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author:("shende, diti")
1.  Imputation of Class I and II HLA Loci using High-density SNPs from ImmunoChip and Their Associations with Kawasaki Disease in Family-based Study 
Kawasaki disease (KD) is the leading cause of acquired heart disease in children in most developed countries including the United States. The etiology of KD is not known; however, epidemiological and immunological data suggest infectious or immune-related factors in the manifestation of the disease. Further, KD has several hereditary features that strongly suggest a genetic component to disease pathogenesis. Human leukocyte antigen (HLA) loci have also been reported to be associated with KD but results have been inconsistent, in part, because of small study samples and varying linkage disequilibrium (LD) patterns observed across different ethnic groups. To maximize the informativeness of single nucleotide polymorphism (SNP) genotypes in the major histocompatibility (MHC) region, we imputed classical HLA I (A, B, C) and HLA II (DRB1, DQA1, DQB1) alleles using SNP2HLA method from genotypes of 6700 SNPs within the extended MHC region contained in the ImmunoChip among 112 white KD patients and their biological parents from North America and tested their association with KD susceptibility using the transmission disequilibrium test. Mendelian consistency in the trios suggested high accuracy and reliability of the imputed alleles (class I=97.5%, class II=96.6%). While several SNPs in the MHC region were individually associated with KD susceptibility, we report over-transmission of HLA-C*15 (z=+2.19, P=0.03) and under-transmission of HLA-B*44 (z=−2.49, P=0.01) alleles from parents to KD patients. HLA-B*44 has been associated with KD in other smaller studies and both HLA-C*15 and HLA-B*44 have biological mechanisms that could potentially be involved in KD pathogenesis. Overall, inferring HLA loci within the same ethnic group, using family based information is a powerful approach. However, larger families are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD.
PMCID: PMC4430380  PMID: 25809546
HLA imputation; Immunochip; Kawasaki disease; MHC
2.  High-density Genotyping of Immune Loci in Kawasaki Disease and IVIG Treatment Response in European-American Case-parent Trio Study 
Genes and immunity  2014;15(8):534-542.
Kawasaki disease (KD) is a diffuse and acute small-vessel vasculitis observed in children and has genetic and autoimmune components. We genotyped 112 case-parent trios of European decent (confirmed by AIMS) using the ImmunoChip array and performed association analyses with susceptibility to KD and IVIG non-response. KD susceptibility was assessed using the transmission disequilibrium test whereas IVIG non-response was evaluated using multivariable logistic regression analysis. We replicated SNPs in three gene regions (FCGR, CD40/CDH22, and HLA-DQB2/HLA-DOB) that have been previously associated with KD and provide support to other findings of several novel SNPs in genes with potential pathway in KD pathogenesis. SNP rs838143 in the 3′ UTR of FUT1 gene (2.7×10-5) and rs9847915 in the intergenic region of LOC730109 ∣ BRD7P2 (6.81×10-7) were the top hits for KD susceptibility in additive and dominant models, respectively. The top hits for IVIG responsiveness were rs1200332 in the intergenic region of BAZ1A ∣ C14orf19 (1.4×10-4) and rs4889606 in the intron of the STX1B gene (6.95×10-5) in additive and dominant models, respectively. Our study suggests that genes and biological pathways involved in autoimmune diseases play an important role in the pathogenesis of KD and IVIG response mechanism.
PMCID: PMC4257866  PMID: 25101798
Mucocutaneous lymph node syndrome; Kawasaki disease; intravenous immunoglobulins therapy; Immunogenetics; Immune-related genes
3.  Influence of Regular Physical Activity on Warfarin Dose and Risk of Hemorrhagic Complications 
Pharmacotherapy  2014;34(6):545-554.
To determine the influence of regular physical activity on stable warfarin dose and risk of major hemorrhage in patients on chronic anticoagulation therapy.
Design, setting and participants
Regular physical activity (maintained over >80% of visits) was ascertained by self-report at initiation of warfarin therapy (target INR = 2–3) in 1272 patients, with changes documented at monthly anticoagulation clinic visits in a population-based prospective cohort. Multi-variable linear regression and survival analysis, respectively, were used to assess influence on warfarin and risk of hemorrhage.
Warfarin dose (mg/day) and major hemorrhage.
There were 683 (53.7%) patients who were regularly physically active (≥30 minutes ≥3 times/week). Physically active patients required warfarin doses that were 6.9% higher (p=0.006) than in physically inactive patients after controlling for sociodemographic factors, vitamin K intake, clinical factors, and genetic variations.
