While the effect of exercise on white adipose tissue browning and metabolic improvement in rodents is clear, there are few studies in humans with inconclusive results. Thus, the aim of the study was ...to assess whether an exercise intervention promotes subcutaneous adipose tissue browning in humans, and whether this response is associated with metabolic improvement in three groups of individuals defined by body mass index (BMI) (kg/m
). Sedentary adult subjects with different BMI were enrolled in a 12-week bicycle-training program (3 times per week, intensity 70-80% HRmax). Brown and beige gene expression in subcutaneous adipose tissue (scWAT) biopsies, and serum glucose, insulin, lipid, adipokine, and myokine levels were compared before and after the exercise intervention. Thirty-three non-diabetic subjects (mean age 30.4 ± 4.6 years; 57.57% female; 13 normal weight, 10 overweight and 10 with obesity) completed the exercise intervention. Without any significant change in body composition, exercise improved several metabolic parameters, most notably insulin resistance and particularly in the overweight group. Circulating adiponectin, apelin, and irisin exercise-induced changes predicted 60% of the insulin sensitivity improvement. After exercise
scWAT expression significantly increased, along with P2RX5 significant positive staining. These changes are compatible with scWAT browning, however, they were not associated with glucose metabolism improvement. In conclusion, 12-weeks of exercise training produced brown/beige gene expression changes in abdominal scWAT of non-diabetic individuals with different BMI, which did not contribute to the metabolic improvement. However, this result should not be interpreted as a lack of effect of browning on metabolic parameters. These findings suggest that a bigger effect is needed and should not preclude the development of more effective strategies of browning. Furthermore, exercise-induced changes in adiponectin, apelin, and irisin predicted insulin sensitivity improvement, supporting the important role of adipokines and myokines in metabolism homeostasis.
Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome ...stability. PV in
,
, and
account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder
PV, identified in three patients with FA from the
community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV,
: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in
. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.
The clinical phenotype of LMNA-associated dilated cardiomyopathy (DCM) varies even among individuals who share the same mutation. LMNA encodes lamin AC, which interacts with the lamin-associated ...protein 2 alpha (LAP2α) encoded by the TMPO gene. The LAP2α/Arg690Cys polymorphism is frequent in Latin America and was previously found to disrupt LAP2α-Lamin AC interactions in vitro. We identified a DCM patient heterozygous for both a lamin AC truncating mutation (Ser431*) and the LAP2α/Arg690Cys polymorphism. We performed protein modeling and docking experiments, and used confocal microscopy to compare leukocyte nuclear morphology among family members with different genotype combinations (wild type, LAP2α Arg690Cys heterozygous, lamin AC/Ser431* heterozygous, and LAP2α Arg690Cys/lamin AC Ser431* double heterozygous). Protein modeling predicted that 690Cys destabilizes the LAP2α homodimer and impairs lamin AC-LAP2α docking. Lamin AC-deficient nuclei (Ser431* heterozygous) showed characteristic blebs and invaginations, significantly decreased nuclear area, and increased elongation, while LAP2α/Arg690Cys heterozygous nuclei showed a lower perimeter and higher circularity than wild-type nuclei. LAP2α Arg690Cys apparently attenuated the effect of LMNA Ser431* on the nuclear area and fully compensated for its effect on nuclear circularity. Altogether, the data suggest that LAP2α/Arg690Cys may be one of the many factors contributing to phenotype variation of LMNA-associated DCM.
Risk of hyperuricemia is modified by genetic and environmental factors. Our aim was to identify factors associated with serum uric acid levels and hyperuricemia in Mexicans. A pilot Genome-wide ...association study GWAS was performed in a subgroup of participants (
= 411) from the Health Workers Cohort Study (HWCS). Single nucleotide polymorphisms (SNPs) associated with serum uric acid levels were validated in all the HWCS participants (
= 1939) and replicated in independent children (
= 1080) and adult (
= 1073) case-control studies. The meta-analysis of the whole HWCS and replication samples identified three
SNPs:
(
= 2.3 × 10
),
(
= 8.2 × 10
) and
(
= 1.1 × 10
); and an
missense SNP,
(
= 1.0 × 10
). Among the non-genetic factors identified, the visceral adiposity index, smoking, the metabolic syndrome and its components (waist circumference, blood pressure, glucose and hyperlipidemia) were associated with increased serum uric acid levels and hyperuricemia (
< 0.05). Among the female HWCS participants, the odds ratio for hyperuricemia was 1.24 (95% CI, 1.01-1.53) per unit increase in soft drink consumption. As reported in other studies, our findings indicate that diet, adiposity and genetic variation contribute to the elevated prevalence of hyperuricemia in Mexico.
