A review of ancestrality and admixture in Latin America and the caribbean focusing on native American and African descendant populations.

Genomics can reveal essential features about the demographic evolution of a population that may not be apparent from historical elements. In recent years, there has been a significant increase in the number of studies applying genomic epidemiological approaches to understand the genetic structure and diversity of human populations in the context of demographic history and for implementing precision medicine. These efforts have traditionally been applied predominantly to populations of European origin. More recently, initiatives in the United States and Africa are including more diverse populations, establishing new horizons for research in human populations with African and/or Native ancestries. Still, even in the most recent projects, the under-representation of genomic data from Latin America and the Caribbean (LAC) is remarkable. In addition, because the region presents the most recent global miscegenation, genomics data from LAC may add relevant information to understand population admixture better. Admixture in LAC started during the colonial period, in the 15th century, with intense miscegenation between European settlers, mainly from Portugal and Spain, with local indigenous and sub-Saharan Africans brought through the slave trade. Since, there are descendants of formerly enslaved and Native American populations in the LAC territory; they are considered vulnerable populations because of their history and current living conditions. In this context, studying LAC Native American and African descendant populations is important for several reasons. First, studying human populations from different origins makes it possible to understand the diversity of the human genome better. Second, it also has an immediate application to these populations, such as empowering communities with the knowledge of their ancestral origins. Furthermore, because knowledge of the population genomic structure is an essential requirement for implementing genomic medicine and precision health practices, population genomics studies may ensure that these communities have access to genomic information for risk assessment, prevention, and the delivery of optimized treatment; thus, helping to reduce inequalities in the Western Hemisphere. Hoping to set the stage for future studies, we review different aspects related to genetic and genomic research in vulnerable populations from LAC countries.

Demographic history differences between Hispanics and Brazilians imprint haplotype features.

Admixture is known to greatly impact the genetic landscape of a population and, while genetic variation underlying human phenotypes has been shown to differ among populations, studies on admixed subjects are still scarce. Latin American populations are the result of complex demographic history, such as 2 or 3-way admixing events, bottlenecks and/or expansions, and adaptive events unique to the American continent. To explore the impact of these events on the genetic structure of Latino populations, we evaluated the following haplotype features: linkage disequilibrium, shared identity by descent segments, runs of homozygosity, and extended haplotype homozygosity (integrated haplotype score) in Latinos represented in the 1000 Genome Project along with array data from 171 Brazilians sampled in the South and Southeast regions of Brazil. We found that linkage disequilibrium decay relates to the amount of American and African ancestry. The extent of identity by descent sharing positively correlates with historical effective population sizes, which we found to be steady or growing, except for Puerto Ricans and Colombians. Long runs of homozygosity, a particular instance of autozygosity, was only enriched in Peruvians and Native Americans. We used simulations to account for random sampling and linkage disequilibrium to filter positive selection indexes and found 244 unique markers under selection, 26 of which are common to 2 or more populations. Some markers exhibiting positive selection signals had estimated time to the most recent common ancestor consistent with human adaptation to the American continent. In conclusion, Latino populations present highly divergent haplotype characteristics that impact genetic architecture and underlie complex phenotypes.

Increased runs of homozygosity in the autosomal genome of Brazilian individuals with neurodevelopmental delay/intellectual disability and/or multiple congenital anomalies investigated by chromosomal microarray analysis.

Runs of homozygosity (ROH) in the human genome may be clinically relevant. The aim of this study was to report the frequency of increased ROH of the autosomal genome in individuals with neurodevelopmental delay/intellectual disability and/or multiple congenital anomalies, and to compare these data with a control group. Data consisted of calls of homozygosity from 265 patients and 289 controls. In total, 7.2% (19/265) of the patients showed multiple ROH exceeding 1% of autosomal genome, compared to 1.4% (4/289) in the control group (p=0.0006). Homozygosity ranged from 1.38% to 22.12% among patients, and from 1.53 to 2.40% in the control group. In turn, 1.9% (5/265) of patients presented ROH ≥10Mb in a single chromosome, compared to 0.3% (1/289) of individuals from the control group (p=0.0801). By excluding cases with reported consanguineous parents (15/24), the frequency of increased ROH was 3.4% (9/250) among patients and 1.7% (5/289) in the control group, considering multiple ROH exceeding 1% of the autosome genome and ROH ≥10Mb in a single chromosome together, although not statistically significant (p=0.1873). These results reinforce the importance of investigating ROH, which with complementary diagnostic tests can improve the diagnostic yield for patients with such conditions.

