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Dive into the research topics where Sampath Prahalad is active.

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Featured researches published by Sampath Prahalad.


Nature Genetics | 2009

Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways.

Rajan P. Nair; Kristina Callis Duffin; Cynthia Helms; Jun Ding; Philip E. Stuart; David E. Goldgar; Johann E. Gudjonsson; Yun Li; Trilokraj Tejasvi; Bing Jian Feng; Andreas Ruether; Stefan Schreiber; Michael Weichenthal; Dafna D. Gladman; Proton Rahman; Steven J. Schrodi; Sampath Prahalad; Stephen L. Guthery; Judith Fischer; Wilson Liao; Pui-Yan Kwok; Alan Menter; G. Mark Lathrop; Carol A. Wise; Ann B. Begovich; John J. Voorhees; James T. Elder; Gerald G. Krueger; Anne M. Bowcock; Gonçalo R. Abecasis

Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 × 10−8). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-α and regulate NF-κB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.


Nature Genetics | 2013

Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis

Anne Hinks; Joanna Cobb; Miranda C. Marion; Sampath Prahalad; Marc Sudman; John Bowes; Paul Martin; Mary E. Comeau; Satria Sajuthi; Robert K Andrews; Milton R. Brown; Wei-Min Chen; Patrick Concannon; Panos Deloukas; Sarah Edkins; Stephen Eyre; Patrick M. Gaffney; Stephen L. Guthery; Joel M. Guthridge; Sarah Hunt; Judith A. James; Mehdi Keddache; Kathy L. Moser; Peter Nigrovic; Suna Onengut-Gumuscu; Mitchell L. Onslow; Carlos D. Rose; Stephen S. Rich; Kathryn Steel; Edward K. Wakeland

We used the Immunochip array to analyze 2,816 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor–negative polyarticular JIA), and 13,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 14 loci reaching genome-wide significance (P < 5 × 10−8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < 1 × 10−6). Dense mapping of loci along with bioinformatics analysis refined the associations to one gene in each of eight regions, highlighting crucial pathways, including the interleukin (IL)-2 pathway, in JIA disease pathogenesis. The entire Immunochip content, the HLA region and the top 27 loci (P < 1 × 10−6) explain an estimated 18, 13 and 6% of the risk of JIA, respectively. In summary, this is the largest collection of JIA cases investigated so far and provides new insight into the genetic basis of this childhood autoimmune disease.


Arthritis Care and Research | 2012

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

Esi Morgan DeWitt; Yukiko Kimura; Timothy Beukelman; Peter Nigrovic; Karen Onel; Sampath Prahalad; Rayfel Schneider; Matthew L. Stoll; Sheila T. Angeles-Han; Diana Milojevic; Kenneth N. Schikler; Richard K. Vehe; Jennifer E. Weiss; Pamela F. Weiss; Norman T. Ilowite; Carol A. Wallace

There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.


Genes and Immunity | 2006

Negative association between the chemokine receptor CCR5-Δ32 polymorphism and rheumatoid arthritis: A meta-analysis

Sampath Prahalad

Rheumatoid arthritis (RA) is characterized by synovial inflammation mediated by T-cells, monocytes and macrophages. The homing of these cells to the inflamed synovium is regulated by chemokine-receptors and their ligands. A 32-basepair deletion (Δ32) in the gene encoding CCR5, a chemokine-receptor, results in a non-functional receptor. A negative association between CCR5-Δ32 and RA has been described, although other studies found no associations. Furthermore, the observation that individuals homozygous for CCR5-Δ32 develop RA has raised questions about the role of CCR5-Δ32. This meta-analysis of all published case–control association studies confirms the negative association between CCR5-Δ32 and RA (Odds Ratio=0.65; 95% confidence intervals=0.55–0.77; P<0.0001), suggesting that CCR5-Δ32 is protective against the development of RA. CCR5 blockade in animal models of RA results in amelioration of arthritis, suggesting that CCR5 blockade could also modify disease in patients with RA.


Pediatric Rheumatology | 2008

A comprehensive review of the genetics of juvenile idiopathic arthritis

Sampath Prahalad; David N. Glass

Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy of childhood which is believed to be influenced by both genetic and environmental factors. The progress in identifying genes underlying JIA susceptibility using candidate gene association studies has been slow. Several associations between JIA and variants in the genes encoding the human leukocyte antigens (HLA) have been confirmed and replicated in independent cohorts. However it is clear that genetic variants outside the HLA also influence susceptibility to JIA. While a large number of non-HLA candidate genes have been tested for associations, only a handful of reported associations such as PTPN22 have been validated. In this review we discuss the principles behind genetic studies of complex traits like JIA, and comprehensively catalogue non-HLA candidate-gene association studies performed in JIA to date and review several validated associations. Most candidate gene studies are underpowered and do not detect associations, and those that do are often not replicated. We also discuss the principles behind genome-wide association studies and discuss possible implications for identifying genes underlying JIA. Finally we discuss several genetic variants underlying multiple clinically distinct autoimmune phenotypes.


