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Biomedical subjects

Subra Kugathasan

Publications and source records attributed to Subra Kugathasan.

At least 19 recordsLinked to original sources
PubMed2020

PTSD is associated with increased DNA methylation across regions of HLA-DPB1 and SPATC1L.

Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, avoidance, negative alterations in cognitions and mood, and arousal symptoms that adversely affect mental and physical health. Recent evidence links changes in DNA methylation of CpG cites to PTSD. Since clusters of proximal CpGs share similar methylation signatures, identification of PTSD-associated differentially methylated regions (DMRs) may elucidate the pathways defining differential risk and resilience of PTSD. Here we aimed to identify epigenetic differences associated with PTSD. DNA methylation data profiled from blood samples using the MethylationEPIC BeadChip were used to perform a DMR analysis in 187 PTSD cases and 367 trauma-exposed controls from the Grady Trauma Project (GTP). DMRs were assessed with R package bumphunter. We identified two regions that associate with PTSD after multiple test correction. These regions were in the gene body of HLA-DPB1 and in the promoter of SPATC1L. The DMR in HLA-DPB1 was associated with PTSD in an independent cohort. Both DMRs included CpGs whose methylation associated with nearby sequence variation (meQTL) and that associated with expression of their respective genes (eQTM). This study supports an emerging literature linking PTSD risk to genetic and epigenetic variation in the HLA region.

Cytoskeletal Proteins↗
PubMed2006

DLG5 R30Q variant is a female-specific protective factor in pediatric onset Crohn's disease.

OBJECTIVE: A significant association between the DLG5 variant (R30Q) and inflammatory bowel disease (IBD) has been confirmed in several independent adult IBD cohorts. There is growing evidence that gender significantly influences R30Q susceptibility in Crohn's disease (CD). Pediatric onset CD features a significantly lower incidence for female children compared with male children. We, therefore, studied the influence of gender on R30Q susceptibility in an exclusively pediatric onset IBD cohort. DESIGN: A total of 281 CD (181 trios) and 479 population-based controls were genotyped for DLG5 R30Q using Taqman assay. Association was tested by case-control and transmission disequilibrium testing analysis. Multivariate logistic regression was performed to investigate gene-gene and gene-gender interactions, as well as genotype-phenotype correlations. RESULTS: Overall allele frequency for R30Q was 8.5% in CD and 10.3% in controls. Logistic regression showed R30Q had no association with CD (OR 0.81, 95% CI 0.55-1.20, P= 0.3) when the cohort was analyzed as a whole. Stratified by gender, a significant negative association was detected for R30Q in female children (OR 0.39, 95% CI 0.2-0.77, P= 0.006), but not in male children. Gender was found to be an effect modifier of the association between R30Q and CD as the odds ratios in female children and male children differed significantly. The gender-specific association of R30Q and CD was independent of additional CD risk factors such as CARD15 and IBD5. CONCLUSIONS: DLG5 has a gender-specific role in the susceptibility of pediatric CD. Specifically, the significant negative association found between DLG5 R30Q and CD in female children suggests DLG5 may have a protective effect in CD susceptibility for female children.

Age of Onset↗
PubMed2006

Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease.

BACKGROUND & AIMS: The aim of this study was to describe 3-month and 1-year outcomes of children with Crohn's disease (CD) treated with corticosteroids within 30 days of diagnosis, with particular emphasis on the influence of infliximab on these outcomes. We also aimed to determine whether there are clinical or laboratory characteristics associated with corticosteroid therapy outcomes. METHODS: Data from 109 children were drawn from a multicenter observational registry that was started in 2002. Clinical characteristics and data on corticosteroid and other therapies were recorded prospectively. Corticosteroid therapy outcomes at 3 months were defined as complete acute response, partial response, or corticosteroid resistance. At 1 year, corticosteroid responsiveness, dependence, and surgical rates were determined. Infliximab's influence on short- and long-term outcomes also was investigated. RESULTS: At 3 months, 65 of 109 (60%) patients had a complete acute response to corticosteroids, 26 (24%) had a partial response, and 18 (17%) were corticosteroid resistant. At 1 year, 61% were corticosteroid responsive, 31% were corticosteroid dependent, and 8% required surgery. Irrespective of the duration of corticosteroid treatment, 16 of 24 of corticosteroid-dependent/resistant patients rapidly discontinued corticosteroids after starting infliximab. No clinical or laboratory characteristics at diagnosis predicted short-term outcome. Growth impairment at diagnosis increased risk for corticosteroid dependence or surgery at 1 year. CONCLUSIONS: At 3 months, 84% of children had a complete or partial response to corticosteroids. However, despite concomitant immunomodulators, at 1 year 31% were corticosteroid dependent and 8% required surgery. Infliximab improves outcomes of corticosteroid-dependent/resistant patients because the duration of corticosteroid use can be controlled by initiating treatment with infliximab.

