RESUMO
BACKGROUND: Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of ß-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. METHODS: Women without DM who had fasting glucose (FG) and insulin (FI) data forâ ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FGâ ≥â 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1câ ≥â 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. RESULTS: Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction = .02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI], .32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, CD4 cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI, .70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction < .01), among PLWH. CONCLUSIONS: Mitochondrial genetic variation is associated with ß-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Infecções por HIV , Resistência à Insulina , Negro ou Afro-Americano , Glicemia , DNA Mitocondrial/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Feminino , HIV , Infecções por HIV/complicações , Humanos , Incidência , Resistência à Insulina/genéticaRESUMO
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.
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Leiomioma/genética , Polimorfismo de Nucleotídeo Único , Adulto , Mapeamento Cromossômico , Feminino , Ligação Genética , Predisposição Genética para Doença , Técnicas de Genotipagem , Humanos , Pessoa de Meia-IdadeRESUMO
Like other members of the γ-herpesvirus family, human herpes virus 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 seven 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.
Assuntos
Biomarcadores Tumorais/genética , Infecções por HIV/complicações , HIV/patogenicidade , Polimorfismo de Nucleotídeo Único/genética , Sarcoma de Kaposi/diagnóstico , Sarcoma de Kaposi/etiologia , Estudos de Casos e Controles , Seguimentos , Infecções por HIV/genética , Infecções por HIV/virologia , Humanos , Estudos Longitudinais , Masculino , Prognóstico , Estudos Prospectivos , Biologia de SistemasRESUMO
DNA variants in the tumor necrosis factor-α (TNF) and linked lymphotoxin-α genes, and specific alleles of the highly polymorphic human leukocyte antigen B (HLA-B) gene have been implicated in a plethora of immune and infectious diseases. However, the tight linkage disequilibrium characterizing the central region of the human major histocompatibility complex (MHC) containing these gene loci has made difficult the unequivocal interpretation of genetic association data. To alleviate these difficulties and facilitate the design of more focused follow-up studies, we investigated the structure and distribution of HLA-B-specific MHC haplotypes reconstructed in a European population from unphased genotypes at a set of 25 single nucleotide polymorphism sites spanning a 66-kilobase long region across TNF. Consistent with the published data, we found limited genetic diversity across the so-called TNF block, with the emergence of seven common MHC haplotypes, termed TNF block super-haplotypes. We also found that the ancestral haplotype 8.1 shares a TNF block haplotype with HLA-B*4402. HLA-B*5701, a known protective allele in HIV-1 pathogenesis, occurred in a unique TNF block haplotype.
Assuntos
Antígenos HLA-B/genética , Complexo Principal de Histocompatibilidade/genética , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , População Branca/genética , Proteínas Adaptadoras de Transdução de Sinal , Estudos de Coortes , RNA Helicases DEAD-box/genética , Progressão da Doença , Predisposição Genética para Doença , Variação Genética , Infecções por HIV/genética , Haplótipos/genética , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Íntrons/genética , Proteínas Mitocondriais/genética , ATPases Vacuolares Próton-Translocadoras/genéticaRESUMO
While recent genomic surveys reveal growing numbers of di-allelic copy number variations, it is genes with multiallelic (>2) copy numbers that have shown association with distinct phenotypes. Current high-throughput laboratory methods are restricted to enumerating total gene copy numbers (GCNs) per individual and not the "genotype," i.e. gene copy per chromosome. Thus, association studies of multiallelic GCNs have been limited to comparison of median copies in different groups. Our new nonparametric statistical approach is based on GCN information within a trio-based study design. We present theoretical derivation of the statistics and results of simulation studies that show robustness of our approach and power under several genetic models.
