Acute rheumatic fever is considered to be a heritable condition, but the magnitude of the genetic effect is unknown. The objective of this study was to conduct a systematic review and meta-analysis ...of twin studies of concordance of acute rheumatic fever in order to derive quantitative estimates of the size of the genetic effect.
We searched PubMed/MEDLINE, ISI Web of Science, EMBASE, and Google Scholar from their inception to 31 January 2011, and bibliographies of retrieved articles, for twin studies of the concordance for acute rheumatic fever or rheumatic heart disease in monozygotic versus dizygotic twins that used accepted diagnostic criteria for acute rheumatic fever and zygosity without age, gender or language restrictions. Twin similarity was measured by probandwise concordance rate and odds ratio (OR), and aggregate probandwise concordance risk was calculated by combining raw data from each study. ORs from separate studies were combined by random-effects meta-analysis to evaluate association between zygosity status and concordance. Heritability was estimated by fitting a variance components model to the data.
435 twin pairs from six independent studies met the inclusion criteria. The pooled probandwise concordance risk for acute rheumatic fever was 44% in monozygotic twins and 12% in dizygotic twins, and the association between zygosity and concordance was strong (OR 6.39; 95% confidence interval, 3.39 to 12.06; P<0.001), with no significant study heterogeneity (P = 0.768). The estimated heritability across all the studies was 60%.
Acute rheumatic fever is an autoimmune disorder with a high heritability. The discovery of all genetic susceptibility loci through whole genome scanning may provide a clinically useful genetic risk prediction tool for acute rheumatic fever and its sequel, rheumatic heart disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In the 20 years since the first drafts of the human genome were made public, an explosion in genome sequencing has revealed how our evolutionary history and health can be understood by analysing the ...diversity in our genomes.
Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide ...analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10
). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. siRNA transfection of murine Zranb3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating Zranb3 in β-cell functional response to high glucose conditions. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.
The African continent is regarded as the cradle of modern humans and African genomes contain more genetic variation than those from any other continent, yet only a fraction of the genetic diversity ...among African individuals has been surveyed
. Here we performed whole-genome sequencing analyses of 426 individuals-comprising 50 ethnolinguistic groups, including previously unsampled populations-to explore the breadth of genomic diversity across Africa. We uncovered more than 3 million previously undescribed variants, most of which were found among individuals from newly sampled ethnolinguistic groups, as well as 62 previously unreported loci that are under strong selection, which were predominantly found in genes that are involved in viral immunity, DNA repair and metabolism. We observed complex patterns of ancestral admixture and putative-damaging and novel variation, both within and between populations, alongside evidence that Zambia was a likely intermediate site along the routes of expansion of Bantu-speaking populations. Pathogenic variants in genes that are currently characterized as medically relevant were uncommon-but in other genes, variants denoted as 'likely pathogenic' in the ClinVar database were commonly observed. Collectively, these findings refine our current understanding of continental migration, identify gene flow and the response to human disease as strong drivers of genome-level population variation, and underscore the scientific imperative for a broader characterization of the genomic diversity of African individuals to understand human ancestry and improve health.
European-ancestry populations are recognized as stratified but not as admixed, implying that residual confounding by locus-specific ancestry can affect studies of association, polygenic adaptation, ...and polygenic risk scores. We integrate individual-level genome-wide data from ~19,000 European-ancestry individuals across 79 European populations and five European American cohorts. We generate a new reference panel that captures ancestral diversity missed by both the 1000 Genomes and Human Genome Diversity Projects. Both Europeans and European Americans are admixed at the subcontinental level, with admixture dates differing among subgroups of European Americans. After adjustment for both genome-wide and locus-specific ancestry, associations between a highly differentiated variant in LCT (rs4988235) and height or LDL-cholesterol were confirmed to be false positives whereas the association between LCT and body mass index was genuine. We provide formal evidence of subcontinental admixture in individuals with European ancestry, which, if not properly accounted for, can produce spurious results in genetic epidemiology studies.
