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1.  SNP screening of central MHC identified HLA-DMB as a candidate susceptibility gene for HIV-related Kaposi’s sarcoma 
Genes and immunity  2014;15(6):424-429.
The major histocompatibility complex (MHC) region on chromosome 6p21.3 is suspected to host susceptibility loci for HIV-related Kaposi’s sarcoma (HIV-KS). A nested case-control study in the Multicenter AIDS Cohort Study was designed to conduct fine genetic association mapping across central MHC. Individuals co-infected with HIV-1 and HHV-8 who later developed KS were defined as cases (n=354) and were matched 1:1 with co-infected KS-free controls.
We report data for new independent MHC class II and III susceptibility loci. In particular, class II HLA-DMB emerged as a strong candidate, with the intronic variant rs6902982 A>G associated with a 4-fold increase of risk (OR= 4.09; 95% CI: 1.90–8.80; p= 0.0003). A striking multiplicative effect on the estimated risk was associated with further carriage of two non-synonymous variants, rs1800453 A>G (Asp697Gly) and rs4148880 A>G (Ile393Val), in the linked TAP1 gene (OR=10.5; 95% CI: 2.54–43.6; p=0.0012). The class III susceptibility variant is moderately associated with HIV-KS and lies within a 120 Kb-long haplotype (OR=1.52; 95% CI: 1.01–2.28; p=0.047) formed by rs7029 A>G (GPANK1 3’UTR), rs1065356 G>A (LY6G6C), rs3749953 A>G (MSH5-SAPCD1 readthrough) and rs707926 G>A (VARS). Our data suggest that antigen processing by MHC class II molecules is a target pathway in the pathogenesis of HIV-KS.
PMCID: PMC4174341  PMID: 25008864
2.  A candidate gene approach for virally-induced cancer with application to HIV-related Kaposi’s sarcoma 
Like other members of the γ-herpesvirus family, human herpes virus 8 (HHV-8), the etiologic agent of classic and HIV-related Kaposi’s sarcoma (HIV-KS) acquired and evolved several human genes with key immune modulatory and cellular growth control functions. The encoded viral homologs substitute for their human counterparts but escape cellular regulation, leading to uncontrolled cell proliferation. We postulated that DNA variants in the human homologs of viral genes that potentially alter the expression or the binding of the encoded factors controlling the antiviral response may facilitate viral interference. To test whether cellular homologs are candidate susceptibility genes, we evaluated the association of DNA variants in 92 immune-related genes including 7 cellular homologs with the risk for HIV-KS in a matched case and control study nested in the Multicenter AIDS Cohort Study. Low- and high-risk gene-by-gene interactions were estimated by multifactor dimensionality reduction and used as predictors in conditional logistic models. Among the most significant gene interactions at risk (OR=2.84–3.92; Bonferroni-adjusted p= 9.9×10−3−2.6×10−4), three comprised human homologs of two latently expressed viral genes, cyclin D1 (CCND1) and interleukin-6 (IL-6), in conjunction with angiogenic genes (VEGF, EDN-1 and EDNRB). At lower significance thresholds (adjusted p < 0.05), human homologs related to apoptosis (CFLAR) and chemotaxis (CCL2) emerged as candidates. This “proof of concept” study identified human homologs involved in the regulation of type I interferon-induced signaling, cell cycle and apoptosis potentially as important determinants of HIV-KS
PMCID: PMC4007164  PMID: 23818101
Kaposi’s sarcoma; Immunodeficiency; Herpes Virus 8; Multifactor Dimensionality Reduction; Polymorphism; Genetic association
3.  RYR3 gene polymorphisms and cardiovascular disease outcomes in the context of antihypertensive treatment 
The pharmacogenomics journal  2012;13(4):330-334.
Nearly one-third of adults in the U.S. 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 (GenHAT) 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 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 heart failure, the strongest of which was for rs877087, with the smallest p-value =.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 3,058 CHD cases and 1,940 heart failure cases show that a hypertensive patient’s genetic profile may help predict which medication(s) might better lower cardiovascular disease risk.
PMCID: PMC3435442  PMID: 22664477
RYR3 gene; calcium channel blocker; hypertension; coronary heart disease; heart failure; genetic interaction
4.  A Genome-wide Association Study of Host Genetic Determinants of the Antibody Response to Anthrax Vaccine Adsorbed 
Vaccine  2012;30(32):4778-4784.
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=5x10−8), but suggestive associations (p<1x10−5) 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.
