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1.
Nat Med ; 30(5): 1384-1394, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38740997

RESUMO

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.


Assuntos
Cadeias HLA-DRB1 , Feminino , Humanos , Lactente , Masculino , Formação de Anticorpos/genética , Formação de Anticorpos/imunologia , População Negra/genética , Vacinas contra Hepatite B/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Vacina contra Coqueluche/imunologia , Vacina contra Coqueluche/genética , Locos de Características Quantitativas , Uganda , Vacinação , Coqueluche/prevenção & controle , Coqueluche/imunologia , Coqueluche/genética , Burkina Faso , África do Sul , População Africana , População Europeia
2.
bioRxiv ; 2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37986808

RESUMO

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

3.
medRxiv ; 2023 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-37425840

RESUMO

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.

4.
Nat Med ; 28(6): 1163-1166, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35654908

RESUMO

The poor transferability of genetic risk scores (GRSs) derived from European ancestry data in diverse populations is a cause of concern. We set out to evaluate whether GRSs derived from data of African American individuals and multiancestry data perform better in sub-Saharan Africa (SSA) compared to European ancestry-derived scores. Using summary statistics from the Million Veteran Program (MVP), we showed that GRSs derived from data of African American individuals enhance polygenic prediction of lipid traits in SSA compared to European and multiancestry scores. However, our GRS prediction varied greatly within SSA between the South African Zulu (low-density lipoprotein cholesterol (LDL-C), R2 = 8.14%) and Ugandan cohorts (LDL-C, R2 = 0.026%). We postulate that differences in the genetic and environmental factors between these population groups might lead to the poor transferability of GRSs within SSA. More effort is required to optimize polygenic prediction in Africa.


Assuntos
Estudo de Associação Genômica Ampla , Grupos Populacionais , População Negra/genética , LDL-Colesterol/genética , Humanos , Fatores de Risco
5.
Nutr Metab Cardiovasc Dis ; 32(6): 1511-1518, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35461751

RESUMO

BACKGROUND AND AIMS: Obesity is one of the leading causes of non-communicable diseases (NCD). Thus, NCD risk varies in obese individuals based on the location of their fat depots; while subcutaneous adiposity is protective, visceral adiposity increases NCD risk. Although, previously anthropometric traits have been used to quantify body shape in low-income settings, there is no consensus on how it should be assessed. Hence, there is a growing interest to evaluate body shape derived from the principal component analysis (PCA) of anthropometric traits; however, this is yet to be explored in individuals of African ancestry whose body shape is different from those of Europeans. We set out to capture body shape in its multidimensional structure and examine the association between genetic variants and body shape in individuals of African ancestry. METHOD AND RESULTS: We performed a genome-wide association study (GWAS) for body shape derived from PCA analysis of anthropometric traits in the Ugandan General Population Cohort (GPC, n = 6407) and the South African Zulu Cohort (SZC, n = 2595), followed by a GWAS meta-analysis to assess the genetic variants associated with body shape. We identified variants in FGF12, GRM8, TLX1NB and TRAP1 to be associated with body shape. These genes were different from the genes been associated with BMI, height, weight, WC and waist-hip ration in continental Africans. Notably, we also observed that a standard deviation change in body shape was associated with an increase in blood pressure and blood lipids. CONCLUSION: Variants associated with body shape, as a composite variable might be different for those of individual anthropometric traits. Larger studies are required to further explore these phenomena.


Assuntos
Estudo de Associação Genômica Ampla , Doenças não Transmissíveis , Adiposidade/genética , Índice de Massa Corporal , Fatores de Crescimento de Fibroblastos , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Proteínas de Choque Térmico HSP90/genética , Humanos , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/genética , Somatotipos , Relação Cintura-Quadril
6.
Diabetes Care ; 45(3): 717-723, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35015074