Slowly progressive behavioral frontotemporal dementia syndrome in a family co-segregating the C9orf72 expansion and a Synaptophysin mutation.

INTRODUCTION: Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene. METHODS: Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia. RESULTS: We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance. DISCUSSION: Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.

Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy.

We aimed to investigate the role of interleukin-1 beta (IL-1ß) in the mechanisms underlying mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). We assessed a cohort of 194 patients with MTLE+HS and 199 healthy controls. Patients were divided into those with positive and negative antecedent febrile seizures (FS). We used a multidimensional approach, including (i) genetic association with single nucleotide polymorphisms (SNPs) in the IL1B gene; (ii) quantification of the IL1B transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1ß protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364*C in the IL1B gene, regardless of the presence of FS (adjusted p = 9.62e-11 and 5.14e-07, respectively). We found no difference between IL1B transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls (p > 0.05). Nevertheless, we found increased IL-1ß in the plasma of patients with MTLE+HS with FS compared with controls (p = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the IL1B gene.

Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies.

Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic-clonic seizures, and generalized tonic-clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; p-values <3.55e-06). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.

Exploring a Region on Chromosome 8p23.1 Displaying Positive Selection Signals in Brazilian Admixed Populations: Additional Insights Into Predisposition to Obesity and Related Disorders.

We recently reported a deviation of local ancestry on the chromosome (ch) 8p23.1, which led to positive selection signals in a Brazilian population sample. The deviation suggested that the genetic variability of candidate genes located on ch 8p23.1 may have been evolutionarily advantageous in the early stages of the admixture process. In the present work, we aim to extend the previous work by studying additional Brazilian admixed individuals and examining DNA sequencing data from the ch 8p23.1 candidate region. Thus, we inferred the local ancestry of 125 exomes from individuals born in five towns within the Southeast region of Brazil (São Paulo, Campinas, Barretos, and Ribeirão Preto located in the state of São Paulo and Belo Horizonte, the capital of the state of Minas Gerais), and compared to data from two public Brazilian reference genomic databases, BIPMed and ABraOM, and with information from the 1000 Genomes Project phase 3 and gnomAD databases. Our results revealed that ancestry is similar among individuals born in the five Brazilian towns assessed; however, an increased proportion of sub-Saharan African ancestry was observed in individuals from Belo Horizonte. In addition, individuals from the five towns considered, as well as those from the ABRAOM dataset, had the same overrepresentation of Native-American ancestry on the ch 8p23.1 locus that was previously reported for the BIPMed reference sample. Sequencing analysis of ch 8p23.1 revealed the presence of 442 non-synonymous variants, including frameshift, inframe deletion, start loss, stop gain, stop loss, and splicing site variants, which occurred in 24 genes. Among these genes, 13 were associated with obesity, type II diabetes, lipid levels, and waist circumference (PRAG1, MFHAS1, PPP1R3B, TNKS, MSRA, PRSS55, RP1L1, PINX1, MTMR9, FAM167A, BLK, GATA4, and CTSB). These results strengthen the hypothesis that a set of variants located on ch 8p23.1 that result from positive selection during early admixture events may influence obesity-related disease predisposition in admixed individuals of the Brazilian population. Furthermore, we present evidence that the exploration of local ancestry deviation in admixed individuals may provide information with the potential to be translated into health care improvement.

Genetic variability in COVID-19-related genes in the Brazilian population.

