Brahim Aissani

Host genetics and HIV-1 viral load set-point in African-Americans.

Objective:In a recent genome-wide association study of HIV-1-infected individuals in the Euro-CHAVI cohort, viral load set-point was strongly associated with genotypes defined by two single nucleotide polymorphisms (SNPs) (rs9264942 and rs2395029) within the human major histocompatibility complex (MHC) region on chromosome 6. We attempted to confirm this finding in African–Americans and to address whether these SNPs are in linkage disequilibrium with human leukocyte antigen (HLA) class I alleles that mediate innate and adaptive immunity. Design:Our analyses relied on 121 African–American adolescents with chronic HIV-1 infection and quarterly immunological and virological outcome measures in the absence of therapy. Methods:PCR-based techniques were used to genotype two SNPs along with HLA class I alleles. Their associations with HIV-1 viral load set-point and longitudinal CD4+ and CD8+CD38+ T cell counts were tested in univariate and multivariable models. Results:The CC genotype at rs9264942 was associated with reduced viral load, but not with immunological outcomes or category of disease control. Consistent associations of favorable virologic outcomes were observed with B*57 (mostly B*5703) but not with rs2395029G allele at the HCP5 locus, which is in absolute linkage disequilibrium with B*5701 (in individuals of European descent), and not B*5703. Conclusion:Although rs9264942 and B*57 (but not rs2395029G) are clearly associated with control of viral load set-point among African–Americans, fine-mapping of MHC SNPs in populations of African and European descent should help reveal the causative variants and the underlying functional mechanisms.

Interleukin-10 Gene (IL10) Polymorphisms and Human Papillomavirus Clearance among Immunosuppressed Adolescents

Persistent infection with high-risk human papillomavirus (HPV) is a major risk factor for cervical cancer, and HPV clearance seems to be under host genetic influence. This study evaluated associations between three single nucleotide polymorphisms in the IL10 promoter and clearance of low- or high-risk HPV infection in a cohort of 226 largely HIV-1–infected African-American adolescent females. Among immunosuppressed individuals (HIV-1 seropositive and CD4+ ≤ 500), the GCC haplotype in the IL10 promoter was associated with reduced clearance of high-risk HPV16-like [relative hazard (RH), 0.46; 95% confidence interval (95% CI), 0.25-0.85; P = 0.01], HPV18-like (RH, 0.33; 95% CI, 0.16-0.67; P = 0.002), and any high-risk type (RH, 0.37; 95% CI, 0.20-0.68; P = 0.002) but not with low-risk HPV type (RH, 0.60; 95% CI, 0.29-1.25; P = 0.17). No associations were observed among immunocompetent individuals. The IL10 GCC haplotype has been associated with production of relatively high levels of interleukin (IL)-10, which could (a) inhibit cytokines such as IL-2, TNF-α, IL-4, IL-6, and IL-12 that are involved in the TH1-TH2 immunoregulation; (b) down-regulate expression of MHC class I and class II molecules; or (c) induce the transcription of early promoter of HPV, all potentially contributing to duration of HPV infection among immunosuppressed individuals. These results support the hypothesis that IL10 polymorphisms influence the clearance of infection with high-risk HPV types and warrant further studies of host genetic control of HPV pathogenesis and cervical cancer in the context of immunosuppression. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1626–32)

Cytokine signaling pathway polymorphisms and AIDS-related non-Hodgkin lymphoma risk in the multicenter AIDS cohort study.

Background:Cytokine stimulation of B-cell proliferation may be an important causative mechanism for acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). The Epstein–Barr virus (EBV) may be a co-factor, particularly for primary central nervous system (CNS) tumors, which are uniformly EBV-positive in the setting of AIDS. Thus, we examined associations of genetic variation in IL10 and related cytokine-signaling molecules (IL10RA, CXCL12, IL13, IL4, IL4R, CCL5 and BCL6) with AIDS-related NHL risk and evaluated differences between primary CNS and systemic tumors. Patients and materials:We compared 160 Multicenter AIDS Cohort Study (MACS) participants with incident lymphomas, of which 90 followed another AIDS diagnosis, to HIV-1-seropositive controls matched on duration of lymphoma-free survival post-HIV-1 infection (N = 160) or post-AIDS diagnosis (N = 90). We fit conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results:Carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR = 0.3; 95% CI 0.1, 0.7) but not systemically (CC vs. CT/TT: OR = 1.0; 95% CI 0.5, 1.9) (Pheterogeneity = 0.03). Carriage of two copies of the ‘low IL10’ haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend = 0.02). None of the ORs for the other studied polymorphisms was significantly different from 1.0. Conclusion:Excessive IL10 response to HIV-1 infection may be associated with increased risk of NHL, particularly in the CNS. IL10 dysregulation may be an important causative pathway for EBV-related lymphomagenesis.

A Quantitative Trait Locus for Body Fat on Chromosome 1q43 in French Canadians: Linkage and Association Studies

Objective: To explore a quantitative trait locus (QTL) on human chromosome 1q affecting BMI, adiposity, and fat‐free mass phenotypes in the Quebec Family Study cohort.

A genome-wide association study of host genetic determinants of the antibody response to Anthrax Vaccine Adsorbed.

