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Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents.

ABSTRACT: 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.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.

SUBMITTER: Shrestha S

PROVIDER: S-EPMC2954785 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents.

Shrestha Sadeep S Wiener Howard W HW Aissani Brahim B Song Wei W Shendre Aditi A Wilson Craig M CM Kaslow Richard A RA Tang Jianming J

PloS one 20101014 10

<h4>Background</h4>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.<h4>Methodology/principal findings</h4>We examined 104 informative SNPs in IL10, IL19, I ...[more]

PMID: 20976276

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Project description:BackgroundTiming of birth is a major determinant of newborn health. African American women are at increased risk for early birth, particularly via the inflammatory pathway. Variants of the IL1RN gene, which encode the interleukin-1 receptor antagonist (IL-1Ra) protein, are implicated in early birth. The biological pathways linking these variables remain unclear. Evidence also suggests that inflammatory pathways differ by race; however, studies among African American women are lacking.ObjectivesWe assessed whether an IL1RN variant was associated with timing of birth among African American women and whether this relationship was mediated by lower anti-inflammatory IL-1Ra production or related to a decrease in inhibition of proinflammatory IL-1β production.MethodsA candidate gene study using a prospective cohort design was used. We collected blood samples at 28-32 weeks of gestation among African American women experiencing an uncomplicated pregnancy (N = 89). IL1RN single-nucleotide polymorphism (SNP) rs2637988 was genotyped, and lipopolysaccharide-stimulated IL-1Ra and IL-1β production was quantified. Medical record review determined timing of birth.ResultsWomen with GG genotype gave birth earlier than women with AA/AG genotypes (b* = .21, p = .04). There was no indirect effect of IL1RN SNP rs2637988 allele status on timing of birth through IL-1Ra production, as evidenced by a nonsignificant product of coefficients in mediational analyses (ab = .006, 95% CI [-0.05, 0.13]). Women with GG genotype showed less inhibition of IL-1β production for a unit positive difference in IL-1Ra production than women with AA/AG genotypes (b* = .93, p = .03). Greater IL-1β production at 28-32 weeks of pregnancy was marginally associated with earlier birth (b* = .21, p = .05).DiscussionWomen with GG genotype may be at risk for earlier birth because of diminished IL-1β inhibition, allowing for initiation of a robust inflammatory response upon even mild immune challenge. Study of inflammatory contributions to early birth among African American women may be key to identifying potential prognostic markers of risk and targeted preventive interventions.

Project description:Importance:The prevalence of nonischemic dilated cardiomyopathy (DCM) is greater in individuals of African ancestry than in individuals of European ancestry. However, little is known about whether the difference in prevalence or outcomes is associated with functional genetic variants. Objective:We hypothesized that Bcl2-associated anthanogene 3 (BAG3) genetic variants were associated with outcomes in individuals of African ancestry with DCM. Design:This multicohort study of the BAG3 genotype in patients of African ancestry with dilated cardiomyopathy uses DNA obtained from African American individuals enrolled in 3 clinical studies: the Genetic Risk Assessment of African Americans With Heart Failure (GRAHF) study; the Intervention in Myocarditis and Acute Cardiomyopathy Trial-2 (IMAC-2) study; and the Genetic Risk Assessment of Cardiac Events (GRACE) study. Samples of DNA were also acquired from the left ventricular myocardium of patients of African ancestry who underwent heart transplant at the University of Colorado and University of Pittsburgh. Main Outcomes and Measures:The primary end points were the prevalence of BAG3 mutations in African American individuals and event-free survival in participants harboring functional BAG3 mutations. Results:Four BAG3 genetic variants were identified; these were expressed in 42 of 402 African American individuals (10.4%) with nonischemic heart failure and 9 of 107 African American individuals (8.4%) with ischemic heart failure but were not present in a reference population of European ancestry (P?<?.001). The variants included 2 nonsynonymous single-nucleotide variants; 1 three-nucleotide in-frame insertion; and 2 single-nucleotide variants that were linked in cis. The presence of BAG3 variants was associated with a nearly 2-fold (hazard ratio, 1.97 [95% CI, 1.19-3.24]; P?=?.01) increase in cardiac events in carriers compared with noncarriers. Transfection of transformed adult human ventricular myocytes with plasmids expressing the 4 variants demonstrated that each variant caused an increase in apoptosis and a decrease in autophagy when samples were subjected to the stress of hypoxia-reoxygenation. Conclusions and Relevance:This study demonstrates that genetic variants in BAG3 found almost exclusively in individuals of African ancestry were not causative of disease but were associated with a negative outcome in patients with a dilated cardiomyopathy through modulation of the function of BAG3. The results emphasize the importance of biological differences in causing phenotypic variance across diverse patient populations, the need to include diverse populations in genetic cohorts, and the importance of determining the pathogenicity of genetic variants.

Project description:Risk and protective processes are integrated developmental processes that directly or indirectly affect behavioral outcomes. A better understanding of these processes is needed, in order to gauge their contribution to sexual risk behaviors. This retrospective cross-sectional study modeled the ecodevelopmental chain of relationships to examine the social contexts of African-American (AA) adolescents associated with sexually transmitted disease (STD)- and HIV-risk behaviors. We used data from 1,619 AA adolescents with an average age of 16±1.8 years obtained from the first wave of the National Longitudinal Study of Adolescent Health for this study. Confirmatory factor analysis followed by structural equation modeling was conducted to identify the latent constructs that reflect the social-interactional components of the ecodevelopmental theory. Among contextual factors, findings indicated that a feeling of love from father, school, religion, and parent attitudes toward adolescent sexual behavior were all factors that played significant roles in the sexual behavior of AA adolescents. AA adolescents who reported feeling love from their father, feeling a strong negative attitude from their parents toward having sex at a very young age, and having a strong bond with school personnel were associated with better health statuses. The level of parents' involvement in their children's lives was reflected in the adolescents' feeling of love from parents and moderated by their socioeconomic status. Being male, attaining increased age, and being a sexual minority were associated with higher likelihood of exhibiting risky sexual behavior. In contrast, higher socioeconomic status and fathers' level of involvement were indirectly associated with reduced STD/HIV-related sexual risk behavior. In conclusion, our findings suggest that interventions aimed at maximal protection against STD/HIV-related risk behavior among AA adolescents should adopt both self- and context-based strategies that promote positive functioning in the family, school, and peer microsystems.

Dataset Information

Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents.

Publications

Interleukin-10 (IL-10) pathway: genetic variants and outcomes of HIV-1 infection in African American adolescents.

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