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1.  Factors associated with degree of atopy in Latino children in a nationwide pediatric sample: The GALA II Study 
Atopy varies by ethnicity even within Latino groups. This variation may be due to environmental, socio-cultural or genetic factors.
To examine risk factors for atopy within a nationwide study of U.S. Latino children with and without asthma.
Aeroallergen skin test repsonse was analyzed in 1830 US latino subjects. Key determinants of atopy included: country / region of origin, generation in the U.S., acculturation, genetic ancestry and site to which individuals migrated. Serial multivariate zero inflated negative binomial regressions, stratified by asthma status, examined the association of each key determinant variable with the number of positive skin tests. In addition, the independent effect of each key variable was determined by including all key variables in the final models.
In baseline analyses, African ancestry was associated with 3 times as many positive skin tests in participants with asthma (95% CI:1.62–5.57) and 3.26 times as many positive skin tests in control participants (95% CI: 1.02–10.39). Generation and recruitment site were also associated with atopy in crude models. In final models adjusted for key variables, Puerto Rican [exp(β) (95%CI): 1.31(1.02–1.69)] and mixed ethnicity [exp(β) (95%CI):1.27(1.03–1.56)] asthmatics had a greater probability of positive skin tests compared to Mexican asthmatics. Ancestry associations were abrogated by recruitment site, but not region of origin.
Puerto Rican ethnicity and mixed origin were associated with degree of atopy within U.S. Latino children with asthma. African ancestry was not associated with degree of atopy after adjusting for recruitment site. Local environment variation, represented by site, was associated with degree of sensitization.
PMCID: PMC3788073  PMID: 23684070
Latino; atopy; region of origin; genetic ancestry; immigration; skin test; aeroallergen
2.  Evaluation and Integration of Genetic Signature for Prediction Risk of Nasopharyngeal Carcinoma in Southern China 
BioMed Research International  2014;2014:434072.
Genetic factors, as well as environmental factors, play a role in development of nasopharyngeal carcinoma (NPC). A number of single nucleotide polymorphisms (SNPs) have been reported to be associated with NPC. To confirm these genetic associations with NPC, two independent case-control studies from Southern China comprising 1166 NPC cases and 2340 controls were conducted. Seven SNPs in ITGA9 at 3p21.3 and 9 SNPs within the 6p21.3 HLA region were genotyped. To explore the potential clinical application of these genetic markers in NPC, we further evaluate the predictive/diagnostic role of significant SNPs by calculating the area under the curve (AUC). Results. The reported associations between ITGA9 variants and NPC were not replicated. Multiple loci of GABBR1, HLA-F, HLA-A, and HCG9 were statistically significant in both cohorts (Pcombined range from 5.96 × 10−17 to 0.02). We show for the first time that these factors influence NPC development independent of environmental risk factors. This study also indicated that the SNP alone cannot serve as a predictive/diagnostic marker for NPC. Integrating the most significant SNP with IgA antibodies status to EBV, which is presently used as screening/diagnostic marker for NPC in Chinese populations, did not improve the AUC estimate for diagnosis of NPC.
PMCID: PMC4142549  PMID: 25180181
3.  NPHS2 Variation in Sporadic Focal Segmental Glomerulosclerosis 
Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3′ untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR = 4.9, P = 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in European-Americans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR = 0.5, P = 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.
PMCID: PMC4096868  PMID: 17942957
4.  Genetic Variations Affecting Serum Carcinoembryonic Antigen Levels and Status of Regional Lymph Nodes in Patients with Sporadic Colorectal Cancer from Southern China 
PLoS ONE  2014;9(6):e97923.
Serum carcinoembryonic antigen (sCEA) level might be an indicator of disease. Indeed, an elevated sCEA level is a prognostic factor in colorectal cancer (CRC) patients. However, the genetic determinants of sCEA level in healthy and CRC population remains unclear. Thus we investigated the genetic markers associated with elevated serum sCEA level in these two populations and its clinical implications.