Several lines of evidence have supported a host genetic contribution to vaccine response, but genome-wide assessments for specific determinants have been sparse. Here we describe a genome-wide association study (GWAS) of protective antigen-specific antibody (AbPA) responses among 726 European-Americans who received Anthrax Vaccine Adsorbed (AVA) as part of a clinical trial. After quality control, 736,996 SNPs were tested for association with the AbPA response to 3 or 4 AVA vaccinations given over a 6-month period. No SNP achieved the threshold of genome-wide significance (p=5 × 10(-8)), but suggestive associations (p<1 × 10(-5)) were observed for SNPs in or near the class II region of the major histocompatibility complex (MHC), in the promoter region of SPSB1, and adjacent to MEX3C. Multivariable regression modeling suggested that much of the association signal within the MHC corresponded to previously identified HLA DR-DQ haplotypes involving component HLA-DRB1 alleles of *15:01, *01:01, or *01:02. We estimated the proportion of additive genetic variance explained by common SNP variation for the AbPA response after the 6 month vaccination. This analysis indicated a significant, albeit imprecisely estimated, contribution of variation tagged by common polymorphisms (p=0.032). Future studies will be required to replicate these findings in European Americans and to further elucidate the host genetic factors underlying variable immune response to AVA.

The major histocompatibility complex conserved extended haplotype 8.1 in AIDS-related non-Hodgkin lymphoma.

Background:Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with human leukocyte antigens HLA-B*08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in whites most likely represents a true etiologic factor remains uncertain. Objective:We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL. Methods:SNPs in LTA and TNF and in 6 other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study. Results:The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A), and rs6467 (C)) were associated with AIDS-NHL (odds ratio = 2.7, 95% confidence interval: 1.5 to 4.8, P = 0.0009; and odds ratio = 3.2, 95% confidence interval: 1.6 to 6.6, P = 0.0008; respectively). These 2 haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. Conclusion:The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.

Follow-up to genome-wide linkage and admixture mapping studies implicates components of the extracellular matrix in susceptibility to and size of uterine fibroids

OBJECTIVE To conduct a follow-up association mapping to independent genome-wide linkage and admixture mapping studies of uterine leiomyoma. DESIGN Case-control, cross-sectional study. SETTING Not applicable. PATIENT(S) A total of 1,045 premenopausal North American participants in the National Institute of Environmental Health Sciences Uterine Fibroid Study. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) We genotyped 2,772 single-nucleotide polymorphisms from candidate genes located in peaks of linkage (2q37, 3p21, 5p13, 10p11, 11p15, 12q14, and 17q25) or admixture linkage disequilibrium (2q37, 4p16.1, and 10q26) mapping and reported to have regulated expression in uterine fibroids. RESULT(S) We report significant associations of variant members of the collagen gene family with risk and tumor size, including missense variants in COL6A3 and COL13A, with replications in African American and European American study groups. Furthermore, the cell-matrix Rho GTPase-encoding ARHGAP26 gene, and MAN1C1, a gene encoding a Golgi mannosidase involved in the maturation of procollagens, emerged as new candidate uterine leiomyoma genes affecting both risk and tumor size. CONCLUSION(S) Our data converge onto a possible model of uterine leiomyoma pathogenesis resulting from altered regulation, maintenance, and/or renewal of the extracellular matrix.

RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment

Nearly one-third of adults in the United States have hypertension, which is associated with increased cardiovascular disease (CVD) morbidity and mortality. The goal of antihypertensive pharmacogenetic research is to enhance understanding of drug response based on the interaction of individual genetic architecture and antihypertensive therapy to improve blood pressure control and ultimately prevent CVD outcomes. In the context of the Genetics of Hypertension Associated Treatment study and using a case-only design, we examined whether single-nucleotide polymorphisms in RYR3 interact with four classes of antihypertensive drugs, particularly the calcium channel blocker amlodipine versus other classes, to modify the risk of coronary heart disease (CHD; fatal CHD and non-fatal myocardial infarction combined) and heart failure (HF) in high-risk hypertensive individuals. RYR3 mediates the mobilization of stored Ca+2 in cardiac and skeletal muscle to initiate muscle contraction. There was suggestive evidence of pharmacogenetic effects on HF, the strongest of which was for rs877087, with the smallest P-value=0.0005 for the codominant model when comparing amlodipine versus all other treatments. There were no pharmacogenetic effects observed for CHD. The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3058 CHD cases and 1940 HF cases show that a hypertensive patients genetic profile may help predict which medication(s) might better lower CVD risk.

Admixture mapping of genetic variants for uterine fibroids

Uterine leiomyoma (UL) are benign neoplasms arising from the smooth muscle cells of the uterus. One of the established risk factors for UL is African American ethnicity. Studies have consistently shown that African Americans have two to three times higher risk compared with that of non-Hispanic Whites. However, there is still no adequate explanation for the higher risk among African Americans. To investigate the genetic contribution to the observed difference between the African American and European American populations, we conducted an admixture scan in 525 eligible African American women participants to the NIEHS uterine fibroid study (NIEHS-UFS). In models with no stratification, we found multiple genomic regions showing significant and suggestive evidence of association, with chromosomal band 2q32.2 at rs256552 showing the highest score (Z-score=7.86, Bonferroni adjusted P-value=5.5 × 10−12) consistent with the suggestive evidence reported for this genomic region in the Black Women’s Health Study. However, in models stratified by the body mass index (BMI) covariate, chromosome 1q42.2 was the sole genomic region that consistently showed suggestive associations across the BMI categories tested (Z-scores ⩽−3.96, Bonferroni adjusted P-values ⩽0.107). In age-stratified models, a significant association was observed in the older category (age >40) reaching a Z-score of 6.44 (Bonferroni-adjusted P-value=1.64 × 10−7) at rs256552. The mean percentage of European ancestry among cases was lower than that among controls in the NIEHS-UFS study. However, our study did not show a significant association between mean percentage of European ancestry and UL.

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.