Arthritis & Rheumatism | 1999

Age-specific effects of juvenile rheumatoid arthritis-associated HLA alleles

Kevin J. Murray; Marta B. Moroldo; Patricia Donnelly; Sampath Prahalad; Murray H. Passo; Edward H. Giannini; David N. Glass

OBJECTIVE To define the onset and duration of effect of the HLA alleles that are associated with disease susceptibility and protection in juvenile rheumatoid arthritis (JRA) and 2 of its subtypes. METHODS We typed 680 patients with JRA and 254 ethnically matched unrelated controls for HLA class I and II genes. The frequency of each allele was calculated for each of the age-at-onset, onset type, and sex categories and plotted against the allele frequency in the control population. Survival analysis (with onset of disease as the terminating event) was used to calculate the age by which 50% (St0.5) and 80% (St0.2) of the children with particular alleles and combinations of alleles develop disease. This allele-specific survival analysis also allowed for the comparison of the overall survival functions for the various JRA subtype and sex categories. RESULTS Certain alleles are strongly associated with early susceptibility to pauciarticular JRA, including HLA-A2, DR8, DR5, and DPB1*0201. Fifty percent of the children carrying at least 1 of these alleles had disease onset prior to their third birthday. Among children who carried HLA-A2 and any 2 HLA-DR alleles (DR3, DR5, DR6, or DR8), the median age at the onset of pauciarticular disease was 2.7 years. Combinations of A2 and DPB1*0201 and one DR allele narrowed the window further to a median age at onset of 2.4 years. B27 and DR4 were associated with protection early in life but with increased risk later in childhood, with St0.5 values of 7.3 and 6.6 years, respectively, for pauciarticular JRA and St0.5 values of 10.2 and 10.7 years, respectively, for polyarticular JRA. Sex strongly influenced the age at which many of the alleles have their effect. CONCLUSION These data define at what age and for how long various HLA alleles influence susceptibility and protection (window-of-effect) in patients with JRA. In addition, these data establish more clearly the boundaries of ages-at-onset for 2 of the subtypes of the disease.


Arthritis & Rheumatism | 2010

The susceptibility loci Juvenile Idiopathic Arthritis shares with other autoimmune diseases extend to PTPN2, COG6 and ANGPT1

Susan D. Thompson; Marc Sudman; Paula S. Ramos; Miranda C. Marion; Mary Ryan; Monica Tsoras; Tracey Weiler; Michael Wagner; Mehdi Keddache; J. Peter Haas; Cornelia Mueller; Sampath Prahalad; John F. Bohnsack; Carol Wise; Marilynn Punaro; Dongping Zhang; Carlos D. Rosé; Mary E. Comeau; Jasmin Divers; David N. Glass; Carl D. Langefeld

OBJECTIVE To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA). METHODS Published autoimmune disease genome-wide association studies were reviewed, and 519 single-nucleotide polymorphisms (SNPs) were selected for association testing. The initial cohort included 809 JIA cases and 3,535 controls of non-Hispanic, European ancestry. Of the SNPs, 257 were successfully genotyped, while 168 were imputed with quality. Based on findings in the initial cohort, replication was sought for 21 SNPs in a second cohort of 1,015 JIA cases and 1,569 controls collected in the US and Germany. For the initial cohort, tests for association were adjusted for potential confounding effects of population structure by including principal components derived from a genome-wide association study as covariates in logistic regression models. Odds ratios (ORs) and 95% confidence intervals were calculated. RESULTS Testing for association of previously reported autoimmune disease genetic associations in the initial cohort suggested associations with JIA in 13 distinct loci. Of these, 7 were validated in the replication cohort. Meta-analysis results for the replicating loci included PTPN22 (rs6679677 [OR 1.58, P = 1.98 × 10(-12) ], rs2476601 [OR 1.64, P = 1.90 × 10(-13) ], and rs2488457 [OR 1.32, P = 6.74 × 10(-8) ]), PTPN2 (rs1893217 [OR = 1.33, P = 1.60 × 10(-9) ] and rs7234029 [OR 1.35, P = 1.86 × 10(-10) ]), ADAD1-IL2-IL21 (rs17388568 [OR 1.24, P = 1.13 × 10(-6) ] and rs13143866 [OR 0.83, P = 1.95 × 10(-4) ]), STAT4 (rs3821236 [OR = 1.27, P = 2.36 × 10(-6) ] and rs7574865 [OR = 1.31, P = 2.21 × 10(-6) ]), C12orf30 (rs17696736 [OR = 1.19, P = 2.59 × 10(-5) ]), COG6 (rs7993214 [OR = 0.76, P = 1.10 × 10(-5) ]), and ANGPT1 (rs1010824 [OR = 0.79, P = 2.91 × 10(-4) ]). These polymorphisms have been reported in diseases such as rheumatoid arthritis, type 1 diabetes mellitus, Crohns disease, and multiple sclerosis. CONCLUSION General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.