Adolescent↗
PubMed2006

The natural history of corticosteroid therapy for ulcerative colitis in children.

BACKGROUND & AIMS: The aim of this study was to determine the clinical outcome after corticosteroid therapy in children who are newly diagnosed with ulcerative colitis (UC). METHODS: Data were gathered prospectively from the Pediatric Inflammatory Bowel Disease Collaborative Research Group Registry database between January 2002 and March 2005. All children who were newly diagnosed with inflammatory bowel disease younger than the age of 16 years were managed according to the dictates of their respective physicians. Demographic, clinical, and laboratory data were collected at diagnosis, at 30 days, and then quarterly. Patients were classified as corticosteroid responsive, corticosteroid dependent, or refractory, and outcomes were determined at 3 months and at 1 year. RESULTS: Ninety-seven patients had a diagnosis of UC and a minimum of 1 year of follow-up evaluation; 77 (79%) received corticosteroids (62 within 30 days of diagnosis [early] and 15 between 31 days and 6 months [late]). At diagnosis, 81% of corticosteroid-treated patients (age, 11.3 +/- 3.5 y) had moderate/severe disease, and 81% had pancolitis. For those treated early with corticosteroids, disease activity at 3 months was inactive in 60%, mild in 27%, and moderate/severe in 11%. At 1 year, 31 of 62 (50%) of the early corticosteroid-treated patients were considered corticosteroid responsive and 28 (45%) were corticosteroid dependent. A total of 4 patients receiving corticosteroids (5%) required colectomy in the first year. Immunomodulators were used in 61% of all corticosteroid-treated patients. CONCLUSIONS: Although short-term clinical response to corticosteroids in children with newly diagnosed UC is excellent, even with the common use of immunomodulators corticosteroid dependence is seen in 45% of patients.

Adolescent↗
PubMed2006

Evidence of transmission ratio distortion of DLG5 R30Q variant in general and implication of an association with Crohn disease in men.

Recently, we described the association of genetic variation in the discs large homolog 5 (DLG5) gene with inflammatory bowel disease (IBD) in a large European study sample (Stoll et al. in Nat Genet 36:476-480, 2004). Here, we report that the R30Q variant constitutes a susceptibility factor for Crohn disease (CD) in men [odds ratio (OR)=2.49, 95% confidence interval (CI) 1.53-4.06, P<0.001] but not women (OR=1.01, 95% CI=0.70-1.45, P=0.979) using multivariate logistic regression analyses in a unified study sample from Germany, Italy and Quebec. R30Q is a significant predictor for CD in men even when accounting for CARD15 and IBD5 risk variants (adjusted OR=2.41, 95% CI=1.41-4.12, P=0.001). The observed association is driven by a gender-dependent transmission ratio distortion (TRD) among healthy controls (frequency of Q allele: men 5.2%, women 11.3%), an effect that is offset in CD patients (frequency of Q allele: men 10.1%, women 10.9%). This finding is further substantiated by two non-IBD study samples, one of which consists of a newborn screening sample (newborn males 7.1%; newborn females 11%, P=0.036). Further investigation of the observed TRD may contribute towards enlightening the role of DLG5 in physiological processes influencing transmission of chromosomes to the surviving offspring, which, in turn, may help in understanding its implication in the development of CD among men.

Adult↗
PubMed2006

Inflammatory bowel disease--environmental modification and genetic determinants.

Inflammatory bowel disease (IBD) is a complex disease, controlled by multiple risk factors that evolve and interact together. In a genetically susceptible host, there are multiple processing steps controlled by the host and the environment, from environmental exposure to the clinical and biological expression of IBD-related phenotypes. This article discusses the recent genetic discoveries, along with the proposed environmental risk factors that have been implicated in IBD. Technical advances of the HapMap project and the promise of whole genome association scans have given hopes for clarifying gene-environmental interactions in IBD that ultimately lead to a clearer understanding of the pathogenesis.

Child↗
PubMed2006

Functional genomics and its implications for molecular medicine.