SARS-CoV-2 utilizes the angiotensin-converting enzyme 2 (ACE2) receptor and transmembrane serine protease (TMPRSS2) to infect human lung cells. Previous studies have suggested that different host ACE2 and TMPRSS2 genetic backgrounds might contribute to differences in the rate of SARS-CoV-2 infection or COVID-19 severity. Recent studies have also shown that variants in 15 genes related to type I interferon immunity to influenza virus might predispose patients toward life-threatening COVID-19 pneumonia. Other genes (SLC6A20, LZTFL1, CCR9, FYCO1, CXCR6, XCR1, IL6, CTSL, ABO, and FURIN) and HLA alleles have also been implicated in the response to infection with SARS-CoV-2. Currently, Brazil has recorded the third-highest number of COVID-19 cases worldwide. We aimed to investigate the genetic variation present in COVID-19-related genes in the Brazilian population. We analyzed 27 candidate genes and HLA alleles in 954 admixed Brazilian exomes. We used the information available in two public databases (http://www.bipmed.org and http://abraom.ib.usp.br/) and additional exomes from individuals born in southeast Brazil, the region of the country with the highest number of COVID-19 patients. Variant allele frequencies were compared with the 1000 Genomes Project phase 3 (1KGP) and gnomAD databases. We detected 395 nonsynonymous variants; of these, 325 were also found in the 1KGP and/or gnomAD. Six of these variants were previously reported to influence the rate of infection or clinical prognosis of COVID-19. The remaining 70 variants were identified exclusively in the Brazilian sample, with a mean allele frequency of 0.0025. In silico analysis revealed that seven of these variants are predicted to affect protein function. Furthermore, we identified HLA alleles previously associated with the COVID-19 response at loci DQB1 and DRB1. Our results showed genetic variability common to other populations and rare and ultrarare variants exclusively found in the Brazilian population. These findings might lead to differences in the rate of infection or response to infection by SARS-CoV-2 and should be further investigated in patients with this disease.

Inheritance pattern of molar-incisor hypomineralization.

The aim of this study was to investigate the segregation patterns of molar incisor hypomineralization (MIH) in families, given the evidence that its etiology is influenced by genetics. Clinically, MIH may be detected in parents and/or siblings of MIH-affected children. Our study included children with at least one first permanent molar affected by MIH (proband) and their first-degree relatives (parents and siblings). The participants were examined clinically to detect MIH, according to the European Academy of Paediatric Dentistry criteria (2003). A total of 101 nuclear families (391 individuals) were studied. Proband diagnosis was followed by MIH classification of the subject, his parents and siblings, as affected, unaffected, or unknown. Segregation analysis was performed using the multivariate logistic regression model of the Statistical Analysis for Genetic Epidemiology package, and segregation models (general transmission, environmental, major gene, dominant, codominant and recessive models). The Akaike information criterion (AIC) was used to evaluate the most parsimonious model. In all, 130 affected individuals, 165 unaffected individuals, and 96 unknown individuals were studied. Severe MIH was found in 50.7% of the cases. A segregation analysis performed for MIH revealed the following different models: environmental and dominance (p = 0.05), major gene (p = 0.04), codominant (p = 0.15) and recessive models (p = 0.03). According to the AIC values, the codominant model was the most parsimonious (AIC = 308.36). Our results suggest that the codominant model could be the most likely for inheriting MIH. This result strengthens the evidence that genetic factors, such as multifactorial complex defect, influence MIH.

New avenues in molecular genetics for the diagnosis and application of therapeutics to the epilepsies.

Genetic epidemiology studies have shown that most epilepsies involve some genetic cause. In addition, twin studies have helped strengthen the hypothesis that in most patients with epilepsy, a complex inheritance is involved. More recently, with the development of high-density single-nucleotide polymorphism (SNP) microarrays and next-generation sequencing (NGS) technologies, the discovery of genes related to the epilepsies has accelerated tremendously. Especially, the use of whole exome sequencing (WES) has had a considerable impact on the identification of rare genetic variants with large effect sizes, including inherited or de novo mutations in severe forms of childhood epilepsies. The identification of pathogenic variants in patients with these childhood epilepsies provides many benefits for patients and families, such as the confirmation of the genetic nature of the diseases. This process will allow for better genetic counseling, more accurate therapy decisions, and a significant positive emotional impact. However, to study the genetic component of the more common forms of epilepsy, the use of high-density SNP arrays in genome-wide association studies (GWAS) seems to be the strategy of choice. As such, researchers can identify loci containing genetic variants associated with the common forms of epilepsy. The knowledge generated over the past two decades about the effects of the mutations that cause the monogenic epilepsy is tremendous; however, the scientific community is just starting to apply this information in order to generate better target treatments.