RESUMO

OBJECTIVE: Polygenic prediction of type 2 diabetes (T2D) in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of T2D from Africa and the poor transferability of European-derived polygenic risk scores (PRSs) in diverse ethnicities. We set out to evaluate if African American, European, or multiethnic-derived PRSs would improve polygenic prediction in continental Africans. RESEARCH DESIGN AND METHODS: Using the PRSice software, ethnic-specific PRSs were computed with weights from the T2D GWAS multiancestry meta-analysis of 228,499 case and 1,178,783 control subjects. The South African Zulu study (n = 1,602 case and 981 control subjects) was used as the target data set. Validation and assessment of the best predictive PRS association with age at diagnosis were conducted in the Africa America Diabetes Mellitus (AADM) study (n = 2,148 case and 2,161 control subjects). RESULTS: The discriminatory ability of the African American and multiethnic PRSs was similar. However, the African American-derived PRS was more transferable in all the countries represented in the AADM cohort and predictive of T2D in the country combined analysis compared with the European and multiethnic-derived scores. Notably, participants in the 10th decile of this PRS had a 3.63-fold greater risk (odds ratio 3.63; 95% CI 2.19-4.03; P = 2.79 × 10-17) per risk allele of developing diabetes and were diagnosed 2.6 years earlier than those in the first decile. CONCLUSIONS: African American-derived PRS enhances polygenic prediction of T2D in continental Africans. Improved representation of non-European populations (including Africans) in GWAS promises to provide better tools for precision medicine interventions in T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , População Negra , Diabetes Mellitus Tipo 2/etnologia , Humanos , Herança Multifatorial/genética , Fatores de Risco , África do Sul
7.
Sci Rep ; 12(1): 1131, 2022 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-35064169

RESUMO

Haematological traits are linked to cardiovascular, metabolic, infectious and immune disorders, as well as cancer. Here, we examine the role of genetic variation in shaping haematological traits in two isolated Mediterranean populations. Using whole-genome sequencing data at 22× depth for 1457 individuals from Crete (MANOLIS) and 1617 from the Pomak villages in Greece, we carry out a genome-wide association scan for haematological traits using linear mixed models. We discover novel associations (p < 5 × 10-9) of five rare non-coding variants with alleles conferring effects of 1.44-2.63 units of standard deviation on red and white blood cell count, platelet and red cell distribution width. Moreover, 10.0% of individuals in the Pomak population and 6.8% in MANOLIS carry a pathogenic mutation in the Haemoglobin Subunit Beta (HBB) gene. The mutational spectrum is highly diverse (10 different mutations). The most frequent mutation in MANOLIS is the common Mediterranean variant IVS-I-110 (G>A) (rs35004220). In the Pomak population, c.364C>A ("HbO-Arab", rs33946267) is most frequent (4.4% allele frequency). We demonstrate effects on haematological and other traits, including bilirubin, cholesterol, and, in MANOLIS, height and gestation age. We find less severe effects on red blood cell traits for HbS, HbO, and IVS-I-6 (T>C) compared to other b+ mutations. Overall, we uncover allelic diversity of HBB in Greek isolated populations and find an important role for additional rare variants outside of HBB.


Assuntos
Índices de Eritrócitos/genética , Genética Populacional , Globinas beta/genética , Estudos de Coortes , Análise Mutacional de DNA , Contagem de Eritrócitos , Frequência do Gene , Variação Genética , Estudo de Associação Genômica Ampla , Grécia , Humanos , Contagem de Leucócitos , Mutação , Testes de Função Plaquetária , Sequenciamento Completo do Genoma
8.
Diabet Med ; 38(11): e14605, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34028093

RESUMO

OBJECTIVE: South Africa has a high burden of HIV infection and anaemia. These conditions may cause HbA1c to over- or underestimate glycaemia; however, this has not been comprehensively investigated in African populations. We assessed the association of anaemia, HIV infection and antiretroviral therapy (ART) with HbA1c , and implications for the detection and diagnosis of diabetes, in a black South African population. RESEARCH DESIGN AND METHODS: In this population-based cross-sectional study in eThekwini municipality (Durban), South Africa, we assessed HbA1c and conducted oral glucose tolerance tests (OGTTs), HIV diagnostic tests and full blood count measurements among 1067 participants without a history of diabetes diagnosis. Linear regression was used to examine differences in HbA1c by anaemia (comparator: no anaemia), or HIV and ART (comparator: no HIV) status. HbA1c -based diabetes prevalence was compared with OGTT-based prevalence among individuals with anaemia and with untreated and ART-treated HIV. RESULTS: In adjusted analyses, normocytic and microcytic anaemia were associated with higher HbA1c compared with no anaemia, whereas macrocytic anaemia and ART-treated HIV were associated with lower HbA1c compared with no anaemia and no HIV, respectively. However, magnitudes of association were small (range: ß  = -3.4 mmol/mol or -0.31%, p < 0.001 [macrocytic anaemia] to ß = 2.1 mmol/mol or 0.19%, p < 0.001 [microcytic anaemia]). There was no significant difference in diabetes prevalence based on HbA1c or OGTT among individuals with anaemia (2.9% vs. 3.3%, p = 0.69), untreated HIV (1.6% vs. 1.6% p = 1.00) or ART-treated HIV (2.9% vs. 1.2%, p = 0.08). CONCLUSIONS: Our results suggest that anaemia and HIV status appear unlikely to materially affect the utility of HbA1c for diabetes detection and diagnosis in this population. Further studies are needed to examine these associations in sub-Saharan African populations.