Technological development in genetics and genomics provides unprecedented possibilities to identify the underlying molecular basic of many common diseases. With the availability of the human genome sequence and growing information on the most frequent DNA variations combined with the molecular analysis on the RNA expression and protein level, diseases might be characterized in the future at the molecular level. Describing gene function anf the specific role of DNA, RNA, and proteins in the disease process provides novel diagnosis tools and treatment. Ultimately how the unique genetic signature of an individual influences the risk and prognosis of disease will be the basis for individualized medicine in the years to come.

DNA Mutational Analysis↗
PubMed2006

Health-related quality of life in the first year after a diagnosis of pediatric inflammatory bowel disease.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is of increasing importance in the evaluation of new therapies for inflammatory bowel disease (IBD). Available data concerning HRQOL in pediatric patients are sparse and uniformly cross-sectional. The aim of this study was to describe HRQOL and influential factors in newly diagnosed pediatric patients with Crohn's disease and ulcerative colitis during the first 12 months after diagnosis. MATERIALS AND METHODS: Participants were drawn from a large, prospectively derived observational IBD registry of pediatric patients studied through 18 U.S. and Canadian centers. Patients who had completed a baseline IMPACT questionnaire and for whom there were 12 months of follow-up data available were included. In addition to description of cohort, factors that were believed to influence HLQOL were assessed during the course of the year from diagnosis. RESULTS: Two hundred eighteen children met inclusion criteria (77% Crohn's disease, 23 % ulcerative colitis, mean age 12.7 +/- 1.9 years). Mean total IMPACT score at baseline was 154, 181 at 6 months, and 191 at 1 year (possible range 0-238, with increasing scores representing better quality of life). Repeated measures analysis showed that age and disease severity significantly negatively affected the IMPACT scores during the course of the year. CONCLUSIONS: In this large prospective pediatric IBD cohort, significant improvement in HRQOL is noted during the year from diagnosis. Mean IMPACT scores varied significantly depending on the disease severity and also decreased with increasing age.

Adolescent↗
PubMed2006

Challenges in pediatric inflammatory bowel disease.

It is estimated that of the >1 million individuals in the United States with inflammatory bowel disease (IBD), approximately 100,000 are children. IBD that begins in childhood affects the individual at a critical period of growth and development. Children with Crohn's disease and ulcerative colitis may experience complications such as growth failure, school absence, and depression. In addition, because children with IBD have fewer environmental confounders such as smoking, children may be an excellent population to study microbial and immune interactions. Despite these opportunities, the discipline of pediatric IBD investigation is still in its infancy. In September of 2005, a group of investigators with expertise in pediatric IBD met in Boston (Massachusetts) to review the current status of childhood IBD research and to develop research priorities that warranted funding from the Crohn's and Colitis Foundation of America. The group included pediatricians, internists, basic scientists, clinical investigators, and members of the administrative staff and board of the Crohn's and Colitis Foundation of America. The research needs in respective areas were outlined by the heads of 10 focus groups, each with expertise in their respective fields (genetics, psychosocial issues, epidemiology, microbiology, immunology, quality improvement, pharmacogenomics, nutrition, growth and skeletal health, and clinical trials). Before the conference, heads of the research focus groups developed their proposals with experts in the field. At the end of the conference, members of the focus groups and members of the steering committee rated the proposed areas of study in terms of feasibility and importance. It was recommended that the Crohn's and Colitis Foundation of America focus its initial efforts in pediatric IBD in 5 areas: the effects of inflammation on growth and skeletal development, the genetics of early-onset IBD, the development of quality improvement interventions to standardize and improve clinical care of children with IBD, the immunology of childhood IBD, and the diagnosis and treatment of psychosocial sequelae of childhood IBD. At the conclusion of the meeting, investigators discussed the formation of a multicenter collaborative network to advance clinical and basic research in the field.

Child↗
PubMed2006

Molecular stratification of Crohn's disease by chemokine receptors: fractalkine receptor polymorphisms define a fibrostenosing ileal subgroup.