Assuntos
Dosagem de Genes , Estudos de Associação Genética/métodos , Alelos , Biometria/métodos , Feminino , Estudos de Associação Genética/estatística & dados numéricos , Genótipo , Humanos , Masculino , Fenótipo , Estatísticas não ParamétricasRESUMO
BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Infecções por HIV/genética , HIV-1/patogenicidade , Seleção Genética , África , África Subsaariana , América , Ásia , Europa (Continente) , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Oriente MédioRESUMO
BACKGROUND: We hypothesized that carriage of presumably high Hsp70-producing gene variants on a specific human major histocompatibility complex haplotype, the 8.1 ancestral haplotype (8.1AH), may predispose HIV-infected individuals to AIDS-non-Hodgkin lymphoma (NHL). SETTING: We compared serum Hsp70 levels in the years preceding the diagnosis of AIDS-NHL in a matched case-control study (n = 151 pairs) nested in the Multicenter AIDS Cohort Study. METHODS: We tested the impact of 8.1AH-specific single-nucleotide polymorphism (SNP) and joint SNP-human leukocyte antigen extended haplotypes previously associated with AIDS-NHL in the Multicenter AIDS Cohort Study on the circulating Hsp70 levels in mixed linear models. RESULTS: We report elevated serum levels of Hsp70 in the 4 years preceding the diagnosis of AIDS-NHL in cases that carry 8.1AH, but not in noncarrier cases and not in carrier- or non-carrier-matched controls. The strongest predictor of higher serum Hsp70 was the haplotype A-G-A-C formed by SNPs rs537160(A) and rs1270942(G) in the complement factor CFB gene cluster, and rs2072633(A) and rs6467(C) in nearby RDBP and CYP21A2 located 70 Kb apart from the Hsp70 gene cluster. The association with A-G-A-C haplotype (beta = 0.718; standard error = 0.182; P = 0.0002) and with other 8.1AH-specific haplotypes including the high-producing tumor necrosis factor-alpha haplotype rs909253(G)-rs1800629(A) (beta = 0.308; standard error = 0.140; P = 0.032) were observed only with NHL identified as an AIDS-defining condition, but not as a post-AIDS condition, nor in combined AIDS and post-AIDS cases. CONCLUSION: Our combined genetic and functional approach suggests that the altered level of Hsp70 is a correlate of 8.1AH-mediated AIDS-NHL. Further investigation of the Hsp70 gene cluster and nearby loci that are tagged by A-G-A-C could better elucidate the genetic determinants of the malignancy.
Assuntos
Antígeno HLA-B8/genética , Antígeno HLA-DR3/genética , Proteínas de Choque Térmico HSP70/sangue , Linfoma Relacionado a AIDS/diagnóstico , Linfoma não Hodgkin/diagnóstico , Estudos de Casos e Controles , Predisposição Genética para Doença , Infecções por HIV , Proteínas de Choque Térmico HSP70/genética , Haplótipos , Homossexualidade Masculina , Humanos , Linfoma Relacionado a AIDS/genética , Linfoma não Hodgkin/genética , Masculino , Família Multigênica , Polimorfismo de Nucleotídeo ÚnicoRESUMO
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-alpha, IL-4, IL-6, and IL-12 that are involved in the T(H)1-T(H)2 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.
Assuntos
Infecções por HIV/imunologia , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/imunologia , Hospedeiro Imunocomprometido , Interleucina-10/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/patologia , Criança , Estudos de Coortes , Citosina , Feminino , Seguimentos , Guanina , Soronegatividade para HIV/imunologia , Soropositividade para HIV/imunologia , HIV-1/imunologia , Haplótipos/genética , Humanos , Infecções por Papillomavirus/imunologia , Regiões Promotoras Genéticas/genética , Fatores de RiscoRESUMO
INTRODUCTION: Evidence for linkage and association of obesity-related quantitative traits to chromosome 1q43 has been reported in the Quebec Family Study (QFS) and in populations of Caribbean Hispanic ancestries yet no specific candidate locus has been replicated to date. METHODS: Using a set of 1,902 single nucleotide polymorphisms (SNPs) genotyped in 525 African American (AA) and 391 European American (EA) women enrolled in the NIEHS uterine fibroid study (NIEHS-UFS), we generated a fine association map for the body mass index (BMI) across a 2.3 megabase-long interval delimited by RGS7 (regulator of G-protein signaling 7) and PLD5 (Phospholipase D, member 5). Multivariable-adjusted linear regression models were fitted to the data to evaluate the association in race-stratified analyses and meta-analysis. RESULTS: The strongest associations were observed in a recessive genetic model and peaked in the 3' end of RGS7 at intronic rs261802 variant in the AA group (p = 1.0 x 10-4) and in meta-analysis of AA and EA samples (p = 9.0 x 10-5). In the EA group, moderate associations peaked at rs6429264 (p = 2.0 x 10-3) in the 2 Kb upstream sequence of RGS7. In the reference populations for the European ancestry in the 1,000 genomes project, rs6429264 occurs in strong linkage disequilibrium (D' = 0.94) with rs1341467, the strongest candidate SNP for total body fat in QFS that failed genotyping in the present study. Additionally we report moderate associations at the 3' end of PLD5 in meta-analysis (3.2 x 10-4 ≤ p ≤ 5.8 x 10-4). CONCLUSION: We report replication data suggesting that RGS7, a gene abundantly expressed in the brain, might be a putative body fat QTL on human chromosome 1q43. Future genetic and functional studies are required to substantiate our observations and to potentially link them to the neurobehavioral phenotypes associated with the RGS7 region.
