0810 Executive Center Drive

Little Rock, AR, United States

0810 Executive Center Drive

Little Rock, AR, United States
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Systemic lupus erythematosus (SLE) is a complex disorder. Genetic association studies of complex disorders suffer from the following three major issues: phenotypic heterogeneity, false positive (type I error), and false negative (type II error) results. Hence, genes with low to moderate effects are missed in standard analyses, especially after statistical corrections. OASIS is a novel linkage disequilibrium clustering algorithm that can potentially address false positives and negatives in genome-wide association studies (GWAS) of complex disorders such as SLE. OASIS was applied to two SLE dbGAP GWAS datasets (6077 subjects; ∼0.75 million single-nucleotide polymorphisms). OASIS identified three known SLE genes viz. IFIH1, TNIP1, and CD44, not previously reported using these GWAS datasets. In addition, 22 novel loci for SLE were identified and the 5 SLE genes previously reported using these datasets were verified. OASIS methodology was validated using single-variant replication and gene-based analysis with GATES. This led to the verification of 60% of OASIS loci. New SLE genes that OASIS identified and were further verified include TNFAIP6, DNAJB3, TTF1, GRIN2B, MON2, LATS2, SNX6, RBFOX1, NCOA3, and CHAF1B. This study presents the OASIS algorithm, software, and the meta-analyses of two publicly available SLE GWAS datasets along with the novel SLE genes. Hence, OASIS is a novel linkage disequilibrium clustering method that can be universally applied to existing GWAS datasets for the identification of new genes. © 2017 The Author(s)


Larsen C.P.,0810 Executive Center Drive | Ismail W.,Beni Suef University | Kurtin P.J.,Mayo Medical School | Vrana J.A.,Mayo Medical School | And 2 more authors.
Modern Pathology | Year: 2016

Large case series of renal amyloidosis subtypes have recently been published in the United States and Europe showing AL amyloidosis to be the predominant subtype in this part of the world. However, the most common subtypes of renal amyloidosis throughout the rest of the world are unknown. We present here the first large case series detailing the subtypes of renal amyloidosis among Egyptians. In this population, AA amyloidosis was the most common type of amyloidosis on renal biopsy at 48%. The newly described leukocyte chemotactic factor 2 amyloidosis (ALECT2) was the second most common type and represented nearly one-third of renal amyloid cases at 31%. AL accounted for only 20% of cases. The pathologic findings in ALECT2 cases were similar to those previously described in other case series. Thus ALECT2, which was initially thought to affect mainly Hispanics in the United States, appears to represent an important and likely underrecognized etiology of chronic kidney disease among Egyptians and probably in other ethnic groups around the world. © 2016 USCAP, Inc All rights reserved.


Boils C.L.,0810 Executive Center Drive | Nasr S.H.,Mayo Medical School | Walker P.D.,0810 Executive Center Drive | Couser W.G.,University of Washington | Larsen C.P.,0810 Executive Center Drive
Kidney International | Year: 2015

Glomerulonephritis (GN) due to infective endocarditis (IE) is well documented, but most available data are based on old autopsy series. To update information, we now present the largest biopsy-based clinicopathologic series on IE-associated GN. The study group included 49 patients (male-to-female ratio of 3.5:1) with a mean age of 48 years. The most common presenting feature was acute kidney injury. Over half of the patients had no known prior cardiac abnormality. However, the most common comorbidities were cardiac valve disease (30%), intravenous drug use (29%), hepatitis C (20%), and diabetes (18%). The cardiac valve infected was tricuspid in 43%, mitral in 33%, and aortic in 29% of patients. The two most common infective bacteria were Staphylococcus (53%) and Streptococcus (23%). Hypocomplementemia was found in 56% of patients tested and ANCA antibody in 28%. The most common biopsy finding was necrotizing and crescentic GN (53%), followed by endocapillary proliferative GN (37%). C3 deposition was prominent in all cases, whereas IgG deposition was seen in <30% of cases. Most patients had immune deposits detectable by electron microscopy. Thus, IE-associated GN most commonly presents with AKI and complicates staphylococcal tricuspid valve infection. Contrary to infection-associated glomerulonephritis in general, the most common pattern of glomerular injury in IE-associated glomerulonephritis was necrotizing and crescentic glomerulonephritis. © 2015 International Society of Nephrology.


Saeed M.,0810 Executive Center Drive | Beggs M.L.,0810 Executive Center Drive | Walker P.D.,0810 Executive Center Drive | Larsen C.P.,0810 Executive Center Drive
Genes and Immunity | Year: 2014

Membranous glomerulopathy (MG) is most commonly caused by autoantibodies directed against the podocyte phospholipase A2 receptor (PLA2R1) and common variants in this gene are associated with MG. Here for the first time, we carried out a large case-control association study (n=1512) of PLA2R-positive and-negative MG to determine the extent of association in these pathologic subtypes. We performed four separate sets of analyses to determine significance of the single-nucleotide polymorphisms (SNPs) and their haplotypes followed by joint analysis and trans-ethnic mapping to increase power. The PLA2R1 SNP rs35771982 was most strongly associated with PLA2R-positive MG (P=1.4 × 10-14, odds ratio (OR GG)=1.98). The associations of other SNPs in PLA2R1 could be explained because of linkage disequilibrium with the G-allele. Haplotypes in PLA2R1 did not exceed the significance of rs35771982 even after 10 000 permutations. PLA2R1 variants were only associated with PLA2R-positive MG and predominantly in Caucasians. PLA2R1 variants did not associate with MG in African Americans (AA). There was strong epistasis between HLA-DQA1 SNP rs2187668 and the PLA2R1 variant rs35771982. Thus, common variants in the PLA2R1, particularly rs35771982, modulate PLA2R-positive MG with HLA-DQA1 in Caucasians. PLA2R-negative MG especially in AA, may provide a novel opportunity to discover new genes underlying MG. © 2014 Macmillan Publishers Limited All rights reserved.