The association of NOD2/CARD15 gene mutations with Crohn's disease (CD) has also provided proof of principle that anatomic location (ileal disease) and stricturing behavior is associated with specific genetic variants. However, the majority of CD patients of Caucasian descent, and essentially all minority CD patients do not possess NOD2/CARD15 mutations. Although these early lessons from NOD2/CARD15 genotype/phenotype correlations are encouraging, much more needs to be done to adequately understand the CD spectrum of subgroups. The study by Brand et al. demonstrates that a chemokine receptor polymorphism (CX3CR1 T280) can also influence disease location and behavior, suggesting yet another genetic variant that can help to subgroup CD patients. Findings similar to the study by Brand and colleagues in this issue of American Journal of Gastroenterology suggest that panels of susceptibility alleles and polymorphisms will ultimately allow an early genetic determination that will correspond with unique clinical patterns of CD: increased expression of the chemokine fractalkine in Crohn's disease and association of the factalkine receptor T280M polymorphism with a fibrostenosing disease phenotype.

CX3C Chemokine Receptor 1↗
PubMed2006

Contribution of OCTN variants within the IBD5 locus to pediatric onset Crohn's disease.

BACKGROUND & AIMS: The IBD5 locus on chromosome 5q31 is a confirmed Crohn's disease (CD) susceptibility locus in adults. Recently, two polymorphisms in the organic cation transporter (OCTN) gene cluster within the IBD5 locus have been found to be associated with CD. Although the original report of significant linkage to IBD5 was in families with at least one case of early age at onset CD, there are no published reports on the role of OCTN genes in pediatric onset CD. We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations. METHODS: 264 Caucasian CD children (172 of them were trios) were genotyped along with 527 controls for OCTN1 (SLC22A4 C1672T), OCTN2 (SLC22A5 G-207C), and two haplotype-tagging SNPs (IGR2230 and IGR2198). RESULTS: TDT confirmed the association of SLC22A4 and SLC22A5. Case-control analysis of the SLC22A4 1672T, SLC22A5-207C diplotype showed significant association (p=0.04) with CD susceptibility compared with controls. Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype. There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs. CONCLUSIONS: We confirm the association of the OCTN variants (SLC22A4 and SLC22A5) in pediatric onset CD as seen in adult CD cohorts. However, when an extended IBD5 haplotype was examined, no independent association between OCTN variants and pediatric onset CD can be demonstrated. Compared with adults, a relatively weak association of the OCTN variants was observed in our CD cohort. No definitive genotype-phenotype correlation or gene-gene interactions with CARD15 were observed. Although the IBD5 locus is associated with pediatric onset CD, no definitive conclusions can be drawn about OCTN variants as causative genes in pediatric CD at this point.

Child↗
PubMed2005

Asymptomatic inflammatory bowel disease presenting with mucocutaneous findings.

Although inflammatory bowel disease (IBD) typically presents with gastrointestinal complaints, mucocutaneous lesions are commonly associated and can precede gastrointestinal symptoms, thereby alerting the clinician to the diagnosis of IBD before the onset of gastrointestinal symptoms. Nine children are reported who had no gastrointestinal symptoms suggestive of IBD but presented with mucocutaneous findings of IBD and were subsequently diagnosed with Crohn's disease or ulcerative colitis based on characteristic features on gastrointestinal endoscopy and/or biopsies. The majority of the patients had oral and perianal lesions. We believe that IBD is a common etiology for persistent oral lesions in the pediatric population. In addition to a good history, children with unexplained oral mucous membrane lesions should have an examination of the rectal and genital mucosa as well as tests for complete blood count, iron levels, sedimentation rate, albumin, and occult blood in the stool with endoscopy and biopsies to rule out IBD if indicated.

Child↗
PubMed2005

Comparative phenotypic and CARD15 mutational analysis among African American, Hispanic, and White children with Crohn's disease.

BACKGROUND: Despite a large body of literature on the subject of Crohn's disease (CD), very little information is available on racial/ethnic differences related to disease presentation, clinical course, and genetics. The first identified CD susceptibility gene, CARD15, seems to be present in up to 40% of white children with CD. However, the frequency of this gene among patients with CD of other racial/ethnic groups in the United States is not known. METHODS: We conducted a multicenter study on African American and Hispanic children with CD to describe the phenotypic and genotypic (CARD15) features in comparison with white children with CD. We also analyzed the frequency of CARD15 mutations in large control samples from white, African American, and Hispanic children. RESULTS: The disease location and behavior were similar among all 3 groups, with inflammatory behavior and the ileocolonic location being the most frequent phenotype. However, significantly lower frequencies of CARD15 mutations were seen in African American (P < 0.0001) and Hispanic (P < 0.0001) children with CD compared with white children with CD. This lower CARD15 frequency among African American patients with CD was also mirrored in the general population. CONCLUSIONS: Phenotypic features of CD are similar among African American and Hispanic children compared with white children. CARD15 mutations are not increased among African American and Hispanic children with CD. CARD15 mutational frequencies among African American and Hispanic children within the general population are lower compared with white children within the general population. Future genetics studies will be required to determine the relationships between genotype and CD phenotype in various ethnic and racial groups.