Methods and Findings
Genome-wide association study (GWAS) was conducted in a cohort study with 4,346 healthy male adults using the Illumina Omni 1 M chip. Candidate SNPs associated with elevated sCEA levels were validated in 194 CRC patients on ABI Taqman platform. Eight candidate SNPs were validated in CRC patients. The rs1047781 (chr19- FUT2) (A/T) was associated with elevated sCEA levels, and rs8176746 (chr9- ABO) was associated with the regional lymph metastasis in the CRC patients. The preoperative sCEA level was a risk factor for tumor recurrence in 5 years after operation (OR = 1.427, 95% CI: 1.005∼1.843, P = 0.006). It was also one of the risk factors for regional lymph node metastasis (OR = 2.266, 95% CI: 1.196∼4.293, P = 0.012). The sCEA level in rs1047781-T carriers was higher than that in the A carriers in CRC patients without lymph node metastasis (P = 0.006). The regional lymph node metastasis in patients with homozygote AA of rs8176746 was more common than that in the heterozygote AG carriers (P = 0.022). In addition, rs1047781-AT and TT CRC patients exhibited a worse disease-free survival than AA genotype carriers (P = 0.023).
We found candidate SNPs associated with elevated sCEA levels in both healthy males and CRC population. Rs1047781 (chr19- FUT2) may be the susceptible locus for recurrence of CRC in a population from Southern China.
PMCID: PMC4062418  PMID: 24941225
5.  APOL1 Risk Variants, Race, and Progression of Chronic Kidney Disease 
The New England journal of medicine  2013;369(23):2183-2196.
Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients.
In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline.
In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons).
Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.)
PMCID: PMC3969022  PMID: 24206458
6.  F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort 
Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk.
Design and Methods
Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed.
H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development.
H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
PMCID: PMC3521089  PMID: 22958194
F8 haplotype; FVIII inhibitors; haplotype mismatch
7.  Genome-Wide and Differential Proteomic Analysis of Hepatitis B Virus and Aflatoxin B1 Related Hepatocellular Carcinoma in Guangxi, China 
PLoS ONE  2013;8(12):e83465.
Both hepatitis B virus (HBV) and aflatoxin B1 (AFB1) exposure can cause liver damage as well as increase the probability of hepatocellular carcinoma (HCC). To investigate the underlying genetic changes that may influence development of HCC associated with HBV infection and AFB1 exposure, HCC patients were subdivided into 4 groups depending upon HBV and AFB1 exposure status: (HBV(+)/AFB1(+), HBV(+)/AFB1(-), HBV(-)/AFB1(+), HBV(-)/AFB1(-)). Genetic abnormalities and protein expression profiles were analyzed by array-based comparative genomic hybridization and isobaric tagging for quantitation. A total of 573 chromosomal aberrations (CNAs) including 184 increased and 389 decreased were detected in our study population. Twenty-five recurrently altered regions (RARs; chromosomal alterations observed in ≥10 patients) in chromosomes were identified. Loss of 4q13.3-q35.2, 13q12.1-q21.2 and gain of 7q11.2-q35 were observed with a higher frequency in the HBV(+)/AFB1(+), HBV(+)/AFB1(-) and HBV(-)/AFB1(+) groups compared to the HBV(-)/AFB(-) group. Loss of 8p12-p23.2 was associated with high TNM stage tumors (P = 0.038) and was an unfavorable prognostic factor for tumor-free survival (P =0.045). A total of 133 differentially expressed proteins were identified in iTRAQ proteomics analysis, 69 (51.8%) of which mapped within identified RARs. The most common biological processes affected by HBV and AFB1 status in HCC tumorigenesis were detoxification and drug metabolism pathways, antigen processing and anti-apoptosis pathways. Expression of AKR1B10 was increased significantly in the HBV(+)/AFB1(+) and HBV(-)/AFB1(+) groups. A significant correlation between the expression of AKR1B10 mRNA and protein levels as well as AKR1B10 copy number was observered, which suggest that AKR1B10 may play a role in AFB1-related hepatocarcinogenesis. In summary, a number of genetic and gene expression alterations were found to be associated with HBV and AFB1- related HCC. The possible synergistic effects of HBV and AFB1 in hepatocarcinogenesis warrant further investigations.