Assuntos
Anemia/etnologia , População Negra , Glicemia/análise , Diabetes Mellitus/etnologia , Hemoglobinas Glicadas/análise , Infecções por HIV/etnologia , HIV , Adulto , Comorbidade , Estudos Transversais , Diabetes Mellitus/sangue , Feminino , Humanos , Masculino , Vigilância da População , Prevalência , África do Sul/epidemiologia
9.
BMC Med ; 19(1): 115, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34011341

RESUMO

BACKGROUND: Children living in sub-Saharan Africa have a high burden of rickets and infectious diseases, conditions that are linked to vitamin D deficiency. However, data on the vitamin D status of young African children and its environmental and genetic predictors are limited. We aimed to examine the prevalence and predictors of vitamin D deficiency in young African children. METHODS: We measured 25-hydroxyvitamin D (25(OH)D) and typed the single nucleotide polymorphisms, rs4588 and rs7041, in the GC gene encoding the vitamin D binding protein (DBP) in 4509 children aged 0-8 years living in Kenya, Uganda, Burkina Faso, The Gambia and South Africa. We evaluated associations between vitamin D status and country, age, sex, season, anthropometric indices, inflammation, malaria and DBP haplotypes in regression analyses. RESULTS: Median age was 23.9 months (interquartile range [IQR] 12.3, 35.9). Prevalence of vitamin D deficiency using 25(OH)D cut-offs of < 30 nmol/L and < 50 nmol/L was 0.6% (95% CI 0.4, 0.9) and 7.8% (95% CI 7.0, 8.5), respectively. Overall median 25(OH)D level was 77.6 nmol/L (IQR 63.6, 94.2). 25(OH)D levels were lower in South Africa, in older children, during winter or the long rains, and in those with afebrile malaria, and higher in children with inflammation. 25(OH)D levels did not vary by stunting, wasting or underweight in adjusted regression models. The distribution of Gc variants was Gc1f 83.3%, Gc1s 8.5% and Gc2 8.2% overall and varied by country. Individuals carrying the Gc2 variant had lower median 25(OH)D levels (72.4 nmol/L (IQR 59.4, 86.5) than those carrying the Gc1f (77.3 nmol/L (IQR 63.5, 92.8)) or Gc1s (78.9 nmol/L (IQR 63.8, 95.5)) variants. CONCLUSIONS: Approximately 0.6% and 7.8% of young African children were vitamin D deficient as defined by 25(OH)D levels < 30 nmol/L and < 50 nmol/L, respectively. Latitude, age, season, and prevalence of inflammation and malaria should be considered in strategies to assess and manage vitamin D deficiency in young children living in Africa.


Assuntos
Deficiência de Vitamina D , Adulto , Criança , Pré-Escolar , Haplótipos , Humanos , Prevalência , Estações do Ano , África do Sul , Vitamina D , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologia , Proteína de Ligação a Vitamina D/genética , Adulto Jovem
10.
Nat Med ; 27(4): 653-658, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33619371

RESUMO

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.


Assuntos
Deficiências de Ferro , Malária/complicações , Absorção Fisiológica , Adolescente , África , Criança , Pré-Escolar , Feminino , Geografia , Hepcidinas/metabolismo , Humanos , Lactente , Masculino , Análise da Randomização Mendeliana , Traço Falciforme/complicações
11.
Nat Commun ; 11(1): 3849, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737300

RESUMO

Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr Virus (EBV) establish life-long infections and are associated with malignancies. Striking geographic variation in incidence and the fact that virus alone is insufficient to cause disease, suggests other co-factors are involved. Here we present epidemiological analysis and genome-wide association study (GWAS) in 4365 individuals from an African population cohort, to assess the influence of host genetic and non-genetic factors on virus antibody responses. EBV/KSHV co-infection (OR = 5.71(1.58-7.12)), HIV positivity (OR = 2.22(1.32-3.73)) and living in a more rural area (OR = 1.38(1.01-1.89)) are strongly associated with immunogenicity. GWAS reveals associations with KSHV antibody response in the HLA-B/C region (p = 6.64 × 10-09). For EBV, associations are identified for VCA (rs71542439, p = 1.15 × 10-12). Human leucocyte antigen (HLA) and trans-ancestry fine-mapping substantiate that distinct variants in HLA-DQA1 (p = 5.24 × 10-44) are driving associations for EBNA-1 in Africa. This study highlights complex interactions between KSHV and EBV, in addition to distinct genetic architectures resulting in important differences in pathogenesis and transmission.


