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.

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.

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.

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.

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.

Unraveling Signatures of Local Adaptation among Indigenous Groups from Mexico.

Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/ß catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.

Effect of the Melanocortin 4-Receptor Ile269Asn Mutation on Weight Loss Response to Dietary, Phentermine and Bariatric Surgery Interventions.

The loss of function melanocortin 4-receptor (MC4R) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5-9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: -4.0 kg (-2.9%) in patient 1, and -1.8 kg (-1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (-2.9 kg; -2.8%). Phentermine treatment produced similar weight loss in six carriers (-12.7 kg; 15.5%) and 18 non-carriers (-11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.

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.

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.

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.

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.

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.

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

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

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.

The genomic landscape of Mexican Indigenous populations brings insights into the peopling of the Americas.

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15-30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4-9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far.

Alterations of DNA methylation during adipogenesis differentiation of mesenchymal stem cells isolated from adipose tissue of patients with obesity is associated with type 2 diabetes.

Adipogenesis regulation is crucial for mature adipocyte function. In obesity, a major driver of type 2 diabetes (T2D), this process is disrupted and remains poorly characterized. Here we identified altered DNA methylation profiles in diabetic obese patients, during three adipocytes differentiation stages. We isolated mesenchymal cells from visceral adipose tissue of obese patients with and without T2D to analyse DNA methylation profiles at 0, 3, and 18 days of ex vivo differentiation and documented their impact on gene expression. Methylation and gene expression were analysed with EPIC and Clarion S arrays, respectively. Patients with T2D had epigenetic alterations in all the analysed stages, and these were mainly observed in genes important in adipogenesis, insulin resistance, cell death programming, and immune effector processes. Importantly, at 3 days, we found six-fold more methylated CpG alterations than in the other stages. This is the first study to document epigenetic markers that persist through all three adipogenesis stages and their impact on gene expression, which could be a cellular metabolic memory involved in T2D. Our data provided evidence that, throughout the adipogenesis process, alterations occur in methylation that might impact mature adipocyte function, cause tissue malfunction, and potentially, lead to the development of T2D.

The L125F MATE1 variant enriched in populations of Amerindian origin is associated with increased plasma levels of metformin and lactate.

Genetic factors that affect variability in metformin response have been poorly studied in the Latin American population, despite its being the initial drug therapy for type 2 diabetes, one of the most prevalent diseases in that region. Metformin pharmacokinetics is carried out by members of the membrane transporters superfamily (SLCs), being the multidrug and toxin extrusion protein 1 (MATE1), one of the most studied. Some genetic variants in MATE1 have been associated with reduced in vitro metformin transport. They include rs77474263 p.[L125F], a variant present at a frequency of 13.8% in Latin Americans, but rare worldwide (less than 1%). Using exome sequence data and TaqMan genotyping, we revealed that the Mexican population has the highest frequency of this variant: 16% in Mestizos and 27% in Amerindians, suggesting a possible Amerindian origin. To elucidate the metformin pharmacogenetics, a children cohort was genotyped, allowing us to describe, for the first time, a MATE1 rs77474263 TT homozygous individual. An additive effect of the L125F variant was observed on blood metformin accumulation, revealing the highest metformin and lactate serum levels in the TT homozygote, and intermediate metformin values in the heterozygotes. Moreover, a molecular dynamics analysis suggested that the genetic variant effect on metformin efflux could be due to a decreased protein permeability. We conclude that pharmacogenetics could be useful in enhancing metformin pharmacovigilance in populations having a high frequency of the risk genotype, especially considering that these populations also have a higher susceptibility to the diseases for which metformin is the first-choice drug.

Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum.

BACKGROUND: We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample of 509 unrelated adults with type 2 diabetes and 459 controls, all belonging to the DMS1 SIGMA-cohort (ExAC). We performed in silico analysis on missense variants using Variant Effect Predictor software. To evaluate co-segregation, predicted pathogenic variants were genotyped in other family members. We performed molecular dynamics analysis for the co-segregating variants. RESULTS: After filtering, Mendelian genotypes were confirmed in two probands bearing two novel variants, p.Arg252His and p.Lys68Gln. Both variants co-segregated with the AOMS3 phenotype in classic dominant autosomal inheritance with full penetrance. In silico analysis revealed impairment of the DYRK1B protein function by both variants. For the first time, we describe age-dependent variable expressivity of this entity, with central obesity and insulin resistance apparent in childhood; morbid obesity, severe hypertriglyceridemia, and labile type 2 diabetes appearing before 40 years of age; and hypertension emerging in the fifth decade of life. We also report the two youngest individuals suffering from AOMS3. CONCLUSIONS: Monogenic forms of metabolic diseases could be misdiagnosed and should be suspected in families with several affected members and early-onset metabolic phenotypes that are difficult to control. Early diagnostic strategies and medical interventions, even before symptoms or complications appear, could be useful.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.