Inheritance pattern of molar-incisor hypomineralization

Abstract The aim of this study was to investigate the segregation patterns of molar incisor hypomineralization (MIH) in families, given the evidence that its etiology is influenced by genetics. Clinically, MIH may be detected in parents and/or siblings of MIH-affected children. Our study included children with at least one first permanent molar affected by MIH (proband) and their first-degree relatives (parents and siblings). The participants were examined clinically to detect MIH, according to the European Academy of Paediatric Dentistry criteria (2003). A total of 101 nuclear families (391 individuals) were studied. Proband diagnosis was followed by MIH classification of the subject, his parents and siblings, as affected, unaffected, or unknown. Segregation analysis was performed using the multivariate logistic regression model of the Statistical Analysis for Genetic Epidemiology package, and segregation models (general transmission, environmental, major gene, dominant, codominant and recessive models). The Akaike information criterion (AIC) was used to evaluate the most parsimonious model. In all, 130 affected individuals, 165 unaffected individuals, and 96 unknown individuals were studied. Severe MIH was found in 50.7% of the cases. A segregation analysis performed for MIH revealed the following different models: environmental and dominance (p = 0.05), major gene (p = 0.04), codominant (p = 0.15) and recessive models (p = 0.03). According to the AIC values, the codominant model was the most parsimonious (AIC = 308.36). Our results suggest that the codominant model could be the most likely for inheriting MIH. This result strengthens the evidence that genetic factors, such as multifactorial complex defect, influence MIH.

The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations.

The development of precision medicine strategies requires prior knowledge of the genetic background of the target population. However, despite the availability of data from admixed Americans within large reference population databases, we cannot use these data as a surrogate for that of the Brazilian population. This lack of transferability is mainly due to differences between ancestry proportions of Brazilian and other admixed American populations. To address the issue, a coalition of research centres created the Brazilian Initiative on Precision Medicine (BIPMed). In this study, we aim to characterise two datasets obtained from 358 individuals from the BIPMed using two different platforms: whole-exome sequencing (WES) and a single nucleotide polymorphism (SNP) array. We estimated allele frequencies and variant pathogenicity values from the two datasets and compared our results using the BIPMed dataset with other public databases. Here, we show that the BIPMed WES dataset contains variants not included in dbSNP, including 6480 variants that have alternative allele frequencies (AAFs) >1%. Furthermore, after merging BIPMed WES and SNP array data, we identified 809,589 variants (47.5%) not present within the 1000 Genomes dataset. Our results demonstrate that, through the incorporation of Brazilian individuals into public genomic databases, BIPMed not only was able to provide valuable knowledge needed for the implementation of precision medicine but may also enhance our understanding of human genome variability and the relationship between genetic variation and disease predisposition.

Gene Variants Associated With Venous Thrombosis: A Replication Study in a Brazilian Multicentre Study.

Single nucleotide polymorphisms (SNP) associated with Venous Thromboembolism (VTE) risk have been identified in European and American populations. Replicate SNPs associated with VTE in a Brazilian multicenter case-control study of the Southeast region. Patients with previous VTE assisted at the Outpatient Clinics of 3 centers of the Southeast Brazilian region were compared to normal controls of the same geographic region. We evaluated 29 SNPs associated with VTE risk in other populations, and 90 SNPs for stratification analysis of the population. Due to high admixture of Brazilian population and lack of previous studies, the calculation of the sample power was performed after genotyping. Sample size, allelic frequency and Hardy-Weinberg equilibrium were estimated. The association and odds ratio analyses were estimated by logistic regression and the results were adjusted for multiple tests using Bonferroni correction. The evaluation of the genetic structure similarity in the cases and controls was performed by AMOVA. 436 cases and 430 controls were included. It was demonstrated that this sample has a statistical power to detect a genetic association of 79.4%. AMOVA showed that the genetic variability between groups was 0.0% and 100% within each group. None of the SNPs showed association with VTE in our population. A Brazilian multicenter case-control study with adequate sample power, high genetic variability though no stratification between groups, showed no replication of SNPs associated with VTE. The high admixture of Brazilian population may be responsible for these results, emphasizing the influence of the population genetic structure in association studies.