Assuntos
Tecido Adiposo , Mapeamento Cromossômico , Cromossomos Humanos Par 1 , Locos de Características Quantitativas , Adulto , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Mapeamento Cromossômico/métodos , Matriz Extracelular/fisiologia , Ligação Genética/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Matriz Extracelular/patologia , Feminino , Seguimentos , Humanos , Leiomioma/diagnóstico , Pessoa de Meia-Idade , Neoplasias Uterinas/diagnósticoRESUMO
We conducted a follow-up association study across extended candidate chromosomal regions for uterine leiomyoma (UL), or fibroids, to search for loci influencing the size of UL in 916 premenopausal North American women participants to the NIEHS uterine fibroid study. Proportional odds models with adjustments for confounders were fitted to evaluate the association of a final set of 2,484 single nucleotide polymorphisms (SNPs) with the size of uterine fibroids measured by transabdominal and transvaginal ultrasounds. SNP association with UL size was tested in a case-only design comparing three categories of tumor size (small, medium and large tumors) and in a design that included UL-free controls as the lowest category of a four-level ordinal outcome to account for misclassifications due to small, undetected tumors. In the case-only design, rs2285789 in SORCS2 (sortilin-related VPS10 domain containing receptor 2) was the sole variant that remained significant after correction for multiple testing (Bonferroni-adjusted P=0.037). Several other SNPs, namely those located in MYT1L, TMCC1 and BRCA1, reached promising associations. In the design that included the controls, several genes of potential relevance to UL pathogenesis were associated (Bonferroni-unadjusted P < 0.01) with tumor size, particularly LIFR-AS1 (leukemia inhibitory factor receptor alpha-antisense RNA 1), which showed the strongest association (Bonferroni-unadjusted P=0.0006) among the genes with regulated expression in UL. In conclusion, SORCS2, a known GWAS candidate for circulating IGF-I and IGFBP-3, may act through IGF-I signaling to affect the size of fibroids. Through down-regulation of LIFR, LIFR-AS1 may mediate the inhibitory action of LIF (leukemia inhibitory factor), a cytokine involved in embryonic uterine development. Replication analyses are needed to substantiate our reported associations of SORCS2 and LIFR-AS1 with the size of fibroids.
RESUMO
We evaluated the association of 56 candidate SNPs identified in two published genome-wide association studies (GWAS) of uterine leiomyoma (UL), or fibroids, with the risk and tumor size in the multi-ethnic uterine fibroid study (NIEHS-UFS). The selected SNPs were genotyped in 916 premenopausal women of African American (AA) and European American (EA) descents and their association with the outcomes was evaluated in race-stratified models and in meta-analysis of risk in NIEHS-UFS and discovery and replication GWAS in the Japanese population. We report moderate associations of variant rs4954368 in THSD7B (thrombospondin, type I, domain containing 7B) with tumor size in pooled analysis of AA and EA samples (P = 0.004), and at TNRC6B (trinucleotide repeat containing 6B) variants rs138039 and rs139909 in EA (P = 0.001 and 0.008, respectively). The most significant associations with risk in meta-analysis were observed at TNRC6B variants rs739182 (P = 3.7 × 10(-10)) and rs2072858 (P = 1.1 × 10(-9)) and were stronger than those reported in the discovery GWAS (P = 2.01 × 10(-8) and 2.58 × 10(-8), respectively). The present study failed to replicate the associations reported for CCDC57 and FASN in a discovery GWAS in populations of European descent. Consistent with previous replication studies in the Right From the Start Study (RFTS) and the BioVU DNA repository, we provide independent evidence for association of TNRC6B with both risk and size of UL. The present study is the first to report a replicated association of THSD7B with UL, albeit with tumor size and not with risk.
