Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.

Reconstruction of ancient microbial genomes from the human gut.

Loss of gut microbial diversity1-6 in industrial populations is associated with chronic diseases7, underscoring the importance of studying our ancestral gut microbiome. However, relatively little is known about the composition of pre-industrial gut microbiomes. Here we performed a large-scale de novo assembly of microbial genomes from palaeofaeces. From eight authenticated human palaeofaeces samples (1,000-2,000 years old) with well-preserved DNA from southwestern USA and Mexico, we reconstructed 498 medium- and high-quality microbial genomes. Among the 181 genomes with the strongest evidence of being ancient and of human gut origin, 39% represent previously undescribed species-level genome bins. Tip dating suggests an approximate diversification timeline for the key human symbiont Methanobrevibacter smithii. In comparison to 789 present-day human gut microbiome samples from eight countries, the palaeofaeces samples are more similar to non-industrialized than industrialized human gut microbiomes. Functional profiling of the palaeofaeces samples reveals a markedly lower abundance of antibiotic-resistance and mucin-degrading genes, as well as enrichment of mobile genetic elements relative to industrial gut microbiomes. This study facilitates the discovery and characterization of previously undescribed gut microorganisms from ancient microbiomes and the investigation of the evolutionary history of the human gut microbiota through genome reconstruction from palaeofaeces.

Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Comparing signals of natural selection between three Indigenous North American populations.

While many studies have highlighted human adaptations to diverse environments worldwide, genomic studies of natural selection in Indigenous populations in the Americas have been absent from this literature until very recently. Since humans first entered the Americas some 20,000 years ago, they have settled in many new environments across the continent. This diversity of environments has placed variable selective pressures on the populations living in each region, but the effects of these pressures have not been extensively studied to date. To help fill this gap, we collected genome-wide data from three Indigenous North American populations from different geographic regions of the continent (Alaska, southeastern United States, and central Mexico). We identified signals of natural selection in each population and compared signals across populations to explore the differences in selective pressures among the three regions sampled. We find evidence of adaptation to cold and high-latitude environments in Alaska, while in the southeastern United States and central Mexico, pathogenic environments seem to have created important selective pressures. This study lays the foundation for additional functional and phenotypic work on possible adaptations to varied environments during the history of population diversification in the Americas.

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10(-13); odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10(-4); OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.

Metabolic syndrome in indigenous communities in Mexico: a descriptive and cross-sectional study.

BACKGROUND: An Amerindian genetic background could play an important role in susceptibility to metabolic diseases, which have alarmingly increased in recent decades. Mexico has one of the highest prevalences of metabolic disease worldwide. The purpose of this study was to determine the prevalence of metabolic syndrome and its components in a population with high Amerindian ancestry. METHODS: We performed a descriptive, quantitative, and analytical cross-sectional study of 2596 adult indigenous volunteers from 60 different ethnic groups. Metabolic syndrome and its components were evaluated using the American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement criteria. RESULTS: The overall prevalence of metabolic syndrome in the indigenous Mexican population was 50.3%. Although females had a higher prevalence than males (55.6% vs. 38.2%), the males presented with combinations of metabolic syndrome components that confer a higher risk of cardiovascular disease. The most frequent metabolic syndrome component in both genders was low HDL-cholesterol levels (75.8%). Central obesity was the second most frequent component in females (61%), though it had a low prevalence in males (16.5%). The overall prevalence of elevated blood pressure was 42.7% and was higher in males than females (48.8 vs. 40%). We found no gender differences in the overall prevalence of elevated triglycerides (56.7%) or fasting glucose (27.9%). CONCLUSIONS: We documented that individuals with Amerindian ancestry have a high prevalence of metabolic syndrome. Health policies are needed to control the development of metabolic disorders in a population with high genetic risk.

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Exome Sequence Data of Eight SLC Transporters Reveal That SLC22A1 and SLC22A3 Variants Alter Metformin Pharmacokinetics and Glycemic Control.

