Mehdi Keddache

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (42)214.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: -Bicuspid aortic valve (BAV) is the most common congenital cardiovascular malformation (CVM). Although highly heritable, few causal variants have been identified. The purpose of this study was to identify genetic variants underlying BAV by whole exome sequencing (WES) a multiplex BAV kindred.
    Circulation Cardiovascular Genetics 08/2014; · 6.73 Impact Factor
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    ABSTRACT: Objective To evaluate the performance of a next-generation sequencing (NGS)-based targeted resequencing genetic test, OtoSeq, to identify the sequence variants in the genes causing sensorineural hearing loss (SNHL).Study DesignRetrospective study.SettingTertiary children's hospital.Subjects and MethodsA total of 8 individuals presenting with prelingual hearing loss were used in this study. The coding and flanking intronic regions of 24 well-studied SNHL genes were enriched using microdroplet polymerase chain reaction and sequenced on an Illumina HiSeq 2000 sequencer. The filtered high-quality sequence reads were mapped to reference sequence, and variants were detected using NextGENe software.ResultsA total of 1148 sequence variants were detected in 8 samples in 24 genes. Using in-house developed NGS data analysis criteria, we classified 810 (~71%) of these variants as potential true variants that include previously detected pathogenic mutations in 5 patients. To validate our strategy, we Sanger sequenced the target regions of 5 of the 24 genes, accounting for about 29.2% of all target sequence. Our results showed >99.99% concordance between NGS and Sanger sequencing in these 5 genes, resulting in an analytical sensitivity and specificity of 100% and 99.997%, respectively. We were able to successfully detect single base substitutions, small deletions, and insertions of up to 22 nucleotides.Conclusion This study demonstrated that our NGS-based mutation screening strategy is highly sensitive and specific in detecting sequence variants in the SNHL genes. Therefore, we propose that this NGS-based targeted sequencing method would be an alternative to current technologies for identifying the multiple genetic causes of SNHL.
    Otolaryngology Head and Neck Surgery 03/2013; · 1.73 Impact Factor
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    ABSTRACT: Gaucher disease type 1, an inherited lysosomal storage disorder, is caused by mutations in GBA1 leading to defective glucocerebrosidase (GCase) function and consequent excess accumulation of glucosylceramide/glucosylsphingosine in visceral organs. Enzyme replacement therapy (ERT) with the biosimilars, imiglucerase (imig) or velaglucerase alfa (vela) improves/reverses the visceral disease. Comparative transcriptomic effects (microarray and mRNA-Seq) of no ERT and ERT (imig or vela) were done with liver, lung, and spleen from mice having Gba1 mutant alleles, termed D409V/null. Disease-related molecular effects, dynamic ranges, and sensitivities were compared between mRNA-Seq and microarrays and their respective analytic tools, i.e. Mixed Model ANOVA (microarray), and DESeq and edgeR (mRNA-Seq). While similar gene expression patterns were observed with both platforms, mRNA-Seq identified more differentially expressed genes (DEGs) (∼3-fold) than the microarrays. Among the three analytic tools, DESeq identified the maximum number of DEGs for all tissues and treatments. DESeq and edgeR comparisons revealed differences in DEGs identified. In 9V/null liver, spleen and lung, post-therapy transcriptomes approximated WT, were partially reverted, and had little change, respectively, and were concordant with the corresponding histological and biochemical findings. DEG overlaps were only 8-20% between mRNA-Seq and microarray, but the biological pathways were similar. Cell growth and proliferation, cell cycle, heme metabolism, and mitochondrial dysfunction were most altered with the Gaucher disease process. Imig and vela differentially affected specific disease pathways. Differential molecular responses were observed in direct transcriptome comparisons from imig- and vela-treated tissues. These results provide cross-validation for the mRNA-Seq and microarray platforms, and show differences between the molecular effects of two highly structurally similar ERT biopharmaceuticals.