Benign ethnic neutropenia (BEN) is a hematologic condition associated with people of African ancestry and specific Middle Eastern ethnic groups. Prior genetic association studies in large population ...showed that rs2814778 in Duffy Antigen Receptor for Chemokines (DARC) gene, specifically DARC null red cell phenotype, was associated with BEN. However, the mechanism of this red cell phenotype leading to low white cell count remained elusive.
We conducted an extreme phenotype design genome-wide association study (GWAS), analyzed ~16 million single nucleotide polymorphisms (SNP) in 1,178 African-Americans individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and replicated from 819 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. Conditional analyses on rs2814778 were performed to identify additional association signals on chromosome 1q22. In a separate cohort of healthy individuals with and without BEN, whole genome gene expression from peripheral blood neutrophils were analyzed for DARC.
We confirmed that rs2814778 in DARC was associated with BEN (p = 4.09×10-53). Conditioning on rs2814778 abolished other significant chromosome 1 associations. Inflammatory cytokines (IL-2, 6, and 10) in participants in the Howard University Family Study (HUFS) and Multi-Ethnic Study in Atherosclerosis (MESA) showed similar levels in individuals homozygous for the rs2814778 allele compared to others, indicating cytokine sink hypothesis played a minor role in leukocyte homeostasis. Gene expression in neutrophils of individuals with and without BEN was also similar except for low DARC expression in BEN, suggesting normal function. BEN neutrophils had slightly activated profiles in leukocyte migration and hematopoietic stem cell mobilization pathways (expression fold change <2).
These results in humans support the notion of DARC null erythroid progenitors preferentially differentiating to myeloid cells, leading to activated DARC null neutrophils egressing from circulation to the spleen, and causing relative neutropenia. Collectively, these human data sufficiently explained the mechanism DARC null red cell phenotype causing BEN and further provided a biologic basis that BEN is clinically benign.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A fundamental ethical issue in African genomics research is how socio-cultural factors impact perspectives, acceptance, and utility of genomic information, especially in stigmatizing conditions like ...orofacial clefts (OFCs). Previous research has shown that gatekeepers (e.g., religious, political, family or community leaders) wield considerable influence on the decision-making capabilities of their members, including health issues. Thus, their perspectives can inform the design of engagement strategies and increase exposure to the benefits of genomics testing/research. This is especially important for Africans underrepresented in genomic research. Our study aims to investigate the perspectives of gatekeepers concerning genomic risk information (GRI) in the presence of OFCs in a sub-Saharan African cohort.
Twenty-five focus group discussions (FGDs) consisting of 214 gatekeepers (religious, community, ethnic leaders, and traditional birth attendants) in Lagos, Nigeria, explored the opinions of participants on genomic risk information (GRI), OFC experience, and the possibility of involvement in collaborative decision-making in Lagos, Nigeria. Transcripts generated from audio recordings were coded and analyzed in NVivo using thematic analysis.
Three main themes-knowledge, beliefs, and willingness to act-emerged from exploring the perspective of gatekeepers about GRI in this group. We observed mixed opinions regarding the acceptance of GRI. Many participants believed their role is to guide and support members when they receive results; this is based on the level of trust their members have in them. However, participants felt they would need to be trained by medical experts to do this. Also, religious and cultural beliefs were crucial to determining participants' understanding of OFCs and the acceptance and utilization of GRI.
Incorporating cultural sensitivity into public engagement could help develop appropriate strategies to manage conflicting ideologies surrounding genomic information in African communities. This will allow for more widespread access to the advances in genomics research in underrepresented populations. We also recommend a synergistic relationship between community health specialists/scientists, and community leaders, including spiritual providers to better understand and utilize GRI.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
There is growing support for the use of genetic risk scores (GRS) in routine clinical settings. Due to the limited diversity of current genomic discovery samples, there are ...concerns that the predictive power of GRS will be limited in non-European ancestry populations. GRS for cardiometabolic traits were evaluated in sub-Saharan Africans in comparison with African Americans and European Americans.
Methods
We evaluated the predictive utility of GRS for 12 cardiometabolic traits in sub-Saharan Africans (AF; n = 5200), African Americans (AA; n = 9139) and European Americans (EUR; n = 9594). GRS were constructed as weighted sums of the number of risk alleles. Predictive utility was assessed using the additional phenotypic variance explained and the increase in discriminatory ability over traditional risk factors age, sex and body mass index (BMI), with adjustment for ancestry-derived principal components.
