Although a reduced glomerular filtration rate (GFR) in old people has been attributed to physiologic aging, it may be associated with kidney disease or superimposed comorbidities. This study aims to ...assess the prevalence of decreased GFR in a geriatric population in a developing country and its prevalence in the absence of simultaneous diseases.
This is a cross-sectional study of data from the Saúde, Bem-Estar e Envelhecimento cohort study (SABE studyHealth, Well-Being and Aging), a multiple cohorts study. A multistage cluster sample composed of 1,253 individuals representative of 1,249,388 inhabitants of São Paulo city aged ≥60 years in 2010 was analyzed. The participants answered a survey on socio-demographic factors and health, had blood pressure measured and urine and blood samples collected. GFR was estimated and defined as decreased when <60 mL/min/1.73m2. Kidney damage was defined as dipstick-positive hematuria or urinary protein:creatinine > 0.20 g/g.
The prevalence of GFR <60 mL/min/1.73m2 was 19.3%. Individuals with GFR <60 mL/min/1.73m2 were older (75±1 versus 69±1 years, p<0.001), had lower schooling (18 versus 30% with complete 8-year basic cycle, p = 0.010), and higher prevalence of hypertension (82 versus 63%, p<0.001), diabetes (34 versus 26%, p = 0.021), cardiovascular disease (43 versus 24%, p<0.001) and kidney damage (35% versus 15%, p<0.001). Only 0.7% of the entire studied population had GFR <60 mL/min/1.73m2 without simultaneous diseases or kidney damage. Among the individuals with GFR <60 mL/min/1.73m2, 3.5% had neither renal damage nor associated comorbidities, whereas among those with GFR ≥60 mL/min/1.73m2, 11.0% had none of these conditions. Logistic regression showed that older age, cardiovascular disease and hypertension were associated with GFR<60 mL/min/1.73m2.
Decreased GFR was highly prevalent among the geriatric population in a megalopolis of a developing country. It was rarely present without simultaneous chronic comorbidities or kidney damage.
The inference of genetic ancestry plays an increasingly prominent role in clinical, population, and forensic genetics studies. Several genotyping strategies and analytical methodologies have been ...developed over the last few decades to assign individuals to specific biogeographic regions. However, despite these efforts, ancestry inference in populations with a recent history of admixture, such as those in Brazil, remains a challenge. In admixed populations, proportion and components of genetic ancestry vary on different levels: (i) between populations; (ii) between individuals of the same population, and (iii) throughout the individual's genome. The present study evaluated 1171 admixed Brazilian samples to compare the genetic ancestry inferred by tri-/tetra-hybrid admixture models and evaluated different marker sets from those with small numbers of ancestry informative markers panels (AIMs), to high-density SNPs (HDSNP) and whole-genome-sequence (WGS) data. Analyses revealed greater variation in the correlation coefficient of ancestry components within and between admixed populations, especially for minority ancestral components. We also observed positive correlation between the number of markers in the AIMs panel and HDSNP/WGS. Furthermore, the greater the number of markers, the more accurate the tri-/tetra-hybrid admixture models.
Brazilians are highly admixed with ancestry from Europe, Africa, America, and Asia and yet still underrepresented in genomic databanks. We hereby present a collection of exomic variants from 609 ...elderly Brazilians in a census‐based cohort (SABE609) with comprehensive phenotyping. Variants were deposited in ABraOM (Online Archive of Brazilian Mutations), a Web‐based public database. Population representative phenotype and genotype repositories are essential for variant interpretation through allele frequency filtering; since elderly individuals are less likely to harbor pathogenic mutations for early‐ and adult‐onset diseases, such variant databases are of great interest. Among the over 2.3 million variants from the present cohort, 1,282,008 were high‐confidence calls. Importantly, 207,621 variants were absent from major public databases. We found 9,791 potential loss‐of‐function variants with about 300 mutations per individual. Pathogenic variants on clinically relevant genes (ACMG) were observed in 1.15% of the individuals and were correlated with clinical phenotype. We conducted incidence estimation for prevalent recessive disorders based upon heterozygous frequency and concluded that it relies on appropriate pathogenicity assertion. These observations illustrate the relevance of collecting demographic data from diverse, poorly characterized populations. Census‐based datasets of aged individuals with comprehensive phenotyping are an invaluable resource toward the improved understanding of variant pathogenicity.
