002241-
    Abstract: Data on the association between longitudinal trajectory patterns of albuminuria and subsequent end-stage kidney disease (ESKD) and all-cause mortality in diabetic kidney disease (DKD) are sparse. Research design and methods Drawing on nationally representative data of 329 patients with biopsy-proven DKD and an estimated glomerular filtration rate above 30 mL/min/1.73 m 2 at the time of biopsy, we used joint latent class mixed models to identify different 2-year trajectory patterns of urine albumin to creatinine ratio (UACR) and assessed subsequent rates of competing events: ESKD and all-cause death. Results A total of three trajectory groups of UACR were identified: ‘high-increasing’ group (n=254; 77.2%), ‘high-decreasing’ group (n=24; 7.3%), and ‘low-stable’ group (n=51; 15.5%). The ‘low-stable’ group had the most favorable risk profile, including the baseline UACR (median (IQR) UACR (mg/g creatinine): ‘low-stable’, 109 (50–138); ‘high-decreasing’, 906 (468–1740); ‘high-increasing’, 1380 (654–2502)), and had the least subsequent risk of ESKD and all-cause death among the groups. Although there were no differences in baseline characteristics between the ‘high-decreasing’ group and the ‘high-increasing’ group, the ‘high-decreasing’ group had better control over blood pressure, blood glucose, and total cholesterol levels during the first 2 years of follow-up, and the incidence rates of subsequent ESKD and all-cause death were lower in the ‘high-decreasing’ group compared with the ‘high-increasing’ group (incidence rate of ESKD (per 1000 person-years): 32.7 vs 77.4, p=0.014; incidence rate of all-cause death (per 1000 person-years): 0.0 vs 25.4, p=0.007). Conclusions Dynamic changes in albuminuria are associated with subsequent ESKD and all-cause mortality in DKD. Reduction in albuminuria by improving risk profile may decrease the risk of ESKD and all-cause death.
    Type of Medium: Online Resource
    ISSN: 2052-4897
    URL: Article
    DOI: 10.1136/bmjdrc-2021-002241
    Language: English
    Publisher: BMJ
    Publication Date: 2021
    detail.hit.zdb_id: 2732918-5
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  • 4
    Online Resource
    Online Resource
    Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study
    BMJ ; 2022
    In:  Annals of the Rheumatic Diseases Vol. 81, No. 9 ( 2022-09), p. 1273-1280
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 81, No. 9 ( 2022-09), p. 1273-1280
    Abstract: Genome-wide association studies (GWAS) have identified 〉 100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4 + and CD8 + T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p 〈 1.0×10 –5 ); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p 〈 7.7×10 –8 ). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10 –9 ) around CD83 . For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1 , and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2022-222345
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 1481557-6
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  • 5
    Online Resource
    Online Resource
    GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes
    BMJ ; 2017
    In:  Annals of the Rheumatic Diseases Vol. 76, No. 5 ( 2017-05), p. 869-877
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 76, No. 5 ( 2017-05), p. 869-877
    Abstract: A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p 〈 5.0×10 −8 ): urate transporter genes ( SLC22A12 and SLC17A1 ) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10 −8 ). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2016-209632
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2017
    detail.hit.zdb_id: 1481557-6
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