Arthritis & Rheumatism | 2009

Variants in TNFAIP3, STAT4, and C12orf30 loci associated with multiple autoimmune diseases are also associated with juvenile idiopathic arthritis.

Sampath Prahalad; Sterling Hansen; Stephen L. Guthery; Bronte Clifford; Bernadette McNally; Andrew Zeft; John F. Bohnsack; Lynn B. Jorde

OBJECTIVE Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. METHODS Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. CONCLUSION We have demonstrated associations between JIA and variants in the TNFAIP3, STAT4, and C12orf30 regions that have previously shown associations with other autoimmune diseases, including RA and systemic lupus erythematosus. Our results suggest that clinically distinct autoimmune phenotypes share common genetic susceptibility factors.


Arthritis & Rheumatism | 2000

Juvenile rheumatoid arthritis: linkage to HLA demonstrated by allele sharing in affected sibpairs.

Sampath Prahalad; Mary H. Ryan; Edith S. Shear; Susan D. Thompson; Edward H. Giannini; David N. Glass

OBJECTIVE To test for linkage between the HLA region and juvenile rheumatoid arthritis (JRA), with stratification by onset and course types, in a cohort of affected sibling pairs (ASPs). METHODS Eighty pairs of siblings with JRA who were registered with the Research Registry for JRA ASPs (sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases) were typed for HLA-DR. The observed ratio of sharing of none, one, or both parental DR alleles was compared against the expected ratio of 1:2:1 by goodness-of-fit chi-square tests. A group of 265 unrelated control subjects served as a comparison population for HLA-DR allele frequencies among patients, by Fishers exact test. RESULTS Overall, there was excess sharing of 2 DR alleles among ASPs with JRA. The observed ratio of sharing 0, 1, or 2 DR alleles was 8:40:32, instead of the expected ratio of 20:40:20 (P < 0.001). When stratified by JRA onset type, excess allele sharing was demonstrated among ASPs who were concordant for onset type (P = 0.002). This was true for both pauciarticular and polyarticular onset. When stratified by disease course, excess allele sharing was also demonstrated among ASPs who were concordant for disease course (P < 0.001). This was true for both the pauciarticular and the polyarticular course. Among the 32 ASPs who shared two DR alleles, 5 pairs had both DR8 and DR11, which was significantly more frequent (P < 0.0001) than the incidence in the control group (n = 0). CONCLUSION This study of an independent cohort of multiplex families confirms the previously reported linkage between pauciarticular JRA and the HLA-DR region that was identified using a different analytic method in a cohort of simplex families. Additionally, this study establishes evidence for linkage between polyarticular JRA and the HLA-DR region.


Arthritis & Rheumatism | 2014

Performance of current guidelines for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Sergio Davì; Francesca Minoia; Angela Pistorio; AnnaCarin Horne; Alessandro Consolaro; Silvia Rosina; Francesca Bovis; Rolando Cimaz; Maria Luz Gamir; Norman T. Ilowite; Isabelle Koné-Paut; Sheila Knupp Feitosa de Oliveira; Deborah McCurdy; Clovis A. Silva; Flavio Sztajnbok; Elena Tsitsami; Erbil Ünsal; Jennifer E. Weiss; Nico Wulffraat; Mario Abinun; Amita Aggarwal; Maria Teresa Apaz; Itziar Astigarraga; Fabrizia Corona; Ruben Cuttica; Gianfranco D'Angelo; Eli M. Eisenstein; Soad Hashad; Loredana Lepore; Velma Mulaosmanovic

To compare the capacity of the 2004 diagnostic guidelines for hemophagocytic lymphohistiocytosis (HLH‐2004) with the capacity of the preliminary diagnostic guidelines for systemic juvenile idiopathic arthritis (JIA)–associated macrophage activation syndrome (MAS) to discriminate MAS complicating systemic JIA from 2 potentially confusable conditions, represented by active systemic JIA without MAS and systemic infection.

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Susan D. Thompson

Cincinnati Children's Hospital Medical Center

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Carl D. Langefeld

Cincinnati Children's Hospital Medical Center

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David N. Glass

Cincinnati Children's Hospital Medical Center

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Marc Sudman

Cincinnati Children's Hospital Medical Center

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Wendy Thomson

Manchester Academic Health Science Centre

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