Genomic variants from highly admixed populations are still underrepresented in public databases. ABraOM is a publicly available web database, currently harboring variants from 609 WES data of an elderly population representative cohort of São Paulo metropolis. Over 200K high confidence variants absent from major databases were identified. About 1% of the individuals carry ACMG possibly actionable LoF variants. Reliable pathogenicity assertions remain challenging and elderly cohorts are an invaluable resource to enhance variant interpretation efficacy.
Approximately 5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive ...structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120 kb in length and carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A (encoded by GYPA) and glycophorin B (encoded by GYPB) are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They are receptors for the invasion of the protist parasite Plasmodium falciparum, a causative agent of malaria. A particular complex structural variant, called DUP4, creates a GYPB-GYPA fusion gene known to confer resistance to malaria. Many other structural variants exist across the glycophorin gene cluster, and they remain poorly characterised.
Here, we analyse sequences from 3234 diploid genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection of these variants using fibre-FISH and breakpoint mapping at the sequence level. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by non-allelic homologous recombination and by comparing the structural variant breakpoints with recombination hotspot maps, confirm the importance of a particular meiotic recombination hotspot on structural variant formation in this region.
We identify and validate large structural variants in the human glycophorin A-B-E gene cluster which may be associated with different clinical aspects of malaria.
HLA-G is a promiscuous immune checkpoint molecule. The HLA-G gene presents substantial nucleotide variability in its regulatory regions. However, it encodes a limited number of proteins compared to ...classical HLA class I genes. We characterized the HLA-G genetic variability in 4640 individuals from 88 different population samples across the globe by using a state-of-the-art method to characterize polymorphisms and haplotypes from high-coverage next-generation sequencing data. We also provide insights regarding the HLA-G genetic diversity and a resource for future studies evaluating HLA-G polymorphisms in different populations and association studies. Despite the great haplotype variability, we demonstrated that: (1) most of the HLA-G polymorphisms are in introns and regulatory sequences, and these are the sites with evidence of balancing selection, (2) linkage disequilibrium is high throughout the gene, extending up to HLA-A, (3) there are few proteins frequently observed in worldwide populations, with lack of variation in residues associated with major HLA-G biological properties (dimer formation, interaction with leukocyte receptors). These observations corroborate the role of HLA-G as an immune checkpoint molecule rather than as an antigen-presenting molecule. Understanding HLA-G variability across populations is relevant for disease association and functional studies.
Research in the field of pharmacogenomics (PGx) aims to identify genetic variants that modulate response to drugs, through alterations in their pharmacokinetics (PK) or pharmacodynamics (PD). The ...distribution of PGx variants differs considerably among populations, and whole-genome sequencing (WGS) plays a major role as a comprehensive approach to detect both common and rare variants. This study evaluated the frequency of PGx markers in the context of the Brazilian population, using data from a population-based admixed cohort from Sao Paulo, Brazil, which includes variants from WGS of 1,171 unrelated, elderly individuals.
The Stargazer tool was used to call star alleles and structural variants (SVs) from 38 pharmacogenes. Clinically relevant variants were investigated, and the predicted drug response phenotype was analyzed in combination with the medication record to assess individuals potentially at high-risk of gene-drug interaction.
In total, 352 unique star alleles or haplotypes were observed, of which 255 and 199 had a frequency < 0.05 and < 0.01, respectively. For star alleles with frequency > 5% (
= 97), decreased, loss-of-function and unknown function accounted for 13.4%, 8.2% and 27.8% of alleles or haplotypes, respectively. Structural variants (SVs) were identified in 35 genes for at least one individual, and occurred with frequencies >5% for CYP2D6, CYP2A6, GSTM1, and UGT2B17. Overall 98.0% of the individuals carried at least one high risk genotype-predicted phenotype in pharmacogenes with PharmGKB level of evidence 1A for drug interaction. The Electronic Health Record (EHR) Priority Result Notation and the cohort medication registry were combined to assess high-risk gene-drug interactions. In general, 42.0% of the cohort used at least one PharmGKB evidence level 1A drug, and 18.9% of individuals who used PharmGKB evidence level 1A drugs had a genotype-predicted phenotype of high-risk gene-drug interaction.
This study described the applicability of next-generation sequencing (NGS) techniques for translating PGx variants into clinically relevant phenotypes on a large scale in the Brazilian population and explores the feasibility of systematic adoption of PGx testing in Brazil.
Genetic evaluation has been recognized as an important tool to elucidate the causes of growth disorders.