Background: Type 2 diabetes (T2D) is one of the leading causes of mortality and is a public health challenge worldwide. Metformin is the first-choice treatment for T2D; its pharmacokinetics (PK) is facilitated by members of the solute carrier (SLC) superfamily of transporters, it is not metabolized, and it is excreted by the kidney. Although interindividual variability in metformin pharmacokinetics is documented in the Mexican population, its pharmacogenomics is still underexplored. We aimed to identify variants in metformin SLC transporter genes associated with metformin PK and response in Mexican patients. Methods: Using exome data from 2217 Mexican adults, we identified 86 biallelic SNVs in the eight known genes encoding SLC transporters, with a minor allele frequency ≥ 1%, which were analyzed in an inadequate glycemic control (IGC) association study in T2D metformin treated patients. Metformin PK was evaluated in a pediatric cohort and the effect of associated SNVs was correlated. Results: Functional annotation classified two SNVs as pathogenic. The association study revealed two blocks associated with IGC. These haplotypes comprise rs622591, rs4646272, rs4646273, and rs4646276 in SLC22A1; and rs1810126 and rs668871 in SLC22A3. PK profiles revealed that homozygotes of the SLC22A1 haplotype reached lower plasma metformin concentrations 2 h post administration than the other groups. Conclusions: Our findings highlight the potential of pharmacogenomics studies to enhance precision medicine, which may involve dosage adjustments or the exploration of alternative therapeutic options. These hold significant implications for public health, particularly in populations with a high susceptibility to develop metabolic diseases, such as Latin Americans.

CFTR pathogenic variants spectrum in a cohort of Mexican patients with cystic fibrosis.

Background: Molecular diagnosis of cystic fibrosis (CF) is challenging in Mexico due to the population's high genetic heterogeneity. To date, 46 pathogenic variants (PVs) have been reported, yielding a detection rate of 77%. We updated the spectrum and frequency of PVs responsible for this disease in mexican patients. Methods: We extracted genomic DNA from peripheral blood lymphocytes obtained from 297 CF patients and their parents. First, we analyzed the five most frequent PVs in the Mexican population using PCR-mediated site-directed mutagenesis. In patients with at least one identified allele, CFTR sequencing was performed using next-generation sequencing tools and multiplex ligation-dependent probe amplification. For variants not previously classified as pathogenic, we used a combination of in silico prediction, CFTR modeling, and clinical characteristics to determine a genotype-phenotype correlation. Results: We identified 95 PVs, increasing the detection rate to 87.04%. The most frequent variants were p.(PheF508del) (42.7%), followed by p.(Gly542*) (5.6%), p.(Ser945Leu) (2.9%), p.(Trp1204*) and p.(Ser549Asn) (2.5%), and CFTRdel25-26 and p.(Asn386Ilefs*3) (2.3%). The remaining variants had frequencies of <2.0%, and some were exclusive to one family. We identified 10 novel PVs localized in different exons (frequency range: 0.1-0.8%), all of which produced structural changes, deletions, or duplications in different domains of the protein, resulting in dysfunctional ion flow. The use of different in silico software and American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) criteria allowed us to assume that all of these PVs were pathogenic, causing a severe phenotype. Conclusions: In a highly heterogeneous population, combinations of different tools are needed to identify the variants responsible for CF and enable the establishment of appropriate strategies for CF diagnosis, prevention, and treatment.

Total Antioxidant Capacity in Obese and Non-Obese Subjects and Its Association with Anthropo-Metabolic Markers: Systematic Review and Meta-Analysis.

The total antioxidant capacity (TAC) has been related to the development of and complications associated with chronic diseases, but its importance during obesity is not entirely clear. We conducted a systematic review and meta-analysis to clarify whether there are differences or similarities in the TAC between subjects with obesity (SO) and subjects with normal weight (NW). Following the recommendations of PRISMA and Cochrane, we performed a systematic search in the PubMed, Scopus, Web of Science, Cochrane, and PROSPERO databases, identifying 1607 studies. Among these, 22 studies were included in the final analysis, comprising 3937 subjects (1665 SO and 2272 NW) in whom serum TAC was measured, and from these 19,201 subjects, the correlation of serum TAC with anthropo-metabolic parameters was also estimated. The Newcastle-Ottawa method was used for the evaluation of the risk of bias. Using a random-effect model (REM), TAC was reduced in SO independently of age (SMD, -0.86; 95% CI -1.38 to -0.34; p = 0.0012), whereas malondialdehyde (SMD, 1.50; 95% CI 0.60 to 2.41), oxidative stress index (SMD, 1.0; 95% CI 0.16 to 1.84), and total oxidant status (SMD, 0.80; 0.22 to 1.37) were increased. There were seven significant pooled correlations of TAC with anthropometric and metabolic parameters: weight (r = -0.17), hip circumference (r= -0.11), visceral adipose index (r = 0.29), triglycerides (r = 0.25), aspartate aminotransferase (r = 0.41), alanine aminotransferase (r = 0.38), and uric acid (r = 0.53). Our results confirm a decrease in TAC and an increase in markers of oxidative stress in SO and underpin the importance of these serum biomarkers in obesity.