PMCID: PMC3877066  PMID: 24391771
8.  A Genome-Wide Search for Linkage of Estimated Glomerular Filtration Rate (eGFR) in the Family Investigation of Nephropathy and Diabetes (FIND) 
PLoS ONE  2013;8(12):e81888.
Estimated glomerular filtration rate (eGFR), a measure of kidney function, is heritable, suggesting that genes influence renal function. Genes that influence eGFR have been identified through genome-wide association studies. However, family-based linkage approaches may identify loci that explain a larger proportion of the heritability. This study used genome-wide linkage and association scans to identify quantitative trait loci (QTL) that influence eGFR.
Genome-wide linkage and sparse association scans of eGFR were performed in families ascertained by probands with advanced diabetic nephropathy (DN) from the multi-ethnic Family Investigation of Nephropathy and Diabetes (FIND) study. This study included 954 African Americans (AA), 781 American Indians (AI), 614 European Americans (EA) and 1,611 Mexican Americans (MA). A total of 3,960 FIND participants were genotyped for 6,000 single nucleotide polymorphisms (SNPs) using the Illumina Linkage IVb panel. GFR was estimated by the Modification of Diet in Renal Disease (MDRD) formula.
The non-parametric linkage analysis, accounting for the effects of diabetes duration and BMI, identified the strongest evidence for linkage of eGFR on chromosome 20q11 (log of the odds [LOD] = 3.34; P = 4.4×10−5) in MA and chromosome 15q12 (LOD = 2.84; P = 1.5×10−4) in EA. In all subjects, the strongest linkage signal for eGFR was detected on chromosome 10p12 (P = 5.5×10−4) at 44 cM near marker rs1339048. A subsequent association scan in both ancestry-specific groups and the entire population identified several SNPs significantly associated with eGFR across the genome.
The present study describes the localization of QTL influencing eGFR on 20q11 in MA, 15q21 in EA and 10p12 in the combined ethnic groups participating in the FIND study. Identification of causal genes/variants influencing eGFR, within these linkage and association loci, will open new avenues for functional analyses and development of novel diagnostic markers for DN.
PMCID: PMC3866106  PMID: 24358131
9.  Host genes associated with HIV/AIDS: advances in gene discovery 
Trends in genetics : TIG  2010;26(3):119-131.
Twenty five years after the discovery of HIV as the cause of AIDS, there is still no effective vaccine and no cure for this disease. HIV susceptibility shows a substantial degree of individual heterogeneity, much of which can be conferred by host genetic variation. In an effort to discover host factors required for HIV replication, identify critical pathogenic pathways, and reveal the full armament of host defenses, there has been a shift from candidate gene studies to unbiased genome wide genetic and functional studies. However, the number of securely identified host factors involved in HIV disease remains small, explaining only ~15–20% of the observed heterogeneity – most of which is attributable to HLA. Multidisciplinary approaches integrating genetic epidemiology to systems biology will be required to fully understand viral-host interactions to effectively combat HIV/AIDS.
PMCID: PMC3792714  PMID: 20149939
10.  Risk Factors for Symptomatic Hyperlactatemia and Lactic Acidosis Among Combination Antiretroviral Therapy-Treated Adults in Botswana: Results from a Clinical Trial 
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08–1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1–1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03–3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.
PMCID: PMC3399551  PMID: 22540188
11.  Association Study of Common Genetic Variants and HIV-1 Acquisition in 6,300 Infected Cases and 7,200 Controls 
PLoS Pathogens  2013;9(7):e1003515.
Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6×10−11). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
Author Summary
Comparing the frequency differences between common DNA variants in disease-affected cases and in unaffected controls has been successful in uncovering the genetic component of multiple diseases. This approach is most effective when large samples of cases and controls are available. Here we combine information from multiple studies of HIV infected patients, including more than 6,300 HIV+ individuals, with data from 7,200 general population samples of European ancestry to test nearly 8 million common DNA variants for an impact on HIV acquisition. With this large sample we did not observe any single common genetic variant that significantly associated with HIV acquisition. We further tested 22 variants previously identified by smaller studies as influencing HIV acquisition. With the exception of a deletion polymorphism in the CCR5 gene (CCR5Δ32) we found no convincing evidence to support these previous associations. Taken together these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.
PMCID: PMC3723635  PMID: 23935489
12.  Apolipoprotein L1 gene variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans 
Kidney international  2012;83(1):114-120.
Despite intensive anti-hypertensive therapy there was a high incidence of renal end-points in participants of the African American Study of Kidney Disease and Hypertension (AASK) cohort. To better understand this, coding variants in the apolipoprotein L1 (APOL1) and the non-muscle myosin heavy chain 9 (MYH9) genes were evaluated for an association with hypertension-attributed nephropathy and clinical outcomes in a case-control study. Clinical data and DNA were available for 675 AASK participant cases and 618 African American non-nephropathy control individuals. APOL1 G1 and G2, and MYH9 E1 variants along with 44 ancestry informative markers were genotyped with allele frequency differences between cases and controls analyzed by logistic regression multivariable models adjusting for ancestry, age, and gender. In recessive models, APOL1 risk variants were significantly associated with kidney disease in all cases compared to controls with an odds ratio of 2.57. In AASK cases with more advanced disease, such as a baseline urine protein to creatinine ratio over 0.6 g/g or a serum creatinine over 3 mg/dL during follow-up, the association was strengthened with odds ratios of 6.29 and 4.61, respectively. APOL1 risk variants were consistently associated with renal disease progression across medication classes and blood pressure targets. Thus, kidney disease in AASK participants was strongly associated with APOL1 renal risk variants.
PMCID: PMC3484228  PMID: 22832513
13.  APOBEC3B Deletion and Risk of HIV-1 Acquisition 
The Journal of infectious diseases  2009;200(7):1054-1058.
The human APOBEC3 family of cytidine deaminases provides intrinsic immunity to retroviral infection. A naturally occurring 29.5-kb deletion removes the entire APOBEC3B gene. We examined the impact of the APOBEC3B gene deletion in >4000 individuals from five HIV-1 natural history cohorts. The hemizygous genotype had no effect on either infection or progression. However, the homozygous deletion was significantly associated with unfavorable outcomes for HIV-1 acquisition (OR=7.37, P=0.024), progression to AIDS (RH = 4.01, P=0.03), and viral set-point (P=0.04). These findings suggest that the loss of APOBEC3B may increase host susceptibility to HIV-1/AIDS and warrant further study.
PMCID: PMC3690486  PMID: 19698078
14.  Multicohort Genomewide Association Study Reveals a New Signal of Protection Against HIV-1 Acquisition 
The Journal of Infectious Diseases  2012;205(7):1155-1162.
Background. To date, only mutations in CCR5 have been shown to confer resistance to human immunodeficiency virus type 1 (HIV-1) infection, and these explain only a small fraction of the observed variability in HIV susceptibility.
Methods. We performed a meta-analysis between 2 independent European genomewide association studies, each comparing HIV-1 seropositive cases with normal population controls known to be HIV uninfected, to identify single-nucleotide polymorphisms (SNPs) associated with the HIV-1 acquisition phenotype. SNPs exhibiting P < 10−5 in this first stage underwent second-stage analysis in 2 independent US cohorts of European descent.
Results. After the first stage, a single highly significant association was revealed for the chromosome 8 rs6996198 with HIV-1 acquisition and was replicated in both second-stage cohorts. Across the 4 groups, the rs6996198-T allele was consistently associated with a significant reduced risk of HIV-1 infection, and the global meta-analysis reached genomewide significance: Pcombined = 7.76 × 10−8.