The overall incidence of major hemorrhagic events was 7.6/100 person-years (p-yrs) (95% CI: 6.4 –8.9) in our population. The incidence was lower for physically active patients (5.6/100p-yrs; 95% CI: 4.2–7.2) than in inactive patients (10.3/100 p-yrs; 95% CI: 8.2–12.9; p=0.0004). Active patients had a 38% lower risk of hemorrhage (HR: 0.62; 95% CI: 0.42–0.98; p= 0.03) compared to inactive patients.
Regular physical activity is associated with higher warfarin dose requirements and lower risk of hemorrhage. The influence of physical activity on drug response needs to be further explored, and the mechanisms through which it exerts these effects need to be elucidated.
PMCID: PMC4109410  PMID: 25032265
Physical activity; warfarin; dose; bleeding risk; major hemorrhage
4.  FcγR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response 
Pharmacogenetics and genomics  2013;23(9):455-462.
Kawasaki disease (KD), response to intravenous immunoglobulin (IVIG) therapy, and associated coronary artery disease progression have been associated with genetic polymorphisms in Fc gamma receptor (FcγR) genes. However, it is not known whether the existing gene copy number (GCN) variability relates to KD treatment response, susceptibility, or associated sequelae.
The copy number of individuals with KD (n = 510) and their family members (n = 808) for three variable FcγRs was assessed using pyrosequencing. We performed the transmission disequilibrium test to examine the association of GCN for FcγRs (FcγR2C, FcγR3A, and FcγR3B) with susceptibility and used logistic regression models to determine its association with IVIG treatment outcomes.
FcγR2C and FcγR3B GCN were significantly associated with KD susceptibility. IVIG response was associated with GCN variations of FcγR3B in Whites and FcγR2C in Hispanics, and gene risk score based on single nucleotide polymorphism and GCN in FcγRs were significantly different between IVIG responders and nonresponders among Whites. We found no significant associations between coronary artery disease and any of the FcγR copy numbers.
GCN of FcγR2C and FcγR3B influences IVIG treatment response and predisposes individuals to KD, providing potential insights into understanding the mechanism of the FcγR gene family in the IVIG pathway.
PMCID: PMC4400828  PMID: 23778324
copy number variation; FcγR; genetic risk; intravenous immunoglobulin; Kawasaki disease
5.  RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women’s Interagency HIV Study (WIHS) 
Atherosclerosis  2014;233(2):666-672.
Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women’s Interagency HIV Study (WIHS).
CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel’s method and haplotype association analyses were conducted among the three races separately.
SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41× 10−5), rs11856930 among Whites (p=5.62× 10−4), and rs2572204 among Blacks (p=2.45× 10−3). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics.
Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.
PMCID: PMC3965606  PMID: 24561552
RYR3; single nucleotide polymorphisms; HIV infection; CCA; cIMT; subclinical atherosclerosis
6.  Variants in Interleukin Family of Cytokines Genes Influence Clearance of High Risk HPV in HIV-1 Coinfected African-American Adolescents 
Human immunology  2013;74(12):10.1016/j.humimm.2013.08.010.
Our work aimed to examine the potential influence of variants in interleukin/interleukin receptors genes on high-risk (HR-HPV) HPV clearance. Clearance of genital HR-HPV infection was evaluated for 134 HIV-1 seropositive African-American female adolescents from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort. Genotyping targeted 225 single nucleotide polymorphisms (SNPs) within the exons, 5′ untranslated region (UTR) and 3′ UTR sequences of 27 immune-related candidate genes encoding interleukin family of cytokines. Cox proportional hazard models were used to determine the association of type- specific HPV clearance adjusting for time-varying CD4+ T-cell count and low-risk (LR-HPV) HPV co-infections. HR-HPV clearance rates were significantly (p< 0.001) associated with five SNPs (rs228942, rs419598, rs315950, rs7737000, rs9292618) mapped to coding and regulatory regions in three genes (IL2RB, IL1RN, and IL7R). These data suggest that the analyzed genetic variants in interleukin family of cytokines modulate HR-HPV clearance in HIV-1 seropositive African-Americans that warrants replication.
PMCID: PMC3842375  PMID: 23973891
HPV clearance; genetic association; interleukins; HIV-1 seropositive; African American adolescents
7.  DC-SIGN gene promoter variants and IVIG treatment response in Kawasaki disease 
Genetic variants in the inhibiting FcγRIIB mediate anti-inflammatory responses and influence IVIG refractoriness (IVIG-R). However, these variants are rare in Asian and Hispanic populations so other genes in the pathway could be potentially involved. IVIG is ineffective in mice lacking SIGN-R1, a related molecule to human DC-SIGN. Further, DC-SIGN is a known receptor for sialylated Fc, the component responsible for the anti-inflammatory action of IVIG. Thus, we hypothesized that DC-SIGN would also be involved in the pathway of IVIG response in Kawasaki Disease (KD) patients.