PMCID: PMC3387748  PMID: 22658931
Anthrax vaccines; Bacillus anthracis; bacterial vaccines; vaccination; Genome-wide association study
5.  The Utility of Mitochondrial and Y Chromosome Phylogenetic Data to Improve Correction for Population Stratification 
Frontiers in Genetics  2012;3:301.
Genome-wide association (GWA) studies have become a standard approach for discovering and validating genomic polymorphisms putatively associated with phenotypes of interest. Accounting for population structure in GWA studies is critical to attain unbiased parameter measurements and control Type I error. One common approach to accounting for population structure is to include several principal components derived from the entire autosomal dataset, which reflects population structure signal. However, knowing which components to include is subjective and generally not conclusive. We examined how phylogenetic signal from mitochondrial DNA (mtDNA) and chromosome Y (chr:Y) markers is concordant with principal component data based on autosomal markers to determine whether mtDNA and chr:Y phylogenetic data can help guide principal component selection. Using HAPMAP and other original data from individuals of multiple ancestries, we examined the relationships of mtDNA and chr:Y phylogenetic signal with the autosomal PCA using best subset logistic regression. We show that while the two approaches agree at times, this is independent of the component order and not completely represented in the Eigen values. Additionally, we use simulations to demonstrate that our approach leads to a slightly reduced Type I error rate compared to the standard approach. This approach provides preliminary evidence to support the theoretical concept that mtDNA and chr:Y data can be informative in locating the PCs that are most associated with evolutionary history of populations that are being studied, although the utility of such information will depend on the specific situation.
PMCID: PMC3527715  PMID: 23267368
phylogeny; PCA; Y chromosome; mitochondria; population sub-structure
6.  Natural selection among Eurasians at genomic regions associated with HIV-1 control 
HIV susceptibility and pathogenicity exhibit both interindividual and intergroup variability. The etiology of intergroup variability is still poorly understood, and could be partly linked to genetic differences among racial/ethnic groups. These genetic differences may be traceable to different regimes of natural selection in the 60,000 years since the human radiation out of Africa. Here, we examine population differentiation and haplotype patterns at several loci identified through genome-wide association studies on HIV-1 control, as determined by viral-load setpoint, in European and African-American populations. We use genome-wide data from the Human Genome Diversity Project, consisting of 53 world-wide populations, to compare measures of FST and relative extended haplotype homozygosity (REHH) at these candidate loci to the rest of the respective chromosome.
We find that the Europe-Middle East and Europe-South Asia pairwise FST in the most strongly associated region are elevated compared to most pairwise comparisons with the sub-Saharan African group, which exhibit very low FST. We also find genetic signatures of recent positive selection (higher REHH) at these associated regions among all groups except for sub-Saharan Africans and Native Americans. This pattern is consistent with one in which genetic differentiation, possibly due to diversifying/positive selection, occurred at these loci among Eurasians.
These findings are concordant with those from earlier studies suggesting recent evolutionary change at immunity-related genomic regions among Europeans, and shed light on the potential genetic and evolutionary origin of population differences in HIV-1 control.
PMCID: PMC3141432  PMID: 21689440
7.  The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-related Non-Hodgkin’s Lymphoma 
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’s lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with 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 Caucasians most likely represents a true etiologic factor remains uncertain. 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. SNPs in LTA and TNF and in six 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. 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 (OR=2.7, 95% CI: 1.5–4.8, p=0.0009 and OR=3.2, 95% CI: 1.6–6.6 p=0.0008; respectively). These two haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1. 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.
PMCID: PMC3015185  PMID: 19654554
Human Leukocyte Antigen; HIV; CD4; Multicenter AIDS Cohort NHL Study
8.  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
10.  Host Genetics and HIV-1 Viral Load Set-point in African-Americans 
AIDS (London, England)  2009;23(6):673-677.
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 SNPs (rs9264942 and rs2395029) within the human MHC region on chromosome 6. We attempted to confirm this finding in African-Americans and assess if these SNPs are in linkage disequilibrium (LD) with HLA class I alleles that mediate innate and adaptive immunity.
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.
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 multivariate models.
The CC genotype at rs9264942 was associated with reduced viral load but not with immunological outcomes or category of disease control. Consistent associations of HLA-B*57 (mostly B*5703) with favorable virological and immunological outcomes were observed, but not rs2395029G allele at the HCP5 locus, which is in absolute linkage disequilibrium with B*5701 (in individuals of European descent), and not B*5703.
While 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 true variants and the underlying functional mechanisms.
PMCID: PMC2663898  PMID: 19276793
HIV-1; genetics; viral load; African American

Results 1-10 (10)