    PLoS ONE 01/2013; 8(10):e74912. · 3.53 Impact Factor
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    ABSTRACT: Common variations at the loci harboring the fat mass and obesity gene (FTO), MC4R, and TMEM18 are consistently reported as being associated with obesity and body mass index (BMI) especially in adult population. In order to confirm this effect in pediatric population five European ancestry cohorts from pediatric eMERGE-II network (CCHMC-BCH) were evaluated. Method: Data on 5049 samples of European ancestry were obtained from the Electronic Medical Records (EMRs) of two large academic centers in five different genotyped cohorts. For all available samples, gender, age, height, and weight were collected and BMI was calculated. To account for age and sex differences in BMI, BMI z-scores were generated using 2000 Centers of Disease Control and Prevention (CDC) growth charts. A Genome-wide association study (GWAS) was performed with BMI z-score. After removing missing data and outliers based on principal components (PC) analyses, 2860 samples were used for the GWAS study. The association between each single nucleotide polymorphism (SNP) and BMI was tested using linear regression adjusting for age, gender, and PC by cohort. The effects of SNPs were modeled assuming additive, recessive, and dominant effects of the minor allele. Meta-analysis was conducted using a weighted z-score approach. Results: The mean age of subjects was 9.8 years (range 2-19). The proportion of male subjects was 56%. In these cohorts, 14% of samples had a BMI ≥95 and 28 ≥ 85%. Meta analyses produced a signal at 16q12 genomic region with the best result of p = 1.43 × 10(-) (7) [p (rec) = 7.34 × 10(-) (8)) for the SNP rs8050136 at the first intron of FTO gene (z = 5.26) and with no heterogeneity between cohorts (p = 0.77). Under a recessive model, another published SNP at this locus, rs1421085, generates the best result [z = 5.782, p (rec) = 8.21 × 10(-) (9)]. Imputation in this region using dense 1000-Genome and Hapmap CEU samples revealed 71 SNPs with p < 10(-) (6), all at the first intron of FTO locus. When hetero-geneity was permitted between cohorts, signals were also obtained in other previously identified loci, including MC4R (rs12964056, p = 6.87 × 10(-) (7), z = -4.98), cholecystokinin CCK (rs8192472, p = 1.33 × 10(-) (6), z = -4.85), Interleukin 15 (rs2099884, p = 1.27 × 10(-) (5), z = 4.34), low density lipoprotein receptor-related protein 1B [LRP1B (rs7583748, p = 0.00013, z = -3.81)] and near transmembrane protein 18 (TMEM18) (rs7561317, p = 0.001, z = -3.17). We also detected a novel locus at chromosome 3 at COL6A5 [best SNP = rs1542829, minor allele frequency (MAF) of 5% p = 4.35 × 10(-) (9), z = 5.89]. Conclusion: An EMR linked cohort study demonstrates that the BMI-Z measurements can be successfully extracted and linked to genomic data with meaningful confirmatory results. We verified the high prevalence of childhood rate of overweight and obesity in our cohort (28%). In addition, our data indicate that genetic variants in the first intron of FTO, a known adult genetic risk factor for BMI, are also robustly associated with BMI in pediatric population.
    Frontiers in Genetics 01/2013; 4:268.
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    ABSTRACT: We used the Immunochip array to analyze 2,86 individuals with juvenile idiopathic arthritis (JIA), comprising the most common subtypes (oligoarticular and rheumatoid factor–negative polyarticular JIA), and 3,056 controls. We confirmed association of 3 known JIA risk loci (the human leukocyte antigen (HLA) region, PTPN22 and PTPN2) and identified 4 loci reaching genome-wide significance (P < 5 × 0 −8) for the first time. Eleven additional new regions showed suggestive evidence of association with JIA (P < × 0 −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 < × 0 −6) explain an estimated 8, 3 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. JIA is the most common chronic rheumatic disease of childhood and describes a group of clinically heterogeneous arthritides that begin before the age of 16 years, persist for at least 6 weeks and have an unknown cause 1 . It has been established that there is a strong genetic contribution to the risk of JIA, with a sibling risk ratio of ~11.6 (ref. 2) and higher risk for other autoimmune diseases in the families of individuals with JIA 3 . Using International League of Associations for Rheumatology (ILAR) criteria, JIA can be divided into subtypes on the basis of clinical features 4 . A recent genome-wide association study (GWAS) identified a number of JIA susceptibility regions 5,6 . Additional loci have been identified through candidate gene asso-ciation studies and confirmed in multiple independent studies 7–14 . However, until now, only three loci have reached genome-wide significance (the HLA region, PTPN22 and PTPN2) 5 . Many confirmed and nominally associated JIA susceptibility loci show association with other autoimmune diseases 5 . This marked overlap of autoimmune disease susceptibility loci may occur when Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis
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    ABSTRACT: Adiponectin is an obesity related protein that mediates the risk of type 2 diabetes in obese individuals with its anti-inflammatory and insulin-sensitizing properties. To date, five functional variations have been identified in the adiponectin gene. However, these variations are rare, and fail to fully explain adiponectin variability, suggesting unidentified causal variations exist. Thus, our objective was to identify novel, potentially functional amino acid-changing variations in ADIPOQ exonic regions and relate them to oligomeric forms of adiponectin in serum. We sequenced ADIPOQ exons in 30 adolescents chosen from a school-based cohort based on serum adiponectin and insulin levels. Four coding region changes were identified: a methionine initiation skip (MIS), P32L, R55C, and Y111H, of which R55C and Y111H have been previously identified. Individuals with the novel variations and R55C had low levels of adiponectin and decreased adiponectin oligomerization compared to adolescents with similar body mass index and insulin levels. Further, bioinformatic analysis predicted putative functionality of these variations. In our study, Y111H was unrelated to total circulating adiponectin or adiponectin oligomerization. Given the disruption of adiponectin oligomerization in the individuals with MIS, P32L, and R55C coding changes, these variations may lead to increased metabolic disease risk and warrant further examination in larger cohorts.