Larsen C.P.,0810 Executive Center Drive | Larsen C.P.,University of Arkansas for Medical Sciences | Walker P.D.,0810 Executive Center Drive | Walker P.D.,University of Arkansas for Medical Sciences
Transplantation | Year: 2013

BACKGROUND: Membranous glomerulopathy (MG) is one of the most common glomerulonephritides involving the renal transplant. We sought to determine the utility of phospholipase A2 receptor (PLA2R) staining for the detection of recurrent MG. We also evaluated for increased evidence of antibody-mediated rejection in the de novo group, as some have reported. METHODS: Twenty-two cases of MG occurring in renal transplant biopsies were identified, who had a tissue diagnosis documenting the primary native renal disease. There were 12 biopsies from 11 patients with recurrent MG and 12 biopsies from 11 patients with de novo MG. Morphologic evaluation and PLA2R staining was performed in all cases. RESULTS: Ten of 12 (83%) recurrent MG and 1 of 12 (8%) de novo MG biopsies showed positive glomerular staining for PLA2R, giving PLA2R a sensitivity of 83% (95% confidence interval, 51%-97%) and specificity of 92% (95% confidence interval, 60%-100%) for recurrent MG. There were 2 of 12 (17%) de novo and 1 of 12 (8%) recurrent biopsies showing the presence of microcirculation inflammation. Peritubular capillary C4d staining was negative in all cases. CONCLUSION: Recurrent MG is strongly correlated with PLA2R positivity, with a sensitivity of 83% and specificity of 92% for recurrent MG. There was no morphologic evidence of an association between antibody-mediated rejection and de novo MG, because both groups had a similar degree of microcirculation inflammation and peritubular capillary C4d staining. Most interestingly, PLA2R staining was almost always negative in de novo MG, suggesting a different mechanism in this unique form of MG. Copyright © 2013 by Lippincott Williams & Wilkins.


Larsen C.P.,0810 Executive Center Drive | Larsen C.P.,University of Arkansas for Medical Sciences | Beggs M.L.,0810 Executive Center Drive | Saeed M.,0810 Executive Center Drive | And 2 more authors.
Journal of the American Society of Nephrology | Year: 2013

Collapsing glomerulopathy is a devastating renal disease that primarily affects African Americans and associates with numerous etiologies, such as HIV and auto-immune disease. The presence of APOL1 risk alleles associates with HIV-associated collapsing glomerulopathy, but it is unknown whether these risk alleles also associate with systemic lupus erythematosus (SLE) -associated collapsing glomerulopathy. Here, re-examination of 546 renal biopsies from African-American patients with SLE identified 26 cases of collapsing glomerulopathy, which we genotyped for APOL1 risk alleles using DNA extracted from archived biopsy tissue. APOL1 strongly associated with SLE-associated collapsing glomerulopathy ( P<0.001). In a recessive model, two APOL1 risk alleles conferred 5.4-fold (95% CI=2.4 to 12.1) higher odds of developing SLE-associated collapsing glomerulopathy (P<0.001). In conclusion, APOL1 genotyping of African-American patients with SLE might help identify patients at risk for collapsing glomerulopathy, an entity with a poor prognosis that is often resistant to treatment. Copyright © 2013 by the American Society of Nephrology.


PubMed | 0810 Executive Center Drive
Type: Comparative Study | Journal: Transplantation | Year: 2013

Membranous glomerulopathy (MG) is one of the most common glomerulonephritides involving the renal transplant. We sought to determine the utility of phospholipase A2 receptor (PLA2R) staining for the detection of recurrent MG. We also evaluated for increased evidence of antibody-mediated rejection in the de novo group, as some have reported.Twenty-two cases of MG occurring in renal transplant biopsies were identified, who had a tissue diagnosis documenting the primary native renal disease. There were 12 biopsies from 11 patients with recurrent MG and 12 biopsies from 11 patients with de novo MG. Morphologic evaluation and PLA2R staining was performed in all cases.Ten of 12 (83%) recurrent MG and 1 of 12 (8%) de novo MG biopsies showed positive glomerular staining for PLA2R, giving PLA2R a sensitivity of 83% (95% confidence interval, 51%-97%) and specificity of 92% (95% confidence interval, 60%-100%) for recurrent MG. There were 2 of 12 (17%) de novo and 1 of 12 (8%) recurrent biopsies showing the presence of microcirculation inflammation. Peritubular capillary C4d staining was negative in all cases.Recurrent MG is strongly correlated with PLA2R positivity, with a sensitivity of 83% and specificity of 92% for recurrent MG. There was no morphologic evidence of an association between antibody-mediated rejection and de novo MG, because both groups had a similar degree of microcirculation inflammation and peritubular capillary C4d staining. Most interestingly, PLA2R staining was almost always negative in de novo MG, suggesting a different mechanism in this unique form of MG.

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