RESUMO
Mutations in fumarate hydratase (FH) on chromosome 1q43 cause a rare cancer syndrome, hereditary leiomyomatosis and renal cell cancer (HLRCC), but are rare in nonsyndromic and common uterine leiomyoma (UL) or fibroids. Studies suggested that variants in FH or in a linked gene may also predispose to UL. We re-sequenced 2.3âMb of DNA spanning FH in 96 UL cases and controls from the multiethnic NIEHS-uterine fibroid study, and in 18 HLRCC-associated UL probands from European families then selected 221 informative SNPs for follow-up genotyping. We report promising susceptibility associations with UL peaking at rs78220092 (P=7.0×10(-5)) in the RGS7-FH interval in African Americans. In race-combined analyses and in meta-analyses (n=916), we identified promising associations with risk peaking upstream of a non-protein coding RNA (lncRNA) locus located in the RGS7-FH interval closer to RGS7, and associations with tumor size peaking in the distal phospholipase D family, member 5 (PLD5) gene at rs2654879 (P=1.7×10(-4)). We corroborated previously reported FH mutations in nine out of the 18 HLRCC-associated UL cases and identified two missense mutations in FH in only two nonsyndromic UL cases and one control. Our fine association mapping and integration of existing gene profiling data showing upregulated expression of the lncRNA and downregulation of PLD5 in fibroids, as compared to matched myometrium, suggest a potential role of this genomic region in UL pathogenesis. While the identified variations at 1q43 represent a potential risk locus for UL, future replication analyses are required to substantiate our observation.
Assuntos
Cromossomos Humanos Par 1 , Fumarato Hidratase/genética , Leiomioma/genética , Proteínas RGS/genética , Neoplasias Uterinas/genética , Adulto , Negro ou Afro-Americano/genética , Feminino , Expressão Gênica , Genótipo , Humanos , Leiomioma/patologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante , Carga Tumoral , Neoplasias Uterinas/patologia , População Branca/genéticaRESUMO
Genetic polymorphism along mitochondrial DNA (mtDNA) defines population-specific signatures called mtDNA haplogroups. Estimation of mtDNA haplogroup distribution may be prone to errors, notably if the study sample is not drawn from a multicenter cohort. Here, we report on mtDNA diversity in a sample of African American individuals (n = 343) enrolled in a multicenter cohort. Sequencing of the hypervariable regions I and II of the D-loop control region showed that the most common mitochondrial variants are 73G, 146C, 150T, 152C, 189G, 16278T, and 16311C. In agreement with the published data, we observed 17 common mtDNA haplogroups: L0, L1, L1b, L1c, L2, L2a, L2b, L2c, L2e, L3, L3b, L3d, L3e, L3f, L3h, L3x, and L4. The most commonly observed haplogroup is L2a (19.8%), followed by L1b (10.2%). Overall, the observed mtDNA haplogroup distribution in our study is similar to those published for the African American and the African populations.
Assuntos
Negro ou Afro-Americano/genética , DNA Mitocondrial/genética , Variação Genética , Estudos de Coortes , DNA Mitocondrial/análise , DNA Mitocondrial/classificação , Genética Populacional , Haplótipos , Humanos , Filogenia , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Análise de Sequência de DNARESUMO
Gene copy number variation (CNV) of the CC Chemokine ligand 3-Like-1 (CCL3L1) gene located on chromosome 17q12 has been associated with many diseases, including viral infections and autoimmune diseases. High sequence homology between CCL3L1 and three other related genes within the same cluster, CCL3, CCL3L2, and CCL3L3, make it difficult to determine the copy number of each gene as well as distinguishing variants within each gene versus between genes. We identified a total of 50SNPs, 31 known and 19 novel SNPs, in a subset of West Africa Reference (Yoruba individuals from Ibadan, Nigeria (YRI)) samples from HapMap. One of these previously unidentified variations is a non-synonymous change while several other unreported variations are located near potential regulatory sites. The variations identified in these immune-related genes from this study will shed light in the understanding of both structural and nucleotide polymorphisms that can be used in association studies of diseases in populations.