Brain radiotoxicity-related 15CAcBRT gene expression signature predicts survival prognosis of glioblastoma patients.

BACKGROUND: Glioblastoma is the most common and devastating primary brain cancer. Radiotherapy is standard of care; however, it is associated with brain radiation toxicity (BRT). This study used a multi-omics approach to determine whether BRT-related genes (RGs) harbor survival prognostic value and whether their encoded proteins represent novel therapeutic targets for glioblastoma. METHODS: RGs were identified through analysis of single-nucleotide variants associated with BRT (R-SNVs). Functional relationships between RGs were established using Protein-Protein Interaction networks. The influence of RGs and their functional groups on glioblastoma prognosis was evaluated using clinical samples from the Glioblastoma Bio-Discovery Portal database and validated using the Chinese Glioma Genome Atlas dataset. The identification of clusters of radiotoxic and putative pathogenic variants in proteins encoded by RGs was achieved by computational 3D structural analysis. RESULTS: We identified the BRT-related 15CAcBRT molecular signature with prognostic value in glioblastoma, by analysis of the COMT and APOE protein functional groups. Its external validation confirmed clinical relevance independent of age, MGMT promoter methylation status, and IDH mutation status. Interestingly, the genes IL6, APOE, and MAOB documented significant gene expression levels alteration, useful for drug repositioning. Biological networks associated with 15CAcBRT signature involved pathways relevant to cancer and neurodegenerative diseases. Analysis of 3D clusters of radiotoxic and putative pathogenic variants in proteins coded by RGs unveiled potential novel therapeutic targets in neuro-oncology. CONCLUSIONS: 15CAcBRT is a BRT-related molecular signature with prognostic significance for glioblastoma patients and represents a hub for drug repositioning and development of novel therapies.

Sex differences in the influence of type 2 diabetes (T2D)-related genes, parental history of T2D, and obesity on T2D development: a case-control study.

BACKGROUND: This study investigated the effect of sex and age at type 2 diabetes (T2D) diagnosis on the influence of T2D-related genes, parental history of T2D, and obesity on T2D development. METHODS: In this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤ 45 years; late, ≥ 46 years). Sixty-nine T2D-associated single nucleotide polymorphisms were explored and the percentage contribution (R2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist-hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models. RESULTS: T2D-related genes influenced T2D development most in males who were diagnosed early (R2 = 23.5%; females, R2 = 13.5%; males and females diagnosed late, R2 = 11.9% and R2 = 7.3%, respectively). With an early diagnosis, insulin production-related genes were more influential in males (76.0% of R2) while peripheral insulin resistance-associated genes were more influential in females (52.3% of R2). With a late diagnosis, insulin production-related genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and genes associated with inflammation and other processes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males. CONCLUSIONS: The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.

The prevalence of diabetes worldwide is slightly higher in men than in women, particularly in those aged 50 or younger (16.5% for men versus 13.5% for women). This suggests that hormonal differences could be critical in early development of Type 2 diabetes. Some known factors previously associated with T2D, such as genes, parental history of diabetes and obesity, could have a differential influence between both sexes for the development of T2D. We compared these factors between 1008 healthy individual and 1012 TD2 patients. In this comparison, we calculated the percentage of variability of the disease explained by each factor. As expected, the most noticeable differences between men and women were observed in T2D diagnoses before age 46. Genes had a greater effect in men than in women (23.5% vs. 13.5%). While genes involved in insulin production have a greater influence on men, genes involved in peripheric insulin resistance have a greater influence on women. The overall parental history of T2D influences similarly in males (19.9%) and females (17.5%), however, the unilateral genetic influence of the mother was much greater in males than in females. The influence of global and abdominal obesity played a greater role in men than in women. In T2D diagnoses after age of 45, the influence of genes and parental history of diabetes decreases markedly, and the relative influence of global obesity augments. However, while genes linked to insulin resistance and inflammation predominate in females, genes linked to insulin secretion predominate in males.