Distribution of local ancestry and evidence of adaptation in admixed populations.

Admixed American populations have different global proportions of European, Sub-Saharan African, and Native-American ancestry. However, individuals who display the same global ancestry could exhibit remarkable differences in the distribution of local ancestry blocks. We studied for the first time the distribution of local ancestry across the genome of 264 Brazilian admixed individuals, ascertained within the scope of the Brazilian Initiative on Precision Medicine. We found a decreased proportion of European ancestry together with an excess of Native-American ancestry on chromosome 8p23.1 and showed that this is due to haplotypes created by chromosomal inversion events. Furthermore, Brazilian non-inverted haplotypes were more similar to Native-American haplotypes than to European haplotypes, in contrast to what was found in other American admixed populations. We also identified signals of recent positive selection on chromosome 8p23.1, and one gene within this locus, PPP1R3B, is related to glycogenesis and has been associated with an increased risk of type 2 diabetes and obesity. These findings point to a selection event after admixture, which is still not entirely understood in recent admixture events.

Association and interaction of genetic variants with occurrence of ischemic stroke among Brazilian patients.

Ischemic Stroke (IS) is a severe and complex disorder of high morbidity and mortality rates associated with clinical, environmental, and genetic predisposing factors. Despite previous studies have associated genetic variants to stroke, inconsistent results from different populations pointed to the genetic heterogeneity for IS. Therefore, we may hypothesize that an interaction effect among genetic variants could contribute to IS occurrence rather than genetic variants independently. In this context, we investigated the association and interaction between genetic variants and large-artery atherosclerosis IS (LAAS-IS) and cardioembolic IS (CE-IS). We genotyped 435 patients (195 LAAS-IS; 240 CE-IS) and 535 controls from a population of Joinville, Santa Catarina, Brazil. Association and interaction analysis were performed by chi-square test and Multifactor-dimensionality Reduction test. We found an association between rs2383207*A allele, nearby CDKN2B-AS1, and LAAS-IS [OR 2.35 (95% CI = 1.79-3.08); p = 4.66 × 10-10]. We found an interaction among rs2910829, rs966221 and rs152312, with an accuracy of 0.62 (p = 4.3 × 10-5) demonstrating the interaction effect among variants from different genes can contribute to CE-IS risk. Further prediction analysis confirmed that clinical information, such as hypertension and dyslipidemia, presented high accuracy to predict LAAS-IS (86.47%) and CE-IS (90.47%); however, the inclusion of genetic variant information did not increase the accuracy.

Dysregulation of NEUROG2 plays a key role in focal cortical dysplasia.

OBJECTIVE: Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS: We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS: hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2-target, is upregulated (p < 0.001). In vitro experiments showed that hsa-miR-34a downregulates NEUROG2 by binding to its 5'-untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway. INTERPRETATION: Our findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa-miR-34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623-635.

Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.

OBJECTIVE: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. METHODS: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. RESULTS: We report an association between a rare variant in the complement factor H-related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10-11; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. CONCLUSIONS: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients.

Is cerebral microbleed prevalence relevant as a biomarker in amnestic mild cognitive impairment and mild Alzheimer's disease?