Assuntos
Anticorpos Antivirais/biossíntese , Resistência à Doença/genética , Infecções por Vírus Epstein-Barr/genética , Infecções por Henipavirus/genética , Interações Hospedeiro-Patógeno/genética , Sarcoma de Kaposi/genética , Adolescente , Adulto , Antígenos Virais/genética , Antígenos Virais/imunologia , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Coinfecção , Infecções por Vírus Epstein-Barr/epidemiologia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Antígenos Nucleares do Vírus Epstein-Barr/genética , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , HIV/genética , HIV/imunologia , HIV/patogenicidade , Cadeias alfa de HLA-DQ/genética , Cadeias alfa de HLA-DQ/imunologia , Infecções por Henipavirus/epidemiologia , Infecções por Henipavirus/imunologia , Infecções por Henipavirus/virologia , Herpesvirus Humano 4/genética , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Herpesvirus Humano 8/patogenicidade , Interações Hospedeiro-Patógeno/imunologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , População Rural , Sarcoma de Kaposi/epidemiologia , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/virologia , Uganda/epidemiologia , População Urbana
12.
BMC Public Health ; 20(1): 927, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32539702

RESUMO

BACKGROUND: Leisure-time physical activity (LTPA) is an important contributor to total physical activity and the focus of many interventions promoting activity in high-income populations. Little is known about LTPA in sub-Saharan Africa (SSA), and with expected declines in physical activity due to rapid urbanisation and lifestyle changes we aimed to assess the sociodemographic differences in the prevalence of LTPA in the adult populations of this region to identify potential barriers for equitable participation. METHODS: A two-step individual participant data meta-analysis was conducted using data collected in SSA through 10 population health surveys that included the Global Physical Activity Questionnaire. For each sociodemographic characteristic, the pooled adjusted prevalence and risk ratios (RRs) for participation in LTPA were calculated using the random effects method. Between-study heterogeneity was explored through meta-regression analyses and tests for interaction. RESULTS: Across the 10 populations (N = 26,022), 18.9% (95%CI: 14.3, 24.1; I2 = 99.0%) of adults (≥ 18 years) participated in LTPA. Men were more likely to participate in LTPA compared with women (RR for women: 0.43; 95%CI: 0.32, 0.60; P < 0.001; I2 = 97.5%), while age was inversely associated with participation. Higher levels of education were associated with increased LTPA participation (RR: 1.30; 95%CI: 1.09, 1.55; P = 0.004; I2 = 98.1%), with those living in rural areas or self-employed less likely to participate in LTPA. These associations remained after adjusting for time spent physically active at work or through active travel. CONCLUSIONS: In these populations, participation in LTPA was low, and strongly associated with sex, age, education, self-employment and urban residence. Identifying the potential barriers that reduce participation in these groups is necessary to enable equitable access to the health and social benefits associated with LTPA.


Assuntos
Exercício Físico/psicologia , Promoção da Saúde/estatística & dados numéricos , Atividades de Lazer/psicologia , Fatores Socioeconômicos , Adulto , África Subsaariana , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Inquéritos e Questionários , Adulto Jovem
13.
Science ; 367(6484)2020 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-32193295

RESUMO

Genome sequences from diverse human groups are needed to understand the structure of genetic variation in our species and the history of, and relationships between, different populations. We present 929 high-coverage genome sequences from 54 diverse human populations, 26 of which are physically phased using linked-read sequencing. Analyses of these genomes reveal an excess of previously undocumented common genetic variation private to southern Africa, central Africa, Oceania, and the Americas, but an absence of such variants fixed between major geographical regions. We also find deep and gradual population separations within Africa, contrasting population size histories between hunter-gatherer and agriculturalist groups in the past 10,000 years, and a contrast between single Neanderthal but multiple Denisovan source populations contributing to present-day human populations.