    SpringerPlus 12/2012; 1(1):66.
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    ABSTRACT: Context:Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively.Objectives:The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci.Design and Participants:Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls.Results:Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively.Conclusions:Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology.
    The Journal of Clinical Endocrinology and Metabolism 11/2012; · 6.31 Impact Factor
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    ABSTRACT: The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.
    The Journal of Immunology 08/2012; 189(6):3043-53. · 5.52 Impact Factor
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    ABSTRACT: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.
    Lupus 04/2012; 21(10):1113-8. · 2.78 Impact Factor
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    ABSTRACT: In a genome-wide association study of Caucasian patients with juvenile idiopathic arthritis (JIA), we have previously described findings limited to autoimmunity loci shared by JIA and other diseases. The present study was undertaken to identify novel JIA-predisposing loci using genome-wide approaches. The discovery cohort consisted of Caucasian JIA cases (n = 814) and local controls (n = 658) genotyped on the Affymetrix Genome-Wide SNP 6.0 Array, along with 2,400 out-of-study controls. In a replication study, we genotyped 10 single-nucleotide polymorphisms (SNPs) in 1,744 cases and 7,010 controls from the US and Europe. Analysis within the discovery cohort provided evidence of associations at 3q13 within C3orf1 and near CD80 (rs4688011) (odds ratio [OR] 1.37, P = 1.88 × 10(-6) ) and at 10q21 near JMJD1C (rs647989 [OR 1.59, P = 6.1 × 10(-8) ], rs12411988 [OR 1.57, P = 1.16 × 10(-7) ], and rs10995450 [OR 1.31, P = 6.74 × 10(-5) ]). Meta-analysis provided further evidence of association for these 4 SNPs (P = 3.6 × 10(-7) for rs4688011, P = 4.33 × 10(-5) for rs6479891, P = 2.71 × 10(-5) for rs12411988, and P = 5.39 × 10(-5) for rs10995450). Gene expression data on 68 JIA cases and 23 local controls showed cis expression quantitative trait locus associations for C3orf1 SNP rs4688011 (P = 0.024 or P = 0.034, depending on the probe set) and JMJD1C SNPs rs6479891 and rs12411988 (P = 0.01 or P = 0.04, depending on the probe set and P = 0.008, respectively). Using a variance component liability model, it was estimated that common SNP variation accounts for approximately one-third of JIA susceptibility. Genetic association results and correlated gene expression findings provide evidence of JIA association at 3q13 and suggest novel genes as plausible candidates in disease pathology.
    Arthritis & Rheumatology 02/2012; 64(8):2781-91. · 7.48 Impact Factor
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    ABSTRACT: Pediatric cardiomyopathy is a genetically het-erogeneous disease associated with significant morbidity. Although identification of underlying etiology is important for management, therapy, and screening of at risk family members, molec-ular diagnosis is difficult due to the large num-ber of causative genes, the high rate of private mutations, and cost. In this study, we aimed to define the genetic basis of pediatric cardiomy-opathy and test a novel diagnostic tool using a custom targeted microarray coupled to massive-ly parallel sequencing. Three patients with car-diomyopathy were screened using a custom NimbleGen sequence capture array containing 110 genes and providing 99.9% coverage of the exons of interest. The sensitivity and specificity was over 99% as determined by comparison to long-range polymerase chain reaction (PCR)-based massively parallel sequencing, Sanger sequencing of missense variants, and single nucleotide polymorphisms genotyping using the Illumina Infinium Omni1 array. Overall, 99.73% of the targeted regions were captured and sequenced at over 10x coverage, allowing reli-able mutation calling in all patients. Analysis identified a total of 165 non-synonymous coding single nucleotide polymorphisms (cSNPs) of which 89 were unique and 14 were novel. On average, each patient had 4 cSNPs predicted to be pathogenic. In conclusion, we report a car-diomyopathy sequencing array that allows simul-taneous assessment of 110 genes. Comparison of targeted sequence capture versus PCR-based enrichment methods demonstrates that the for-mer is more sensitive and efficient. Array-based sequence capture technology followed by mas-sively parallel sequencing is promising as a robust and comprehensive tool for genetic screening of cardiomyopathy. These results pro-vide important information about genetic archi-tecture and indicate that improved annotation of variants and interpretation of clinical signifi-cance, particularly in cases with multiple rare variants, are important for clinical practice.