Neuromyelitis Optica Spectrum Disorder (NMOSD) is a demyelinating autoimmune disease of the central nervous system, more prevalent in individuals of non-European ancestry. Few studies have analyzed ...genetic risk factors in NMOSD, and HLA class II gene variation has been associated NMOSD risk in various populations including Mexicans. Thymopoietin (
TMPO
) has not been tested as a candidate gene for NMOSD or other autoimmune disease, however, experimental evidence suggests this gene may be involved in negative selection of autoreactive T cells and autoimmunity. We thus investigated whether the missense
TMPO
variant rs17028450 (Arg630Cys, frequent in Latin America) is associated with NMOSD, and whether this variant shows an interaction with HLA-class II rs9272219, previously associated with NMOSD risk. A total of 119 Mexican NMOSD patients, 1208 controls and 357 Native Mexican individuals were included. The HLA rs9272219 “T” risk allele frequency ranged from 21 to 68%, while the rs17028450 “T” minor allele frequency was as high as 18% in Native Mexican groups. Both rs9272219 and rs17028450 were significantly associated with NMOSD risk under additive models (
OR
= 2.48;
p
= 8 × 10
–10
and
OR
= 1.59;
p
= 0.0075, respectively), and a significant interaction between both variants was identified with logistic regression models (
p
= 0.048). Individuals bearing both risk alleles had an estimated 3.9-fold increased risk of NMOSD. To our knowledge, this is the first study reporting an association of
TMPO
gene variation with an autoimmune disorder and the interaction of specific susceptibility gene variants, that may contribute to the genetic architecture of NMOSD in admixed Latin American populations.
Serum magnesium is inversely associated to coronary artery calcification (CAC) in patients with chronic kidney disease. There is little information on this association in a general healthy ...population.
The aim of this study was to examine the cross-sectional association of serum magnesium levels with CAC.
We included 1276 Mexican-mestizo subjects (50 % women), aged 30-75 years, free of symptomatic cardiovascular disease. CAC was quantified by multidetector computed tomography using the method described by Agatston. Cross-sectional associations of serum magnesium with cardiometabolic factors and subclinical atherosclerosis defined as a CAC score > 0, were examined in logistic regression models adjusted for age, sex, education, smoking status, body mass index, systolic blood pressure, physical activity, elevated abdominal visceral tissue, fasting insulin and glucose, alcohol consumption, menopausal status (women only), low (LDL-C) and high density lipoprotein cholesterol (HDL-C), triglycerides, diuretic use, type 2 diabetes mellitus (DM2), and family history of DM2.
After full adjustment, subjects in the highest quartile of serum magnesium had 48 % lower odds of hypertension (p = 0.028), 69 % lower odds of DM2 (p = 0.003), and 42 % lower odds of CAC score > 0 (p = 0.016) compared to those with the lowest serum magnesium. The analyses also showed that a 0.17 mg/dL (1SD) increment in serum magnesium was independently associated with 16 % lower CAC (OR 0.84, 95 % CI 0.724-0.986).
In a sample of Mexican-mestizo subjects, low serum magnesium was independently associated to higher prevalence not only of hypertension and DM2, but also to coronary artery calcification, which is a marker of atherosclerosis and a predictor of cardiovascular morbidity and mortality.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background
Dilated cardiomyopathy (DCM) is a major cause of nonischemic heart failure and death in young adults. Next generation sequencing (NGS) has become part of the diagnostic workup in ...idiopathic and familial DCM. More than 50 DCM genes have been identified, revealing great molecular heterogeneity and variable diagnostic yield. Interpretation of variant pathogenicity is challenging particularly in underrepresented populations, as pathogenic variant databases include studies mainly from European/Caucasian populations. To date, no studies on genomic diagnosis of DCM have been conducted in Mexico.
Methods
We recruited 55 unrelated DCM patients, 22 familial (F‐DCM), and 33 idiopathic (I‐DCM), and performed site‐directed NGS seeking causal mutations. Diagnostic yield was defined as the proportion of individuals with at least one pathogenic (P) or likely pathogenic (LP) variant in DCM genes.