Assuntos
Quimiocina CCL3/genética , Dosagem de Genes , Polimorfismo de Nucleotídeo Único , População Negra , Quimiocina CCL3/classificação , Quimiocina CCL3/imunologia , Projeto HapMap , Humanos , NigériaRESUMO
OBJECTIVE: To evaluate the impact of mitochondrial DNA (mtDNA) haplogroups on virologic and immunological outcomes of HIV infection. DESIGN: HAART-naive African American adolescent participants to the Reaching for Excellence in Adolescent Care and Health study. METHODS: The mtDNA haplogroups were inferred from sequenced mtDNA hypervariable regions HV1 and HV2 and their predictive value on HIV outcomes were evaluated in linear mixed models, controlled for human leukocyte antigen (HLA)-B27, HLA-B57 and HLA-B35-Px alleles and other covariates. RESULTS: We report data showing that the mtDNA L2 lineage, a group composed of L2a, L2b and L2e mtDNA haplogroups in the studied population, is significantly associated (beta â= -0.08; Bonferroni-adjusted P = 0.004) with decline of CD4 T cells (median loss of 8 ± 1 cells per month) in HAART-naive HIV-infected individuals of African American descent (n = 133). No significant association (P < 0.05) with set-point viral load was observed with any of the tested mtDNA haplogroups. The present data concur with previous findings in the AIDS Clinical Trials Group study 384, implicating the L2 lineage with slower CD4 T-cell recovery after antiretroviral therapy in African Americans. CONCLUSIONS: Whereas the L2 lineage showed an association with unfavorable immunological outcomes of HIV infection, its phylogenetic divergence from J and U5a, two lineages associated with accelerated HIV progression in European Americans, raises the possibility that interactions with common nucleus-encoded variants drive HIV progression. Disentangling the effects of mitochondrial and nuclear gene variants on the outcomes of HIV infection is an important step to be taken toward a better understanding of HIV/AIDS pathogenesis and pharmacogenomics.
Assuntos
DNA Mitocondrial/genética , Variação Genética , Infecções por HIV/imunologia , Infecções por HIV/virologia , Adolescente , Negro ou Afro-Americano , Criança , Estudos de Coortes , DNA Mitocondrial/química , Feminino , Estudos de Associação Genética , Haplótipos , Humanos , Masculino , Análise de Sequência de DNA , Resultado do TratamentoRESUMO
Uterine leiomyomas (or fibroids) are the most common tumors in women of reproductive age. Early studies of two familial cancer syndromes, the multiple cutaneous and uterine leiomyomatosis (MCUL1), and the hereditary leiomyomatosis and renal cell cancer (HLRCC), implicated FH, a gene on chromosome 1q43 encoding the tricarboxylic acid cycle fumarate hydratase enzyme. The role of this metabolic housekeeping gene in tumorigenesis is still a matter of debate and pseudo-hypoxia has been suggested as a pathological mechanism. Inactivating FH mutations have rarely been observed in the nonsyndromic and common form of fibroids; however, loss of heterozygosity across FH appeared as a significant event in the pathogenesis of a subset of these tumors. To assess the role of FH and the linked genes in nonsyndromic uterine fibroids, we explored a two-megabase interval spanning FH in the NIEHS Uterine fibroid study, a cross-sectional study of fibroids in 1152 premenopausal women. Association mapping with a dense set of single nucleotide polymorphisms revealed several peaks of association (p = 10(-2)-8.10(-5)) with the risk and/or growth of fibroids. In particular, genes encoding factors suspected (cytosolic FH) or known (EXO1 - exonuclease 1) to be involved in DNA mismatch repair emerged as candidate susceptibility genes whereas those acting in the autophagy/apoptosis (MAP1LC3C - microtubule-associated protein) or signal transduction (RGS7 - Regulator of G-protein and PLD5- Phospoholipase D) appeared to affect tumor growth. Furthermore, body mass index, a suspected confounder altered significantly but unpredictably the association with the candidate genes in the African and European American populations, suggesting the presence of a major obesity gene in the studied region. With the high potential for occult tumors in common conditions such as fibroids, validation of our data in family-based studies is needed.
Assuntos
Cromossomos Humanos Par 1/genética , Genes Neoplásicos , Leiomioma/genética , Proteínas de Neoplasias/genética , Neoplasias Uterinas/genética , Adulto , População Negra , Feminino , Ligação Genética , Humanos , Masculino , Pessoa de Meia-Idade , População BrancaRESUMO
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.
RESUMO
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.