Introduction The search for a reliable neuroimaging biomarker in Alzheimer's disease is a matter of intense research. The presence of cerebral microbleeds seems to be a potential biomarker. However, it is not clear if the presence of microbleeds has clinical usefulness to differentiate mild Alzheimer's disease and amnestic mild cognitive impairment from normal aging. We aimed to verify if microbleed prevalence differs among three groups: mild Alzheimer's disease, amnestic mild cognitive impairment due to Alzheimer's disease, and normal controls. Moreover, we studied whether microbleeds were associated with apolipoprotein E allele ɛ4 status, cerebrospinal fluid amyloid-beta, total and phosphorylated tau protein levels, vascular factors, and cognition. Methods Twenty-eight mild Alzheimer's disease patients, 34 with amnestic mild cognitive impairment and 36 cognitively normal elderly subjects underwent: magnetic resonance imaging with a susceptibility-weighted imaging sequence on a 3T scanner, apolipoprotein E genotyping and a full neuropsychological evaluation. Only amnestic mild cognitive impairment and mild Alzheimer's disease underwent cerebrospinal fluid analysis. We compared the groups and verified if microbleeds were predicted by all other variables. Results Mild Alzheimer's disease presented a higher prevalence of apolipoprotein E allele ɛ4 in relation to amnestic mild cognitive impairment and control group. No significant differences were found between groups when considering microbleed presence. Logistic regression tests failed to find any relationship between microbleeds and the variables. We performed three different regression models using different independent variables: Model 1 - amyloid-beta, phosphorylated tau protein, total tau, apolipoprotein E allele ɛ4 status, age, and sex; Model 2 - vascular risk factors, age, and sex; Model 3 - cognitive scores sex, age, and education. Conclusion Although microbleeds might be related to the Alzheimer's disease process, their presence is not a good candidate for a neuroimaging biomarker of the disease, especially in its early phases.

Association between interleukin-8 levels and chronic periodontal disease: A PRISMA-compliant systematic review and meta-analysis.

BACKGROUND: Current publications present contradictory findings regarding interleukin-8 (IL-8) levels in patients with chronic periodontitis (CP). This systematic review compile evidences of the IL8 mRNA and protein levels in gingival tissue, saliva, and gingival crevicular fluid (GCF) investigated in patients with CP. Moreover, 2 meta-analyses were made focusing on the IL-8 levels in GCF and saliva of patients with or without CP. METHODS: Electronic searches of the PubMed, Web of Science, and Scopus databases were conducted for publications up to February 2016 that investigated the levels of IL-8 detected in individuals with CP compared with health individuals. A total of 31 publications were included in the systematic review. For meta-analyses, the strength of association was calculated by pooled odds ratios with 95% confidence intervals using RevMan 5.1 software. Heterogeneity was examined using Higgins I-squared, tau-squared, and χ tests. RESULTS: In biopsies of gingival tissue of CP patients, all studies found higher IL8 mRNA levels, and the majority of studies showed higher IL-8 protein levels in this tissue of individuals with moderate to severe CP. Four studies investigating the IL-8 levels in saliva showed inconclusive results. In spite of some studies seemed to indicate higher levels of IL-8 in GCF of CP patients, the meta-analysis results showed significantly lower IL-8 levels (pg/µL) in GCF of CP patients in comparison with periodontally healthy subjects. CONCLUSIONS: We concluded that IL8 gene expression and IL-8 protein levels were higher in gingival tissues of CP patients when compared to periodontally health individuals. Meta-analysis of studies that measured IL-8 (pg/uL) in GCF found lower levels in CP patients. There are conflicting evidences regarding IL-8 levels in saliva.

Inducible Nitric Oxide Synthase Polymorphisms and Nitric Oxide Levels in Individuals with Chronic Periodontitis.

This study aimed to investigate whether the -1026(A>C)(rs2779249) and +2087(A>G)(2297518) polymorphisms in the NOS2 gene were associated with chronic periodontitis (CP) and with salivary levels of nitrite (NO2-) and/or nitrate + nitrite (NOx). A group of 113 mixed-race patients were subjected to periodontal, genetic, and biochemical evaluations (65 CP/48 periodontally healthy subjects). DNA was extracted from oral epithelial cells and used for genotyping by polymerase chain reaction (real-time). Salivary NOx concentrations were determined using an ozone-based chemiluminescence assay. Association of CP with alleles and genotypes of the -1026(A>C) polymorphism was found (X² test, p = 0.0075; 0.0308), but this was not maintained after multiple logistic regression, performed to estimate the effect of covariates and polymorphisms in CP. This analysis demonstrated, after correction for multiple comparisons, that only the female gender was significantly associated with CP. Polymorphisms analyzed as haplotypes were not associated with CP. NOx levels were significantly higher in the control group of heterozygous individuals for both polymorphisms. In conclusion, the female gender was significantly associated with CP, and higher levels of salivary NOx were found in control subjects and associated with the heterozygous state of the NOS2 polymorphisms, reinforcing the potential of NO metabolites as markers of periodontitis status.