To investigate the cause of short stature and to determine the phenotype of patients with IHH ...mutations, including the response to recombinant human growth hormone (rhGH) therapy.
We studied 17 families with autosomal-dominant short stature by using whole exome sequencing and screened IHH defects in 290 patients with growth disorders. Molecular analyses were performed to evaluate the potential impact of N-terminal IHH variants.
We identified 10 pathogenic or possibly pathogenic variants in IHH, an important regulator of endochondral ossification. Molecular analyses revealed a smaller potential energy of mutated IHH molecules. The allele frequency of rare, predicted to be deleterious IHH variants found in short-stature samples (1.6%) was higher than that observed in two control cohorts (0.017% and 0.08%; P < 0.001). Identified IHH variants segregate with short stature in a dominant inheritance pattern. Affected individuals typically manifest mild disproportional short stature with a frequent finding of shortening of the middle phalanx of the fifth finger. None of them have classic features of brachydactyly type A1, which was previously associated with IHH mutations. Five patients heterozygous for IHH variants had a good response to rhGH therapy. The mean change in height standard deviation score in 1 year was 0.6.
Our study demonstrated the association of pathogenic variants in IHH with short stature with nonspecific skeletal abnormalities and established a frequent cause of growth disorder, with a preliminary good response to rhGH.
Human genomics has quickly evolved, powering genome‐wide association studies (GWASs). SNP‐based GWASs cannot capture the intense polymorphism of HLA genes, highly associated with disease ...susceptibility. There are methods to statistically impute HLA genotypes from SNP‐genotypes data, but lack of diversity in reference panels hinders their performance. We evaluated the accuracy of the 1000 Genomes data as a reference panel for imputing HLA from admixed individuals of African and European ancestries, focusing on (a) the full dataset, (b) 10 replications from 6 populations, and (c) 19 conditions for the custom reference panels. The full dataset outperformed smaller models, with a good F1‐score of 0.66 for HLA‐B. However, custom models outperformed the multiethnic or population models of similar size (F1‐scores up to 0.53, against up to 0.42). We demonstrated the importance of using genetically specific models for imputing populations, which are currently underrepresented in public datasets, opening the door to HLA imputation for every genetic population.
The MHC class I region contains crucial genes for the innate and adaptive immune response, playing a key role in susceptibility to many autoimmune and infectious diseases. Genome‐wide association ...studies have identified numerous disease‐associated SNPs within this region. However, these associations do not fully capture the immune‐biological relevance of specific HLA alleles. HLA imputation techniques may leverage available SNP arrays by predicting allele genotypes based on the linkage disequilibrium between SNPs and specific HLA alleles. Successful imputation requires diverse and large reference panels, especially for admixed populations. This study employed a bioinformatics approach to call SNPs and HLA alleles in multi‐ethnic samples from the 1000 genomes (1KG) dataset and admixed individuals from Brazil (SABE), utilising 30X whole‐genome sequencing data. Using HIBAG, we created three reference panels: 1KG (n = 2504), SABE (n = 1171), and the full model (n = 3675) encompassing all samples. In extensive cross‐validation of these reference panels, the multi‐ethnic 1KG reference exhibited overall superior performance than the reference with only Brazilian samples. However, the best results were achieved with the full model. Additionally, we expanded the scope of imputation by developing reference panels for non‐classical, MICA, MICB and HLA‐H genes, previously unavailable for multi‐ethnic populations. Validation in an independent Brazilian dataset showcased the superiority of our reference panels over the Michigan Imputation Server, particularly in predicting HLA‐B alleles among Brazilians. Our investigations underscored the need to enhance or adapt reference panels to encompass the target population's genetic diversity, emphasising the significance of multiethnic references for accurate imputation across different populations.
Objective: To analyze gender differences in incidence and determinants of the components of the frailty phenotype. Method: A total of 1,413 older adults were selected in 2006. To estimate the ...incidence of each frailty component, only individuals who did not exhibit a given component at baseline (independently of the presence of other components) were included in the study. The variables of interest were socioeconomic, behavioral, clinical, anthropometric factors and physical performance. The incidence of each component in 2010 was the outcome. Results: Unintentional weight loss and slowness were more incident in men up to 74 years of age. The other frailty components were more incident in women at all age groups, except weakness. Besides age, the determinants of incidence of the components of frailty were different between genders. Discussion: Strategies for preventing or delaying the installation of frailty need to address gender differences, considering the greater complexity in the network determinants among women.
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