Assuntos
Variação Genética , Genética Populacional , Genoma Humano , Sequenciamento Completo do Genoma , África , América , Animais , Ásia , Variações do Número de Cópias de DNA , Haplótipos , Hominidae/genética , Humanos , Mutação INDEL , Homem de Neandertal/genética , Oceania , Filogenia , Polimorfismo de Nucleotídeo Único , Densidade Demográfica , Grupos Raciais/genética
14.
Sci Adv ; 5(9): eaaw0109, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31517041

RESUMO

Iron acquisition is critical for life. Ferroportin (FPN) exports iron from mature erythrocytes, and deletion of the Fpn gene results in hemolytic anemia and increased fatality in malaria-infected mice. The FPN Q248H mutation (glutamine to histidine at position 248) renders FPN partially resistant to hepcidin-induced degradation and was associated with protection from malaria in human studies of limited size. Using data from cohorts including over 18,000 African children, we show that the Q248H mutation is associated with modest protection against anemia, hemolysis, and iron deficiency, but we found little evidence of protection against severe malaria or bacteremia. We additionally observed no excess Plasmodium growth in Q248H erythrocytes ex vivo, nor evidence of selection driven by malaria exposure, suggesting that the Q248H mutation does not protect from malaria and is unlikely to deprive malaria parasites of iron essential for their growth.


Assuntos
Anemia/genética , Proteínas de Transporte de Cátions/genética , Deficiências de Ferro , Mutação de Sentido Incorreto , Substituição de Aminoácidos , Anemia/metabolismo , Bacteriemia/genética , Bacteriemia/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Eritrócitos/metabolismo , Feminino , Humanos , Lactente , Recém-Nascido , Ferro/metabolismo , Malária/genética , Malária/metabolismo , Masculino
15.
Nat Commun ; 10(1): 4330, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551420

RESUMO

Most genome-wide association studies are based on samples of European descent. We assess whether the genetic determinants of blood lipids, a major cardiovascular risk factor, are shared across populations. Genetic correlations for lipids between European-ancestry and Asian cohorts are not significantly different from 1. A genetic risk score based on LDL-cholesterol-associated loci has consistent effects on serum levels in samples from the UK, Uganda and Greece (r = 0.23-0.28, p < 1.9 × 10-14). Overall, there is evidence of reproducibility for ~75% of the major lipid loci from European discovery studies, except triglyceride loci in the Ugandan samples (10% of loci). Individual transferable loci are identified using trans-ethnic colocalization. Ten of fourteen loci not transferable to the Ugandan population have pleiotropic associations with BMI in Europeans; none of the transferable loci do. The non-transferable loci might affect lipids by modifying food intake in environments rich in certain nutrients, which suggests a potential role for gene-environment interactions.


Assuntos
Povo Asiático/genética , População Negra/genética , Lipídeos/sangue , População Branca/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Lipídeos/genética , Fatores de Risco
16.
Mol Genet Genomic Med ; 7(10): e00950, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31469255

RESUMO

BACKGROUND: Genetic association studies of blood pressure (BP) have mostly been conducted in non-African populations. Using the Entebbe Mother and Baby Study (EMaBS), we aimed to identify genetic variants associated with BP among Ugandan adolescents. METHODS: Systolic and diastolic BP were measured among 10- and 11-year olds. Whole-genome genotype data were generated using Illumina omni 2.5M arrays and untyped variants were imputed. Genome-wide association study (GWAS) was conducted using linear mixed model regression to account for population structure. Linear regression analysis was used to assess whether variants previously associated with BP (p < 5.0 × 10-8 ) in published BP GWASs were replicated in our study. RESULTS: Of the 14 million variants analyzed among 815 adolescents, none reached genome-wide significance (p < 5.0×10-8 ) for association with systolic or diastolic BP. The most strongly associated variants were rs181430167 (p = 6.8 × 10-7 ) for systolic BP and rs12991132 (p = 4.0 × 10-7 ) for diastolic BP. Thirty-three (17 single nucleotide polymorphisms (SNPs) for systolic BP, 15 SNPs for diastolic BP and one SNP for both) of 330 variants previously identified as associated with BP were replicated in this study, but none remained significant after accounting for multiple testing. CONCLUSION: Variants showing suggestive associations are worthy of future investigation. Replication results suggest that variants influencing adolescent BP may overlap somewhat with those already established in previous studies, largely based on adults in Western settings.


