Aditi Shendre

Race influences warfarin dose changes associated with genetic factors

Warfarin dosing algorithms adjust for race, assigning a fixed effect size to each predictor, thereby attenuating the differential effect by race. Attenuation likely occurs in both race groups but may be more pronounced in the less-represented race group. Therefore, we evaluated whether the effect of clinical (age, body surface area [BSA], chronic kidney disease [CKD], and amiodarone use) and genetic factors (CYP2C9*2, *3, *5, *6, *11, rs12777823, VKORC1, and CYP4F2) on warfarin dose differs by race using regression analyses among 1357 patients enrolled in a prospective cohort study and compared predictive ability of race-combined vs race-stratified models. Differential effect of predictors by race was assessed using predictor-race interactions in race-combined analyses. Warfarin dose was influenced by age, BSA, CKD, amiodarone use, and CYP2C9*3 and VKORC1 variants in both races, by CYP2C9*2 and CYP4F2 variants in European Americans, and by rs12777823 in African Americans. CYP2C9*2 was associated with a lower dose only among European Americans (20.6% vs 3.0%, P < .001) and rs12777823 only among African Americans (12.3% vs 2.3%, P = .006). Although VKORC1 was associated with dose decrease in both races, the proportional decrease was higher among European Americans (28.9% vs 19.9%, P = .003) compared with African Americans. Race-stratified analysis improved dose prediction in both race groups compared with race-combined analysis. We demonstrate that the effect of predictors on warfarin dose differs by race, which may explain divergent findings reported by recent warfarin pharmacogenetic trials. We recommend that warfarin dosing algorithms should be stratified by race rather than adjusted for race.

Role of Activating FcγR Gene Polymorphisms in Kawasaki Disease Susceptibility and Intravenous Immunoglobulin Response

Background— A functional polymorphism in the inhibitory IgG-Fc receptor gene Fc&ggr;RIIB 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 (Fc&ggr;RIIA, Fc&ggr;RIIIA, and Fc&ggr;RIIIB) also influence susceptibility, IVIG treatment response, and coronary artery disease in patients with KD. Methods and Results— We genotyped polymorphisms in the activating Fc&ggr;RIIA, Fc&ggr;RIIIA, and Fc&ggr;RIIIB using pyrosequencing in 443 patients with KD, including 266 trios and 150 single parent-child pairs, in northwest United States and genetically determined race with 155 ancestry informative markers. We used family-based association to test for transmission disequilibrium and further generated pseudosibling controls for comparisons with the cases. The Fc&ggr;RIIA-131H variant showed an association with KD (P=0.001) with an additive odds ratio (OR) of 1.51 (95% CI, 1.16–1.96; P=0.002) for the primary combined population, which persisted in both white (P=0.04) and Asian (P=0.01) subgroups and is consistent with the recent genome-wide association study. We also identified overtransmission of the Fc&ggr;RIIIB neutrophil antigen 1 (NA1) variant among IVIG nonresponders (P=0.0002) and specifically to white IVIG nonresponders (P=0.007). ORs for overall and white nonresponders were 3.67 (95% CI, 1.75–7.66; P=0.0006) and 3.60 (95% CI, 1.34–9.70; P=0.01), respectively. Excess NA1 transmission also occurred in patients with KD with coronary artery disease (ORadditive, 2.13; 95% CI, 1.11–4.0; P=0.02). Conclusions— A common variation in Fc&ggr;RIIA is associated with increased KD susceptibility. The Fc&ggr;RIIIB-NA1 variant, which confers higher affinity for IgG than the NA2 variant, is a determining factor for treatment response. These activating Fc&ggr;Rs play an important role in KD pathogenesis and the IVIG antiinflammatory mechanism.

FcγR gene copy number in Kawasaki disease and intravenous immunoglobulin treatment response.

Objective 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 (Fc&ggr;R) genes. However, it is not known whether the existing gene copy number (GCN) variability relates to KD treatment response, susceptibility, or associated sequelae. Methods The copy number of individuals with KD (n=510) and their family members (n=808) for three variable Fc&ggr;Rs was assessed using pyrosequencing. We performed the transmission disequilibrium test to examine the association of GCN for Fc&ggr;Rs (Fc&ggr;R2C, Fc&ggr;R3A, and Fc&ggr;R3B) with susceptibility and used logistic regression models to determine its association with IVIG treatment outcomes. Results Fc&ggr;R2C and Fc&ggr;R3B GCN were significantly associated with KD susceptibility. IVIG response was associated with GCN variations of Fc&ggr;R3B in Whites and Fc&ggr;R2C in Hispanics, and gene risk score based on single nucleotide polymorphism and GCN in Fc&ggr;Rs were significantly different between IVIG responders and nonresponders among Whites. We found no significant associations between coronary artery disease and any of the Fc&ggr;R copy numbers. Conclusion GCN of Fc&ggr;R2C and Fc&ggr;R3B influences IVIG treatment response and predisposes individuals to KD, providing potential insights into understanding the mechanism of the Fc&ggr;R gene family in the IVIG pathway.

Race-Specific Influence of CYP4F2 on Dose and Risk of Hemorrhage among Warfarin Users

The p.V433M in cytochrome P450 4F2 (rs2108622, CYP4F2*3) is associated with a higher warfarin dose and lower risk of hemorrhage among European Americans. We evaluate the influence of CYP4F2*3 on warfarin dose, time to target international normalized ratio (INR), and stable dose, proportion of time spent in target range (PTTR), as well as the risk of overanticoagulation and hemorrhage among European and African Americans.

High-density genotyping of immune loci in Kawasaki disease and IVIG treatment response in European-American case-parent trio study.

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 ancestry informative markers) using the immunoChip array, and performed association analyses with susceptibility to KD and intravenous immunoglobulin (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 single-nucleotide polymorphisms (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 a potential pathway in KD pathogenesis. SNP rs838143 in the 3′-untranslated region of the 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 have an important role in the pathogenesis of KD and IVIG response mechanism.

Interleukin-10 (IL-10) Pathway: Genetic Variants and Outcomes of HIV-1 Infection in African American Adolescents

Background 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. Conclusions/Significance 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.

Influence of Regular Physical Activity on Warfarin Dose and Risk of Hemorrhagic Complications

To determine the influence of regular physical activity on stable warfarin dose and risk of major hemorrhage in patients on chronic anticoagulation therapy.

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 leucocyte 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 patients with KD 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 patients with KD. 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, studies with larger sample sizes are warranted to evaluate the correlations of the strength and directions between the SNPs in MHC region and the imputed HLA alleles with KD.

RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women's Interagency HIV Study (WIHS)

BACKGROUND 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 Womens Interagency HIV Study (WIHS). METHODS 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 Gabriels method and haplotype association analyses were conducted among the three races separately. RESULTS 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. DISCUSSION 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.

DC-SIGN gene promoter variants and IVIG treatment response in Kawasaki disease

BackgroundGenetic variants in the inhibiting Fc γRIIB 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.FindingsA 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.ConclusionsDC-SIGN can potentially complement the role of Fc γRIIB in the anti-inflammatory cascade involved in the IVIG response mechanism.