A case-control approach was performed to examine the differential distribution of five single nucleotide polymorphisms (SNPs) in DC-SIGN promoter with IVIG-R among White (158 vs. 62), Asian (64 vs. 12) and Hispanic (55 vs. 20) KD patients. Distinct differences in allele frequency distributions of several variants in the DC-SIGN promoter were observed in the three ethnic groups. Further, Asians with the major allele “A” in rs2287886 were more likely (OR = 1.76, p = 0.04) to be IVIG non-responder, but this allele is a minor allele in other two ethnic groups, where the association was not apparent.
DC-SIGN can potentially complement the role of FcγRIIB in the anti-inflammatory cascade involved in the IVIG response mechanism.
PMCID: PMC3847673  PMID: 24006904
Kawasaki disease; IVIG treatment response; FcγR; Coronary artery disease; DC-SIGN
8.  Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response 
A functional polymorphism in the inhibitory IgG-Fc receptor FcγRIIB influences intravenous immunoglobulin (IVIG) response in Kawasaki Disease (KD) a vasculitis preferentially affecting the coronary arteries in children. We tested the hypothesis that the polymorphisms in the activating receptors (Fcγ RIIA, Fcγ RIIIA and Fcγ RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease (CAD) in KD patients.
Methods and Results
We genotyped polymorphisms in the activating FcγRIIA, FcγRIIIA and FcγRIIIB genes using pyrosequencing in 443 KD patients, including 266 trios and 150 single parent-child pairs, in northwest US and genetically determined race with 155 ancestry information markers. We used the FBAT program to test for transmission disequilibrium and further generated pseudo-sibling controls for comparisons to the cases. The FcγRIIA-131H variant showed an association with KD (p = 0.001) with ORadditive = 1.51 [1.16–1.96], p = 0.002) for the primary combined population, which persisted in both Caucasian (p = .04) and Asian (p = .01) subgroups and is consistent with the recent genome-wide association study. We also identified over-transmission of FcγRIIIB-NA1 among IVIG non-responders (p = 0.0002), and specifically to Caucasian IVIG non-responders (p = 0.007). Odds ratios for overall and Caucasian non-responders were respectively 3.67 [1.75–7.66], p = 0.0006 and 3.60 [1.34–9.70], p = 0.01. Excess NA1 transmission also occurred to KD with CAD (ORadditive = 2.13 [1.11–4.0], p = 0.02).
A common variation in FcγRIIA is associated with increased KD susceptibility. The FcγRIIIB-NA1, which confers higher affinity for IgG compared to NA2, is a determining factor for treatment response. These activating FcγRs play an important role in KD pathogenesis and mechanism of IVIG anti-inflammatory.
PMCID: PMC3444514  PMID: 22565545
coronary disease; pediatrics; Kawasaki disease; IVIG treatment response; FcγR
9.  Interleukin-10 (IL-10) Pathway: Genetic Variants and Outcomes of HIV-1 Infection in African American Adolescents 
PLoS ONE  2010;5(10):e13384.
Immunological and clinical outcomes can vary considerably at the individual and population levels during both treated and untreated HIV-1 infection. Cytokines encoded by the interleukin-10 gene (IL10) family have broad immunomodulatory function in viral persistence, and several SNPs in the IL10 promoter sequence have been reported to influence pathogenesis or acquisition of HIV-1 infection.
Methodology/Principal Findings
We examined 104 informative SNPs in IL10, IL19, IL20, IL24, IL10RA and IL10RB among 250 HIV-1 seropositive and 106 high-risk seronegative African American adolescents in the REACH cohort. In subsequent evaluation of five different immunological and virological outcomes related to HIV-1 infection, 25 SNPs were associated with a single outcome and three were associated with two different outcomes. One SNP, rs2243191 in the IL19 open reading frame (Ser to Phe substitution) was associated with CD4+ T-cell increase during treatment. Another SNP rs2244305 in IL10RB (in strong linkage disequilibrium with rs443498) was associated with an initial decrease in CD4+ T-cell by 23±9% and 29±9% every 3 months (for AA and AG genotypes, respectively, compared with GG) during ART-free period. These associations were reversed during treatment, as CD4+ T-cell increased by 31±0.9% and 17±8% every 3 months for AA and AG genotype, respectively.
In African Americans, variants in IL10 and related genes might influence multiple outcomes of HIV-1 infection, especially immunological response to HAART. Fine mapping coupled with analysis of gene expression and function should help reveal the immunological importance of the IL10 gene family to HIV-1/AIDS.
PMCID: PMC2954785  PMID: 20976276

Results 1-9 (9)