Results
Overall diagnostic yield was 47.3%, and higher in F‐DCM (63.6%) than in I‐DCM (36.4%, p = 0.047). Overall, NGS disclosed 41 variants of clinical interest (61.0% novel), 27 were classified as P/LP and 14 of unknown clinical significance. Of P/LP variants, 10 were A‐band region TTN truncating variants, five were found in DSP (18.5%), five in MYH7 (18.5%), two in LMNA (7.4%), and one in RBM20, ABCC9, FKTN, ACTA1, and TNNT2. NGS findings suggested autosomal recessive inheritance in three families, two with DSP loss of function mutations in affected individuals. The increasing number of mutation reports in DCM, increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of DCM‐related proteins, the recent refinement ACMG/ClinGen Guidelines, and co‐segregation analysis in DCM families helped increase the diagnostic yield.
Conclusion
This is the first NGS study performed in a group of Mexican DCM patients, contributing to understand the mutational spectrum and complexity of DCM molecular diagnosis.
Molecular diagnosis in dilated cardiomyopathy (DCM) is challenging, particularly in underrepresented populations. We obtained a relatively high diagnostic yield in familial DCM (63.6%) and in idiopathic DCM (47.3%) in a group of Mexican patients. The increasing number of reports of mutations in DCM patients, the increasing knowledge on the functional consequences of mutations, mutational hotspots and functional domains of some DCM‐related proteins, the refinement ACMG/ClinGen Guidelines and co‐segregation analysis helped achieve this higher diagnostic yield.
Culture and genetics rely on two distinct but not isolated transmission systems. Cultural processes may change the human selective environment and thereby affect which individuals survive and ...reproduce. Here, we evaluated whether the modes of subsistence in Native American populations and the frequencies of the ABCA1*Arg230Cys polymorphism were correlated. Further, we examined whether the evolutionary consequences of the agriculturally constructed niche in Mesoamerica could be considered as a gene-culture coevolution model. For this purpose, we genotyped 229 individuals affiliated with 19 Native American populations and added data for 41 other Native American groups (n = 1905) to the analysis. In combination with the SNP cluster of a neutral region, this dataset was then used to unravel the scenario involved in 230Cys evolutionary history. The estimated age of 230Cys is compatible with its origin occurring in the American continent. The correlation of its frequencies with the archeological data on Zea pollen in Mesoamerica/Central America, the neutral coalescent simulations, and the F(ST)-based natural selection analysis suggest that maize domestication was the driving force in the increase in the frequencies of 230Cys in this region. These results may represent the first example of a gene-culture coevolution involving an autochthonous American allele.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Sudden death in a child is a devastating event with important medical implications for surviving relatives. Because it may be the first manifestation of unknown inherited cardiac disease, molecular ...autopsy can be helpful to determine the cause of death and identify at risk family members. The aim of the study was to perform a molecular autopsy in a seven year-old girl with sudden unexplained death, to find evidence supporting the possible pathogenicity of mutations identified in inherited cardiac disease genes, and to clinically and genetically assess first-degree relatives. DNA from the index case was extracted from umbilical cord cells stored at birth, and DNA of first-degree relatives from blood samples. Targeted sequencing was performed using a Haloplex design including 81 cardiogenes. Possible functional consequences of the mutations were analyzed using protein modeling and structural mobility analyses. The child was compound heterozygous for KCNQ1 variants p.Ala300Thr and p.Pro535Thr. Ala300Thr is known to cause long QT syndrome in the homozygous state, while Pro535Thr is novel and of unknown clinical significance. The father and sibling were Ala300Thr heterozygous, and had normal QTc intervals at rest and during exercise. The asymptomatic mother was heterozygous for Pro535Thr, and showed borderline QTc at rest, but prolonged QTc during exercise. Protein modeling predicted that Ala300Thr alters the mobility profile of the Kv7.1 tetramer and Thr535 disrupts a calmodulin-binding site, probably causing co-assembly or trafficking defects of the mutant monomer. Altogether, the evidence strongly suggests that this child was affected with a recessive form of Romano Ward syndrome.
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•Molecular autopsy in sudden unexplained death revealed compound heterozygous KCNQ1 mutations.•Protein modeling predicted the T300 mutation alters tetramer flexibility.•The T535 mutation is predicted to disrupt a calmodulin-binding site.•Defective trafficking of the T535 monomer would simulate a T300 homozygous state.•These predictions are compatible with a severe long QT syndrome phenotype.
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