Conclusions. We provide strong evidence of association for a common variant with HIV-1 acquisition in populations of European ancestry. This protective signal against HIV-1 infection is the first identified outside the CCR5 nexus. First clues point to a potential functional role for a nearby candidate gene, CYP7B1, but this locus warrants further investigation.
PMCID: PMC3295605  PMID: 22362864
15.  HIV-associated nephropathy patients with and without apolipoprotein L1 gene variants have similar clinical and pathologic characteristics 
Kidney international  2012;82(3):338-343.
Recently, an association was found between non-diabetic kidney disease in African Americans and two independent sequence variants in the APOL1 gene, encoding apolipoprotein L1. In this study we determined the frequency of APOL1 risk variants in patients with biopsy-proven HIV-associated nephropathy (HIVAN) and distinctive pathological characteristics potentially driven by those risk variants. Among 76 patients with HIVAN, 60 were successfully genotyped for APOL1 G1 and G2 polymorphisms. In this cohort, 37 had two risk alleles, 18 were heterozygous and 5 had neither risk variant. There were no differences in the pathological findings of HIVAN and the number of APOL1 risk alleles. Further, the progression to end stage kidney disease or death did not differ by the number of risk alleles. Median renal survival was 9.3 months in patients with none or one risk allele compared to 11.7 months in patients with two APOL1 risk alleles. Thus, our study suggests that although the majority of African American patients with HIVAN have two APOL1 risk alleles, other as yet unknown factors in the host including genetic risk variants and environmental or viral factors may influence the development of this disorder in those with none or one APOL1 risk allele.
PMCID: PMC3463138  PMID: 22495294
16.  Evidence for selection at HIV host susceptibility genes in a West Central African human population 
HIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations. We hypothesized that human populations in west central Africa may have been exposed to SIV prior to the pandemic, and that previous outbreaks may have selected for genetic resistance to immunodeficiency viruses. To test this hypothesis, we examined the genomes of Biaka Western Pygmies, who historically resided in communities within the geographic range of the central African chimpanzee subspecies (Pan troglodytes troglodytes) that carries strains of SIV ancestral to HIV-1.
SNP genotypes of the Biaka were compared to those of African human populations who historically resided outside the range of P. t. troglodytes, including the Mbuti Eastern Pygmies. Genomic regions showing signatures of selection were compared to the genomic locations of genes reported to be associated with HIV infection or pathogenesis. In the Biaka, a strong signal of selection was detected at CUL5, which codes for a component of the vif-mediated APOBEC3 degradation pathway. A CUL5 allele protective against AIDS progression was fixed in the Biaka. A signal of selection was detected at TRIM5, which codes for an HIV post-entry restriction factor. A protective mis-sense mutation in TRIM5 had the highest frequency in Biaka compared to other African populations, as did a protective allele for APOBEC3G, which codes for an anti-HIV-1 restriction factor. Alleles protective against HIV-1 for APOBEC3H, CXCR6 and HLA-C were at higher frequencies in the Biaka than in the Mbuti. Biaka genomes showed a strong signal of selection at TSG101, an inhibitor of HIV-1 viral budding.
We found protective alleles or evidence for selection in the Biaka at a number of genes associated with HIV-1 infection or progression. Pygmies have also been reported to carry genotypes protective against HIV-1 for the genes CCR5 and CCL3L1. Our hypothesis that HIV-1 may have shaped the genomes of some human populations in West Central Africa appears to merit further investigation.