Adolescent↗
PubMed2005

A randomized, double-blind trial of Lactobacillus GG versus placebo in addition to standard maintenance therapy for children with Crohn's disease.

Probiotics are widely used by patients with Crohn's disease (CD) in an attempt to improve their health, but few controlled studies have been done to evaluate the efficacy of these therapies. We conducted a randomized, placebo-controlled trial of the probiotic Lactobacillus rhamnosus strain GG (LGG) to see if the addition of LGG to standard therapy prolonged remission in children with CD. Concomitant medications allowed in the study included aminosalicylates, 6-mercaptopurine, azathioprine, and low-dose alternate day corticosteroids. Seventy-five children (age range, 5-21 yr) with CD in remission were randomized to either LGG (n=39) or placebo (n=36) and followed for up to 2 years. The median time to relapse was 9.8 months in the LGG group and 11.0 months in the placebo group (P=0.24); 31% (12/39) of patients in the LGG group developed a relapse compared with 6/36 (17%) of the placebo group (P=0.18). The LGG was well tolerated, with a side effect profile comparable with placebo. This study suggests that LGG does not prolong time to relapse in children with CD when given as an adjunct to standard therapy.

Adolescent↗
PubMed2005

Evaluation of the pediatric crohn disease activity index: a prospective multicenter experience.

BACKGROUND AND OBJECTIVES: Longitudinal assessment of disease activity is necessary for studies of therapeutic intervention in children with Crohn disease. The Pediatric Crohn Disease Activity Index (PCDAI) was developed a decade ago for such a purpose, but it function has only been examined in a small number of studies with a limited number of patients. The primary objectives of the present study were to develop cut scores reflecting disease activity as determined by physician global assessment (PGA) and to evaluate the responsiveness of the PCDAI to changes in patient condition after therapeutic interventions. METHODS: Data were derived from a prospective database of newly diagnosed children with inflammatory bowel disease established in 2002 at 18 pediatric gastroenterology centers in the United States and Canada. At diagnosis, at 30 days and 3 months after diagnosis, and quarterly thereafter, children (<16 years of age) with Crohn disease had disease assessment performed by PGA and PCDAI. Disease management was provided according to the dictates of the attending gastroenterologist and not by predetermined protocol. RESULTS: 181 patients had concomitant PGA and PCDAI performed at diagnosis, and 95 of these had similar assessment at short-term follow up. Mean +/- SD PCDAI scores for mild, moderate, and severe disease by PGA at diagnosis were 19.5 +/- 10.4, 32.2 +/- 12.7, and 47.8 +/- 14.9, respectively (P < 0.001 for all comparisons). Mean +/- SD PCDAI for inactive disease after treatment was 5.2 +/- 5.4. Receiver operating characteristic (ROC) curve analysis suggested that: 1) activity of moderate/severe disease was best reflected by a PCDAI of > or = 30 points, 2) clinical response (moderate/severe disease improving to mild/inactive) was best reflected by a decrease in PCDAI of > or = 12.5 points, and 3) a PCDAI < 10 best reflected inactive disease. CONCLUSIONS: PCDAI scores accurately reflect disease activity as assessed by physician global assessment. A PCDAI score of > or = 30 has acceptable sensitivity and specificity to indicate disease of moderate/severe activity. A PCDAI decrease of 12.5 points or greater following therapeutic intervention accurately reflects a clinically significant response. The PCDAI is an appropriate tool for intervention trials in Crohn disease in children.

Child↗
PubMed2004

Inflammatory bowel disease.

Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD) are idiopathic, life-long, destructive chronic inflammatory conditions of the gastrointestinal tract that typically manifest during late childhood and adolescence. These chronic relapsing diseases may have devastating effects on patients. New medical progress in IBD includes genetics, gut ecology and microflora, immune mechanisms, and targeted biologic therapies. This article reviews the current understanding of the etiopathogenesis of IBD, the emerging epidemiologic data in pediatric IBD, clinical presentations, diagnostic evaluation, distinctions between adult and pediatric-onset disease, and a comprehensive review of both conventional and new therapies, highlighting age-specific issues such as growth, sexual delay, and psychological and behavioral health.

Adolescent↗