Ancestry-dependent genetic structure of the Xq28 risk haplotype in the Mexican population and its association with childhood-onset systemic lupus erythematosus.

Objective: Here we aimed to investigate the association of the Xq28 risk haplotype (H1) with susceptibility to childhood-onset systemic lupus erythematosus (SLE), and to compare its frequency and genetic structure in the Mexican population with those in other continental populations. Methods: We genotyped 15 single-nucleotide variants (SNVs) that form the H1 haplotype, using TaqMan real-time PCR. The association analysis [case-control and transmission disequilibrium test (TDT)] included 376 cases and 400 adult controls, all of whom were mestizos (MEZ). To identify risk alleles in Mexican Indigenous individuals, SNVs were imputed from whole-exome sequencing data of 1,074 individuals. The allelic frequencies determined in MEZ and Indigenous individuals were compared with those of the continental populations from the 1,000 Genomes database phase 3. Linkage disequilibrium (LD) analysis of risk alleles was performed on all populations. Interleukin-1 receptor associated kinase 1 (IRAK1) and methyl CpG binding protein 2 (MECP2) mRNA levels were determined using real-time PCR. Results: Case-control analysis revealed genetic association with childhood-onset SLE for all 15 SNVs (OR = 1.49-1.75; p = 0.0095 to 1.81 × 10-4) and for the Xq28 risk haplotype (OR = 1.97, p = 4 × 10-6). Comparing with individuals of European ancestry (0.14-0.16), the frequencies of the risk alleles were significantly higher in the MEZ individuals (0.55-0.68) and even higher in Indigenous individuals (0.57-0.83). LD analysis indicated a differential haplotype structure within the Indigenous groups, which was inherited to the MEZ population as a result of genetic admixture. Individuals homozygous for the Xq28 risk haplotype exhibited decreased levels of both MECP2A and B transcripts. Conclusion: We found that the H1 risk haplotype differs in its conformation in the Mexican population. This difference could be attributed to positive selection within the Indigenous population, with its inheritance now having an autoimmune health impact in both the Mexican Indigenous and MEZ populations.

MicroRNA delivery systems in glioma therapy and perspectives: A systematic review.

Gliomas are the deadliest of all primary brain tumors, and they constitute a serious global health problem. MicroRNAs (miRNAs) are gene expression regulators associated with glioma pathogenesis. Thus, miRNAs represent potential therapeutic agents for treating gliomas. However, miRNAs have not been established as part of the regular clinical armamentarium. This systemic review evaluates current molecular and pre-clinical studies with the aim of defining the most appealing supramolecular platform for administering therapeutic miRNA to patients with gliomas. An integrated analysis suggested that cationic lipid nanoparticles, functionalized with octa-arginine peptides, represent a potentially specific, practical, non-invasive intervention for treating gliomas. This supramolecular platform allows loading both hydrophilic (miRNA) and hydrophobic (anti-tumor drugs, like temozolomide) molecules. This systemic review is the first to describe miRNA delivery systems targeted to gliomas that integrate several types of molecules as active ingredients. Further experimental validation is warranted to confirm the practical value of miRNA delivery systems.

DNA methylation and gene expression analysis in adipose tissue to identify new loci associated with T2D development in obesity.

BACKGROUND: Obesity is accompanied by excess adipose fat storage, which may lead to adipose dysfunction, insulin resistance, and type 2 diabetes (T2D). Currently, the tendency to develop T2D in obesity cannot be explained by genetic variation alone-epigenetic mechanisms, such as DNA methylation, might be involved. Here, we aimed to identify changes in DNA methylation and gene expression in visceral adipose tissue (VAT) that might underlie T2D susceptibility in patients with obesity. METHODS: We investigated DNA methylation and gene expression in VAT biopsies from 19 women with obesity, without (OND = 9) or with T2D (OD = 10). Differences in genome-scale methylation (differentially methylated CpGs [DMCs], false discovery rate < 0.05; and differentially methylated regions [DMRs], p value < 0.05) and gene expression (DEGs, p value <0.05) between groups were assessed. We searched for overlap between altered methylation and expression and the impact of altered DNA methylation on gene expression, using bootstrap Pearson correlation. The relationship of altered DNA methylation to T2D-related traits was also tested. RESULTS: We identified 11 120 DMCs and 96 DMRs distributed across all chromosomes, with the greatest density of epigenomic alterations at the MHC locus. These alterations were found in newly and previously T2D-related genes. Several of these findings were supported by validation and extended multi-ethnic analyses. Of 252 DEGs in the OD group, 68 genes contained DMCs (n = 88), of which 24 demonstrated a significant relationship between gene expression and methylation (p values <0.05). Of these, 16, including ATP11A, LPL and EHD2 also showed a significant correlation with fasting glucose and HbA1c levels. CONCLUSIONS: Our results revealed novel candidate genes related to T2D pathogenesis in obesity. These genes show perturbations in DNA methylation and expression profiles in patients with obesity and diabetes. Methylation profiles were able to discriminate OND from OD individuals; DNA methylation is thus a potential biomarker.