PMCID: PMC3537702  PMID: 23217182
HIV dependency factors; Single nucleotide polymorphisms; Biaka pygmies; Mbuti pygmies
17.  The Principal Genetic Determinants for Nasopharyngeal Carcinoma in China Involve the HLA Class I Antigen Recognition Groove 
PLoS Genetics  2012;8(11):e1003103.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (PHLA-A-aa-site-62 = 7.4×10−29; P HLA-B-aa-site-116 = 6.5×10−19; P HLA-C-aa-site-156 = 6.8×10−8 respectively). Over 250 NPC-HLA associated variants within HLA were analyzed in concert to resolve separate and largely independent HLA-A, -B, and -C gene influences. Multivariate logistical regression analysis collapsed significant associations in adjacent genes spanning 500 kb (OR2H1, GABBR1, HLA-F, and HCG9) as proxies for peptide binding motifs carried by HLA- A*11:01. A similar analysis resolved an independent association signal driven by HLA-B*13:01, B*38:02, and B*55:02 alleles together. NPC resistance alleles carrying the strongly associated amino acid variants implicate specific class I peptide recognition motifs in HLA-A and -B peptide binding groove as conferring strong genetic influence on the development of NPC in China.
Author Summary
NPC is a deadly throat cancer in China that is dependent on EBV infection. Here, we performed a 1 M SNP genome-wide association study using a large cohort of Chinese study participants at risk for NPC. Although several putative gene regions show significant associations, the strongest statistical signals involved scores of variants within the HLA region on chromosome 6. HLA poses a formidable association-genetics challenge because of extensive linkage disequilibrium, rather low allele frequencies, and multiple physically close interacting genes of diverse function. We examined over 250 NPC-HLA associated variants detected with sequence-based nucleotide alleles and amino acid variants. The multiple associations were collapsed to implicate causal signals by multivariate logistical regression to resolve allele association interaction. One operative variant was identified as the HLA-A*11:01 allele motif, specifically in the peptide binding groove, which recognizes invading antigens; a second involved two aa sites with HLA-B tracking B*13:01 and B*55:02 alleles. We synthesize these new and previous discoveries to help resolve the important gene influences on this disease.
PMCID: PMC3510037  PMID: 23209447
19.  APOBEC3G Expression is Dysregulated in Primary HIV-1 Infection and a Polymorphic Variant Influences CD4+ T Cell Counts and Plasma Viral Load 
AIDS (London, England)  2010;24(2):195-204.
In the absence of HIV-1 Vif, cellular cytosine deaminases such as APOBEC3G, inhibit the virus by inducing hypermutations on viral DNA, among other mechanisms of action. We investigated the association of APOBEC3G mRNA levels and APOBEC3G genetic variants on HIV-1 susceptibility, and early disease pathogenesis using viral load and CD4+ T cell counts as outcomes.
Study subjects were 250 South African females at high risk for HIV-1C infection. We used quantitative real-time PCR to measure the expression of APOBEC3G in HIV−ve and HIV+ve primary infection samples. APOBEC3G variants were identified by DNA re-sequencing and TaqMan genotyping.
We found no correlation between APOBEC3G expression levels and plasma viral loads (r=0.053, p=0.596) or CD4+ T cell counts (r=0.030, p=0.762) in 32 seroconverters. However, APOBEC3G expression levels were significantly higher in HIV−ve individuals compared to HIV+ve individuals (p<0.0001), including matched pre- and post infection samples from the same individuals (n=13, p<0.0001). 25 single nucleotide polymorphisms (SNPs), nine of which were novel, were identified within APOBEC3G by re-sequencing followed by genotyping of 168 individuals. The H186R mutation, a codon changing variant in exon 4, was associated with high viral loads (p=0.0097) and decreased CD4+ T cell levels (p=0.0081).
These data suggest that APOBEC3G transcription is rapidly downregulated upon HIV-1 infection. During primary infection, APOBEC3G expression levels in PBMCs do not correlate with viral loads or CD4+ T cell counts. However, structural variation of APOBEC3G may significantly affect early HIV-1 pathogenesis, although the mechanism remains unclear and warrants further investigation.
PMCID: PMC3470914  PMID: 19996938
APOBEC3G; HIV-1 C; Primary Infection; mRNA Expression; Polymorphisms; Host proteins
20.  Association of Polymorphisms in the LEDGF/p75 Gene (PSIP1) with Susceptibility to HIV-1 Infection and Disease Progression 
AIDS (London, England)  2011;25(14):1711-1719.
LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans.
Integrase binding domain (IBD) of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs, SNP1-SNP4 and one exonic SNP, SNP5 were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV-1 IN was measured by AlphaScreen.
rs2277191A was more frequent among seropositives (p=0.06, Fisher's exact test), and among individuals followed longitudinally trended towards association with higher likelihood of HIV-1 acquisition (RH=2.21, p=0.08; Cox model) and it was also associated with rapid disease progression (RH=5.98, p=0.04; Cox model). rs12339417C was associated with slower decline of CD4+ T cell (p=0.02) and lower levels of LEDGF/p75 (p<0.01). Seroconverters had higher preinfection levels of LEDGF/p75 (p<0.01) but levels decreased after HIV infection (p=0.02).
Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts.
PMCID: PMC3233670  PMID: 21681054
Seven genome-wide association studies (GWAS) have been published in AIDS and only associations in the HLA region on chromosome 6 and CXCR6 have passed genome-wide significance.
We reanalyzed the data from three previously published GWAS, targeting specifically low frequency SNPs (minor allele frequency (MAF)<5%). Two groups composed of 365 slow progressors (SP) and 147 rapid progressors (RP) from Europe and the US were compared with a control group of 1394 seronegative individuals using Eigenstrat corrections.
Of the 8584 SNPs with MAF<5% in cases and controls (Bonferroni threshold=5.8×10−6), four SNPs showed statistical evidence of association with the SP phenotype. The best result was for HCP5 rs2395029 (p=8.54×10−15, OR=3.41) in the HLA locus, in partial linkage disequilibrium with two additional chromosome 6 associations in C6orf48 (p=3.03×10−10, OR=2.9) and NOTCH4 (9.08×10−07, OR=2.32). The fourth association corresponded to rs2072255 located in RICH2 (p=3.30×10−06, OR=0.43) in chromosome 17. Using HCP5 rs2395029 as a covariate, the C6orf48 and NOTCH4 signals disappeared, but the RICH2 signal still remained significant.
Besides the already known chromosome 6 associations, the analysis of low frequency SNPs brought up a new association in the RICH2 gene. Interestingly, RICH2 interacts with BST-2 known to be a major restriction factor for HIV-1 infection. Our study has thus identified a new candidate gene for AIDS molecular etiology and confirms the interest of singling out low frequency SNPs in order to exploit GWAS data.
PMCID: PMC3386792  PMID: 21107268
AIDS; HIV-1; genome-wide association study; SNP; disease progression; RICH2
22.  Genome-wide Association Study Implicates PARD3B-based AIDS Restriction 
The Journal of Infectious Diseases  2011;203(10):1491-1502.
Background. Host genetic variation influences human immunodeficiency virus (HIV) infection and progression to AIDS. Here we used clinically well-characterized subjects from 5 pretreatment HIV/AIDS cohorts for a genome-wide association study to identify gene associations with rate of AIDS progression.
Methods.  European American HIV seroconverters (n = 755) were interrogated for single-nucleotide polymorphisms (SNPs) (n = 700,022) associated with progression to AIDS 1987 (Cox proportional hazards regression analysis, co-dominant model).
Results.  Association with slower progression was observed for SNPs in the gene PARD3B. One of these, rs11884476, reached genome-wide significance (relative hazard = 0.3; P =3. 370 × 10−9) after statistical correction for 700,022 SNPs and contributes 4.52% of the overall variance in AIDS progression in this study. Nine of the top-ranked SNPs define a PARD3B haplotype that also displays significant association with progression to AIDS (hazard ratio, 0.3; P = 3.220 × 10−8). One of these SNPs, rs10185378, is a predicted exonic splicing enhancer; significant alteration in the expression profile of PARD3B splicing transcripts was observed in B cell lines with alternate rs10185378 genotypes. This SNP was typed in European cohorts of rapid progressors and was found to be protective for AIDS 1993 definition (odds ratio, 0.43, P = .025).
