Genetic susceptibility to systemic lupus erythematosus in the genomic era

Deng, Yun; Tsao, Betty P.

doi:10.1038/nrrheum.2010.176

Cited by 325 publications

(252 citation statements)

References 115 publications

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“…at multiple genetic loci are believed to increase the risk of SLE in a hierarchical interactive manner [Moser et al 2009;Nath et al 2004]. Although extensive studies have associated many common genetic variants with SLE [Deng and Tsao, 2010;Flesher et al 2010], the cumulative effect size of the loci identified so far accounts for only 15-20% of the heritability of SLE [Manolio et al 2009]. The variations potentially underlying the remaining 75-80% of the heritability appear to be missing.…”

Section: Biomarkers Originated From Better Understanding Of Sle Pathomentioning

confidence: 99%

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

Liu

Kao

Manzi

et al. 2013

Therapeutic Advances in Musculoskeletal

103

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Abstract:The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.

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Section: Biomarkers Originated From Better Understanding Of Sle Pathomentioning

confidence: 99%

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

Liu

Kao

Manzi

et al. 2013

Therapeutic Advances in Musculoskeletal

103

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“…Candidate gene studies and, more recently, genome-wide association studies (GWAS), have begun to elucidate the complex genetic profile of systemic lupus erythematosus (SLE) with identification of ∼30 risk loci (1)(2)(3). However, for almost all these identified loci, the causal polymorphism that leads to lupus susceptibility has not been discovered.…”

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confidence: 99%

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Jacob

Eisenstein

Dinauer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

157

119

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Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is a debilitating multisystem autoimmune disorder characterized by chronic inflammation and extensive immune dysregulation in multiple organ systems, resulting in significant morbidity and mortality. Here, we present a multidisciplinary approach resulting in the identification of neutrophil cytosolic factor 2 (NCF2) as an important risk factor for SLE and the detailed characterization of its causal variant. We show that NCF2 is strongly associated with increased SLE risk in two independent populations: childhood-onset SLE and adult-onset SLE. The association between NCF2 and SLE can be attributed to a single nonsynonymous coding mutation in exon 12, the effect of which is the substitution of histidine-389 with glutamine (H389Q) in the PB1 domain of the NCF2 protein, with glutamine being the risk allele. Computational modeling suggests that the NCF2 H389Q mutation reduces the binding efficiency of NCF2 with the guanine nucleotide exchange factor Vav1. The model predicts that NCF2/H389 residue interacts with Vav1 residues E509, N510, E556, and G559 in the ZF domain of Vav1. Furthermore, replacing H389 with Q results in 1.5 kcal/ mol weaker binding. To examine the effect of the NCF2 H389Q mutation on NADPH oxidase function, site-specific mutations at the 389 position in NCF2 were tested. Results show that an H389Q mutation causes a twofold decrease in reactive oxygen species production induced by the activation of the Vav-dependent Fcγ receptor-elicited NADPH oxidase activity. Our study completes the chain of evidence from genetic association to specific molecular function.F ine localization of the polymorphisms responsible for genotype-phenotype correlations is emerging as a difficult hurdle in the implementation and interpretation of genetic association studies. Candidate gene studies and, more recently, genome-wide association studies (GWAS), have begun to elucidate the complex genetic profile of systemic lupus erythematosus (SLE) with identification of ∼30 risk loci (1-3). However, for almost all these identified loci, the causal polymorphism that leads to lupus susceptibility has not been discovered. GWAS have been praised for representing an "agnostic" approach that is unbiased by prior assumptions regarding genetic association with the disease. However, such an approach typically ignores all valuable prior information collected over decades about the pathogenesis and genetic basis of diseases that have been previously studied. This inevitably leads to the inclusion of regions (and additional SNPs) that have little to no possibility of being associated with a disease, increasing the number of tests. More tests mean a more stringent multiple testing correction and a reduction of power or a greater number of subjects to overcome the reduction of power. To avoid this reduction of power, we have developed a two-step bioinformatics-driven design that increases the power of gene association studies using a partial Bayesian approach. The...

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“…Recent genome-wide association studies (GWAS) have identified a number of single-nucleotide polymor-phisms (SNPs) associated with the risk of SLE, in genes such as HLA, IRF5, STAT4, TNFAIP3, PTPN22, BLK, BANK1, TNFSF4, ITGAM, KIAA1542, and PXK, in various ethnic groups (2). In addition to SNPs, DNA copy number variations (CNVs) can influence the interindividual differences in the risk of disease via several mechanisms that affect gene expression, such as gene disruption and rearrangements (3)(4)(5).…”

mentioning

confidence: 99%

Deletion Variants of RABGAP1L, 10q21.3, and C4 Are Associated With the Risk of Systemic Lupus Erythematosus in Korean Women

Kim¹,

Jung²,

Bae³

et al. 2013

Arthritis & Rheumatism

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Objective. Several copy number variations (CNVs) have been found to be associated with systemic lupus erythematosus (SLE) through the target gene approach. However, genome-wide features of CNVs and their role in the risk of SLE remain unknown. The aim of this study was to identify SLE-associated CNVs in Korean women.Methods. Genome-wide assessments of CNVs were performed in 382 SLE patients and 191 control subjects, using an Illumina HumanHap610 BeadChip genotyping platform. SLE-associated CNV regions that were identified by genome-wide association study (GWAS) were replicated in quantitative polymerase chain reaction (PCR) and deletion-typing PCR analyses in an independent sample set comprising 564 SLE patients and 511 control subjects.Results. Of 144 common CNV regions, 3 deletiontype CNV regions in 1q25.1, 8q23.3, and 10q21.3 were found to be significantly associated with SLE by GWAS analysis. In the independent replication, the CNV regions in 1q25.1 (RABGAP1L) and 10q21.3 were successfully replicated (odds ratio [OR] 1.30, P ‫؍‬ 0.038 and OR 1.90, P ‫؍‬ 3.6 ؋ 10 ؊5 , respectively), and the associations were confirmed again by deletion-typing PCR. The CNV region in the C4 gene, which showed a potential association in the discovery stage, was included in the replication analysis and was found to be significantly associated with the risk of SLE (OR 1.88, P ‫؍‬ 0.01). Through deletion-typing PCR, the exact sizes and breakpoint sequences of the deletions were defined. Individuals with the deletions in all 3 loci (RABGAP1L, 10q21.3, and C4) had a much higher risk of SLE than did those without any deletions in the 3 loci (OR 5.52, P ‫؍‬ 3.9 ؋ 10 ؊4 ). Conclusion. These CNV regions can be useful to identify the pathogenic mechanisms of SLE, and might be used to more accurately predict the risk of SLE by taking into consideration their synergistic effects on disease susceptibility.

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Genetic susceptibility to systemic lupus erythematosus in the genomic era

Cited by 325 publications

References 115 publications

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase

Deletion Variants of RABGAP1L, 10q21.3, and C4 Are Associated With the Risk of Systemic Lupus Erythematosus in Korean Women

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