Dysferlinopathy misdiagnosed with juvenile polymyositis in the pre-symptomatic stage of hyperCKemia: a case report and literature review.

BACKGROUND: Dysferlinopathy encompasses a group of rare muscular dystrophies caused by recessive mutations in the DYSF gene. The phenotype ranges from asymptomatic elevated serum creatine kinase (hyperCKemia) to selective and progressive involvement of the proximal and/or distal muscles of the limbs. Bohan and Peter criteria are the most widely used for the diagnosis of polymyositis, but they have limitations and can misclassify muscular dystrophies with inflammation as polymyositis. Most dysferlinopathy patients have muscle biopsies with inflammation and thus are vulnerable to misdiagnosis with polymyositis and inappropriate treatment with steroids and immunosuppressors. CASE PRESENTATION: We describe a 14 years-old male patient who was referred for assessment of asymptomatic hyperCKemia (26,372 IU/L). An X-linked dystrophinopathy initially was ruled out by direct genetic testing. Juvenile polymyositis was considered based on muscle biopsy, creatine kinase levels, and electromyography changes. Corticosteroid treatment triggered proximal lower limb muscular weakness, and no full muscular strength recovery was observed after corticosteroid withdrawal. Based on these observations, a limb-girdle muscular dystrophy (LGMD) was suspected, and LGMDR2 was confirmed by whole exome sequencing. CONCLUSION: We report a dysferlinopathy patient who was misdiagnosed with juvenile polymyositis and explore in a literature review how common such misdiagnoses are. With diagnosis based only on routine clinicopathological examinations, distinguishing an inflammatory myopathy from dysferlinopathy is quite difficult. We suggest that before establishing a diagnosis of "definite" or "probable" juvenile polymyositis, according to Bohan and Peter or current ACR/EULAR criteria, a muscular dystrophy must first be ruled out.

Correction: Whole genome variation in 27 Mexican indigenous populations, demographic and biomedical insights.

[This corrects the article DOI: 10.1371/journal.pone.0249773.].

Kazak mitochondrial genomes provide insights into the human population history of Central Eurasia.

As a historical nomadic group in Central Asia, Kazaks have mainly inhabited the steppe zone from the Altay Mountains in the East to the Caspian Sea in the West. Fine scale characterization of the genetic profile and population structure of Kazaks would be invaluable for understanding their population history and modeling prehistoric human expansions across the Eurasian steppes. With this mind, we characterized the maternal lineages of 200 Kazaks from Jetisuu at mitochondrial genome level. Our results reveal that Jetisuu Kazaks have unique mtDNA haplotypes including those belonging to the basal branches of both West Eurasian (R0, H, HV) and East Eurasian (A, B, C, D) lineages. The great diversity observed in their maternal lineages may reflect pivotal geographic location of Kazaks in Eurasia and implies a complex history for this population. Comparative analyses of mitochondrial genomes of human populations in Central Eurasia reveal a common maternal genetic ancestry for Turko-Mongolian speakers and their expansion being responsible for the presence of East Eurasian maternal lineages in Central Eurasia. Our analyses further indicate maternal genetic affinity between the Sherpas from the Tibetan Plateau with the Turko-Mongolian speakers.

Exome Sequencing Data Analysis and a Case-Control Study in Mexican Population Reveals Lipid Trait Associations of New and Known Genetic Variants in Dyslipidemia-Associated Loci.

Background: Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American populations have been underrepresented in these studies. Objective: To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia. Methods: We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r2 threshold of 0.1. Results: Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in BUD13 with hypertriglyceridemia, rs7252453 in CILP2 with decreased risk to hypercholesterolemia and rs11076176 in CETP with increased risk to low high density lipoprotein cholesterol. Conclusions: We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.