Conclusions. These observations suggest a potential unsuspected pathway of host genetic influence on the dynamics of AIDS progression.
PMCID: PMC3080910  PMID: 21502085
23.  Genomewide Linkage Scan for Diabetic Renal Failure and Albuminuria: The FIND Study 
American Journal of Nephrology  2011;33(5):381-389.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals.
A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations.
Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10−5, LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies.
These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.
PMCID: PMC3078269  PMID: 21454968
Albuminuria; Diabetes mellitus; Renal failure; End-stage renal disease; Linkage; Allelic association
24.  A Common HLA–DPA1 Variant is a Major Determinant of Hepatitis B Virus Clearance in Han Chinese 
The Journal of Infectious Diseases  2011;203(7):943-947.
A recent genome-wide study showed that the single nucleotide polymorphisms (SNPs) in the HLA-DP region were associated with chronic hepatitis B virus (HBV) infection in Japanese and Thai persons. We tested the effects of HLA-DP SNPs for all major HBV outcomes in Han Chinese (n = 1742): HBV resistance, clearance, chronic infection, cirrhosis, and hepatocellular carcinoma. HLA - DPA1 rs3077 T was strongly associated with decreased risk of chronic HBV infection (odds ratio, .62; P = .001), consistent with the previous report. We showed for the first time to our knowledge that it is a predictor for HBV clearance (odds ratio, 2.41; P < .001). However, rs3077 was not associated with the development of cirrhosis or hepatocellular carcinoma.
PMCID: PMC3068033  PMID: 21402545
25.  Role of Exonic Variation in Chemokine Receptor Genes on AIDS: CCRL2 F167Y Association with Pneumocystis Pneumonia 
PLoS Genetics  2011;7(10):e1002328.
Chromosome 3p21–22 harbors two clusters of chemokine receptor genes, several of which serve as major or minor coreceptors of HIV-1. Although the genetic association of CCR5 and CCR2 variants with HIV-1 pathogenesis is well known, the role of variation in other nearby chemokine receptor genes remain unresolved. We genotyped exonic single nucleotide polymorphisms (SNPs) in chemokine receptor genes: CCR3, CCRL2, and CXCR6 (at 3p21) and CCR8 and CX3CR1 (at 3p22), the majority of which were non-synonymous. The individual SNPs were tested for their effects on disease progression and outcomes in five treatment-naïve HIV-1/AIDS natural history cohorts. In addition to the known CCR5 and CCR2 associations, significant associations were identified for CCR3, CCR8, and CCRL2 on progression to AIDS. A multivariate survival analysis pointed to a previously undetected association of a non-conservative amino acid change F167Y in CCRL2 with AIDS progression: 167F is associated with accelerated progression to AIDS (RH = 1.90, P = 0.002, corrected). Further analysis indicated that CCRL2-167F was specifically associated with more rapid development of pneumocystis pneumonia (PCP) (RH = 2.84, 95% CI 1.28–6.31) among four major AIDS–defining conditions. Considering the newly defined role of CCRL2 in lung dendritic cell trafficking, this atypical chemokine receptor may affect PCP through immune regulation and inducing inflammation.
Author Summary
Human chemokine receptors are cell surface proteins that may be utilized by HIV-1 for entry into host cells. DNA variation in the HIV-1 major coreceptor CCR5 affects HIV-1 infection and progression. This study comprehensively assesses the role of genetic variation of multiple chemokine receptor genes clustered in the chromosome 3p21 and 3p22 on HIV-1 disease outcomes in HIV-1 natural history cohorts. The multivariate survival analyses identified functional variants that altered disease progression rate in CCRL2, CCR3, and CCR8. CCRL2-F167Y affects the rate to AIDS development through a specific protection against pneumocystis pneumonia (PCP), a common AIDS–defining condition. Our study identified this atypical chemokine receptor CCRL2 as a key factor involved in PCP, possibly through inducing inflammation in the lung.
PMCID: PMC3203199  PMID: 22046140

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