Assuntos
Pressão Sanguínea/genética , Estudo de Associação Genômica Ampla , Proteínas Adaptadoras de Transdução de Sinal/genética , Criança , Loci Gênicos , Genótipo , Humanos , Modelos Lineares , Polimorfismo de Nucleotídeo Único , Fatores de Transcrição/genética , Uganda
17.
Indian Heart J ; 71(2): 149-154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31280828

RESUMO

AIM: The purpose of the present study was to examine whether clinical differences exist between the biodegradable polymer (BDP)-coated Tetrilimus everolimus-eluting stent (EES) and the durable polymer (DP)-coated Xience EES by comparing the major adverse cardiac event (MACE) rate at 12 months in all-comer patients. METHODS: This study was designed as a multicentre, observational, retrospective, investigator-initiated study between January 2016 and October 2016. Two hundred thirteen patients who underwent percutaneous coronary intervention (PCI) with the BDP-EES were compared with 204 patients who underwent PCI with the DP-EES, irrespective of lesion complexity, comorbidities and acute presentation. The primary end point was MACE defined as a composite of cardiac death, myocardial infarction and target lesion revascularization. RESULTS: Baseline clinical and lesion characteristics of both the groups were similar, although the BDP-EES group had a significantly higher number of patients with diabetes mellitus (39.9% vs. 30.4%; p = 0.042) and type C lesion (67.4% vs. 48.1%; p < 0.001) than the DP-EES group. The 12-month MACE rate was 4.2% for the BDP-EES group versus 4.9% for the DP-EES group (p = 0.740). Mortality was lower in the BDP-EES group than in the DP-EES group (0.9% vs. 2.0%; p = 0.441). CONCLUSION: The present comparative analysis shows that the BDP-coated Tetrilimus EES was as safe and effective as the DP-coated Xience EES during the 12-month follow-up period despite complex lesion characteristics.


Assuntos
Doença das Coronárias/tratamento farmacológico , Stents Farmacológicos , Everolimo/administração & dosagem , Imunossupressores/administração & dosagem , Implantes Absorvíveis , Materiais Revestidos Biocompatíveis , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Polímeros , Desenho de Prótese , Estudos Retrospectivos , Resultado do Tratamento
18.
Nat Rev Genet ; 20(9): 562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31270439

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

19.
Nat Rev Genet ; 20(9): 520-535, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31235872

RESUMO

Risk of disease is multifactorial and can be shaped by socio-economic, demographic, cultural, environmental and genetic factors. Our understanding of the genetic determinants of disease risk has greatly advanced with the advent of genome-wide association studies (GWAS), which detect associations between genetic variants and complex traits or diseases by comparing populations of cases and controls. However, much of this discovery has occurred through GWAS of individuals of European ancestry, with limited representation of other populations, including from Africa, The Americas, Asia and Oceania. Population demography, genetic drift and adaptation to environments over thousands of years have led globally to the diversification of populations. This global genomic diversity can provide new opportunities for discovery and translation into therapies, as well as a better understanding of population disease risk. Large-scale multi-ethnic and representative biobanks and population health resources provide unprecedented opportunities to understand the genetic determinants of disease on a global scale.

20.
Front Genet ; 10: 334, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31080455

RESUMO

Genome-wide association studies (GWAS) have found hundreds of novel loci associated with full blood count (FBC) phenotypes. However, most of these studies were performed in a single phenotype framework without putting into consideration the clinical relatedness among traits. In this work, in addition to the standard univariate GWAS, we also use two different multivariate methods to perform the first multiple traits GWAS of FBC traits in ∼7000 individuals from the Ugandan General Population Cohort (GPC). We started by performing the standard univariate GWAS approach. We then performed our first multivariate method, in this approach, we tested for marker associations with 15 FBC traits simultaneously in a multivariate mixed model implemented in GEMMA while accounting for the relatedness of individuals and pedigree structures, as well as population substructure. In this analysis, we provide a framework for the combination of multiple phenotypes in multivariate GWAS analysis and show evidence of multi-collinearity whenever the correlation between traits exceeds the correlation coefficient threshold of r 2 >=0.75. This approach identifies two known and one novel loci. In the second multivariate method, we applied principal component analysis (PCA) to the same 15 correlated FBC traits. We then tested for marker associations with each PC in univariate linear mixed models implemented in GEMMA. We show that the FBC composite phenotype as assessed by each PC expresses information that is not completely encapsulated by the individual FBC traits, as this approach identifies three known and five novel loci that were not identified using both the standard univariate and multivariate GWAS methods. Across both multivariate methods, we identified six novel loci. As a proof of concept, both multivariate methods also identified known loci, HBB and ITFG3. The two multivariate methods show that multivariate genotype-phenotype methods increase power and identify novel genotype-phenotype associations not found with the standard univariate GWAS in the same dataset.

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