    Cardiogenetics. 01/2012; 2(1).
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    ABSTRACT: To investigate secretor gene fucosyltransferase 2 (FUT2) polymorphism and secretor phenotype in relation to outcomes of prematurity. Study infants were ≤32 weeks gestational age. Secretor genotype was determined from salivary DNA. Secretor phenotype was measured with H antigen, the carbohydrate produced by secretor gene enzymes, in saliva samples collected on day 9 ± 5. The optimal predictive cutoff point in salivary H values was identified with Classification and Regression Tree analysis. Study outcomes were death, necrotizing enterocolitis (NEC, Bell's stage II/III), and confirmed sepsis. There were 410 study infants, 26 deaths, 30 cases of NEC, and 96 cases of sepsis. Analyzed by genotype, 13% of 95 infants who were non-secretors, 5% of 203 infants who were heterozygotes, and 2% of 96 infants who were secretor dominant died (P = .01). Analyzed by phenotype, 15% of 135 infants with low secretor phenotype died, compared with 2% of 248 infants with high secretor phenotype (predictive value = 76%, P < .001). Low secretor phenotype was associated (P < .05) with NEC, and non-secretor genotype was associated (P = .05) with gram negative sepsis. Secretor status remained significant after controlling for multiple clinical factors. Secretor genotype and phenotype may provide strong predictive biomarkers of adverse outcomes in premature infants.
    The Journal of pediatrics 05/2011; 158(5):745-51. · 4.02 Impact Factor
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    ABSTRACT: IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.
    The Journal of Immunology 03/2011; 186(8):4693-706. · 5.52 Impact Factor
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    British Journal of Haematology 01/2011; 152(6):780-3. · 4.94 Impact Factor
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    ABSTRACT: Using a small scale ENU mutagenesis approach we identified a recessive germline mutant, designated Lampe1 that exhibited growth retardation and spontaneous hepatosteatosis. Low resolution mapping based on 20 intercrossed Lampe1 mice revealed linkage to a ∼14 Mb interval on the distal site of chromosome 11 containing a total of 285 genes. Exons and 50 bp flanking sequences within the critical region were enriched with sequence capture microarrays and subsequently analyzed by next-generation sequencing. Using this approach 98.1 percent of the targeted DNA was covered with a depth of 10 or more reads per nucleotide and 3 homozygote mutations were identified. Two mutations represented intronic nucleotide changes whereas one mutation affected a splice donor site in intron 11-12 of Palmitoyl Acetyl-coenzyme A oxygenase-1 (Acox1), causing skipping of exon 12. Phenotyping of Acox1(Lampe1) mutants revealed a progression from hepatosteatosis to steatohepatitis, and ultimately hepatocellular carcinoma. The current approach provides a highly efficient and affordable method to identify causative mutations induced by ENU mutagenesis and animal models relevant to human pathology.
    PLoS ONE 01/2011; 6(7):e21979. · 3.53 Impact Factor
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    ABSTRACT: To test for associations between non-major histocompatibility complex susceptibility loci previously reported in autoimmune diseases and juvenile idiopathic arthritis (JIA). 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. 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, Crohn's disease, and multiple sclerosis. General susceptibility loci for autoimmunity are shared across diseases, including JIA, suggesting the potential for common therapeutic targets and mechanisms.