Results
Across all traits, GRS showed up to a 5-fold and 20-fold greater predictive utility in EUR relative to AA and AF, respectively. Predictive utility was most consistent for lipid traits, with percentage increase in explained variation attributable to GRS ranging from 10.6% to 127.1% among EUR, 26.6% to 65.8% among AA and 2.4% to 37.5% among AF. These differences were recapitulated in the discriminatory power, whereby the predictive utility of GRS was 4-fold greater in EUR relative to AA and up to 44-fold greater in EUR relative to AF. Obesity and blood pressure traits showed a similar pattern of greater predictive utility among EUR.
Conclusions
This work demonstrates the poorer performance of GRS in AF and highlights the need to improve representation of multiple ethnic populations in genomic studies to ensure equitable clinical translation of GRS.
Adiponectin has been associated with cardiometabolic traits in observational studies across populations, yet it is unclear if these associations are causal. We performed Mendelian randomization (MR) ...analysis to assess the relationship between adiponectin and cardiometabolic traits in sub-Saharan Africans. We constructed a polygenic risk score (PRS) for adiponectin levels across 3354 unrelated sub-Saharan Africans. The PRS was used as the instrumental variable in two-stage least-squares MR analysis to assess its association with insulin resistance, HDL, LDL, total cholesterol, triglycerides, blood pressure, Type 2 Diabetes (T2D), and hypertension. The adiponectin PRS was causally related with LDL (β = 0.55, 95%CI 0.07-1.04, P-value = 0.024) but not the other traits. This association was observed in both overweight/obese and normal weight individuals, but only reached statistical significance among overweight/obese individuals (β = 0.55, 95%CI 0.01-1.08, P-value = 0.045). In normal weight individuals, the adiponectin PRS was associated with T2D (OR = 0.13, 95%CI 0.02-0.73, P-value = 0.021), and in men with HDL (β = 1.03, 95%CI 0.14-1.92, P-value = 0.023). The findings of this first MR study in sub-Saharan Africans support a causal relationship of adiponectin with LDL, with T2D in normal weight individuals only, and with HDL in men only. These observations add to the small but growing literature on adiponectin MR studies.
Persistent cervical high-risk human papillomavirus (hrHPV) infection is a necessary cause of cervical cancer. However, the host genetic factors underlying its risk are not well understood. We ...hypothesized that immunogenetic variation plays a role in hrHPV infection and persistence. Therefore, we conducted a study of classical HLA alleles and their association with hrHPV infection and persistence among women.
We characterized HPV infection using SPF10/LiPA25in Nigerian women at baseline and at 6 months follow-up visits in 2014. hrHPV infection was prevalent if at least one carcinogenic HPV genotype was detected at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected at the baseline and follow-up visits. Classical HLA alleles were imputed from genotypes in the MHC region using the HLA genotype imputation with attribute bagging (HIBAG) algorithm. HLA association tests were conducted under additive genetic models.
The mean (±SD) age of the 517 study participants was 38 (±8) years, 48% were HIV negative, 24% were hrHPV positive at baseline and 10% had persistent hrHPV infections. In multivariate regression models adjusted for age, HIV status and the first principal component, DQA1*01:02 and DQA1*02:01 were positively associated with prevalent but not persistent hrHPV infections, while DQA1*05:01 was negatively associated with prevalent hrHPV but positively associated with persistent cervical hrHPV infections. Four haplotypes (A*30:01-DQA1*05:01, B*07:02-C*07:02, B*07:02-DQA1*05:01 and C*07:02-DQA1*05:01) were significantly associated with prevalent cervical hrHPV infections and several haplotypes that included the DQA1*05:01 allelic variant were significantly associated with persistent cervical hrHPV infections. Six amino acid positions on DQα1 were associated with prevalent but not persistent cervical hrHPV infections.
In this first study to investigate the association between HLA alleles and persistent hrHPV in African women, we identified important risk alleles that merit further investigation. Our findings provide new insights into risk factors for hrHPV infection in African ancestry women.
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