    Arthritis & Rheumatology 11/2010; 62(11):3265-76. · 7.48 Impact Factor
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    ABSTRACT: Copy number variants (CNVs) have recently been reported to be associated with several autoimmune conditions. Moreover, loci involved in immunity are enriched in CNVs. Therefore, we hypothesized that CNVs in immune genes associated with Graves' disease (GD) may contribute to the etiology of disease. One hundred ninety-one North American Caucasian GD patients and 192 Caucasian controls were analyzed for CNVs in three major immune regulatory genes: CD40, PTPN22, and CTLA-4. Copy number was determined using quantitative-PCR (Q-PCR) assays specifically designed for determining copy numbers in genomic DNA. Additionally, a well-characterized CNV in the amylase gene was typed in a separate dataset of DNA samples that were derived from cell lines or blood. No CNVs could be confirmed in the CD40 and CTLA-4 genes, even though a CD40 CNV is cataloged in the Database of Genomic Variants. Only the PTPN22 CNV was confirmed in our cohort, but it was rare and appeared in only two individuals. A key finding was that the source of DNA has a significant effect on CNV typing. There was a statistically significant increase in amylase locus deletions in cell line-derived DNA compared to blood-derived DNA samples. We conclude that CNV analysis should be performed only using blood-derived DNA Samples. Additionally, the CTLA-4, CD40, and PTPN22 loci do not harbor CNVs that play a role in the etiology of GD.
    Thyroid: official journal of the American Thyroid Association 11/2010; 21(1):69-74. · 2.60 Impact Factor
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    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2010; 24(10):1799-804. · 10.16 Impact Factor
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    ABSTRACT: To analyze the IBD5 locus in a homogenous cohort of Ashkenazi Jewish (AJ) children with Crohn disease (CD). A total of 83 AJ children with CD and 73 AJ healthy controls were studied. Genotyping for single nucleotide polymorphisms (SNPs) including OCTN1 (SLC22A4; 1672C-->T), OCTN2 (SLC22A5; 207G-->C), IGR2096, IGR2198, and IGR2230 genes was performed using the TaqMan system. NOD2/CARD15 variants also were typed using established methods. All IBD5 SNPs tested were in linkage disequilibrium (D'>0.8), and showed significant association with CD in our cohort of AJ children. The IGR2096 SNP, which is not located within the same linkage disequilibrium block as the OCTN1 and 2 SNPs, showed an even stronger association with CD (P = 0.017; odds ratio = 1.7). Patients with CD who had the OCTN1 susceptibility allele were more likely to carry 1 of the 3 NOD2/CARD15 SNPs tested (P = 0.01; odds ratio = 4.8). We have demonstrated a significant association between the IBD5 locus and CD in a homogenous cohort of pediatric AJ patients. Due to the tight linkage disequilibrium in the region, it is not possible to identify the causative IBD5 variant. Future functional studies will ultimately reveal the causative gene variant at this locus.
    Journal of pediatric gastroenterology and nutrition 06/2009; 48(5):531-7. · 2.18 Impact Factor
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    ABSTRACT: Spastic paraplegias (HSPs) and dystonias (DYTs) typically localize to different neuroanatomic systems. We report clinical and genetic data from large Ohio kindred with autosomal dominant (AD) HSP and DYT. Single and multipoint linkage using microsatellite and single nucleotide polymorphism array genotyping were performed on a large, multigenerational family with a novel, AD, highly penetrant neurological disease causing spasticity and DYT. Age of onset of spasticity and weakness is from the first year to the sixth decade, and age of onset of DYT from the first to third decade. There is no ataxia or apparent cognitive involvement. Neuroimaging and peripheral neurophysiology are normal. Generalized DYT improved markedly with deep brain stimulation in 1 child. The disease locus was mapped to a region on chromosome 2q 24-31, flanked by markers rs1424937-rs1559510, proximal to SPG13, in a region where there are no known HSP or DYT genes. A secondary analysis for candidate genes segregating with the DYT phenotype revealed two candidate regions with parametric lod scores above 2.0. On the basis of clinical presentation and linkage results, we conclude that this disease is a novel neurological disorder. Identifying the causative gene may elucidate an important pathway for pyramidal and extrapyramidal disorders.
    Movement Disorders 12/2008; 24(3):364-70. · 5.63 Impact Factor

Publication Stats

871 Citations
214.54 Total Impact Points

Institutions

  • 2005–2014
    • Cincinnati Children's Hospital Medical Center
      • • Department of Pediatrics
      • • Division of Human Genetics
      Cincinnati, Ohio, United States
  • 2010–2012
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, NY, United States
  • 2011
    • University of Cincinnati
      Cincinnati, Ohio, United States