The fatal contribution of serine protease-related genetic variants to COVID-19 outcomes.

Introduction: Serine proteases play a critical role during SARS-CoV-2 infection. Therefore, polymorphisms of transmembrane protease serine 2 (TMPRSS2) and serpine family E member 1 (SERPINE1) could help to elucidate the contribution of variability to COVID-19 outcomes. Methods: To evaluate the genetic variants of the genes previously associated with COVID-19 outcomes, we performed a cross-sectional study in which 1536 SARS-CoV-2-positive participants were enrolled. TMPRSS2 (rs2070788, rs75603675, rs12329760) and SERPINE1 (rs2227631, rs2227667, rs2070682, rs2227692) were genotyped using the Open Array Platform. The association of polymorphisms with disease outcomes was determined by logistic regression analysis adjusted for covariates (age, sex, hypertension, type 2 diabetes, and obesity). Results: According to our codominant model, the GA genotype of rs2227667 (OR=0.55; 95% CI = 0.36-0.84; p=0.006) and the AG genotype of rs2227667 (OR=0.59; 95% CI = 0.38-0.91; p=0.02) of SERPINE1 played a protective role against disease. However, the rs2227692 T allele and TT genotype SERPINE1 (OR=1.45; 95% CI = 1.11-1.91; p=0.006; OR=2.08; 95% CI = 1.22-3.57; p=0.007; respectively) were associated with a decreased risk of death. Similarly, the rs75603675 AA genotype TMPRSS2 had an OR of 1.97 (95% CI = 1.07-3.6; p=0.03) for deceased patients. Finally, the rs2227692 T allele SERPINE1 was associated with increased D-dimer levels (OR=1.24; 95% CI = 1.03-1.48; p=0.02). Discussion: Our data suggest that the rs75603675 TMPRSS2 and rs2227692 SERPINE1 polymorphisms are associated with a poor outcome. Additionally, rs2227692 SERPINE1 could participate in hypercoagulable conditions in critical COVID-19 patients, and this genetic variant could contribute to the identification of new pharmacological targets and treatment strategies to block the inhibition of TMPRSS2 entry into SARS-CoV-2.

Hand function and quality of life in patients with diabetes mellitus before and during the COVID-19 pandemic.

This study aimed to investigate the effects of the coronavirus disease 2019 (COVID-19) pandemic on patients with diabetes mellitus using patient-rated outcome measures focusing on hand function and quality of life, as well as patients' mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It was a part of a longitudinal research involving patients with diabetes mellitus living in Sapporo, Japan. Among the 594 patients surveyed before the COVID-19 pandemic from March to June 2019, 417 patients who could be re-surveyed from March to June 2021 were included. We compared the patient-rated outcome measures, namely the Hand10 for hand function and EuroQol five-dimension questionnaire for assessing quality of life in the same population of patients with diabetes mellitus, before and during the COVID-19 pandemic. The results indicated no deterioration in the Hand10 (3.9 vs 3.6) and quality of life scores (0.89 vs 0.9), including mobility (1.25 vs 1.17), self-care (1.1 vs 1.08), pain/discomfort (1.43 vs 1.35), and anxiety/depression (1.21 vs 1.2), during the COVID-19 pandemic when compared with the pre-pandemic values. Usual activity values on the EuroQol five-dimension subscale significantly improved during the pandemic compared to those before the pandemic (1.21 vs 1.12, p<0.01). This study highlighted the effects of the COVID-19 pandemic on patients with diabetes mellitus by comparing patient-rated outcome measures in two different social situations. Patients with diabetes mellitus living in Sapporo, Japan maintained hand function and quality of life by continuing their usual activities during the COVID-19 pandemic.

Implication of myddosome complex genetic variants in outcome severity of COVID-19 patients.

BACKGROUND/PURPOSE(S): During a viral infection, the immune response is mediated by the toll-like receptors and myeloid differentiation Factor 88 (MyD88) that play an important role sensing infections such as SARS-CoV-2 which has claimed the lives of more than 6.8 million people around the world. METHODS: We carried out a cross-sectional with a population of 618 SARS-CoV-2-positive unvaccinated subjects and further classified based on severity: 22% were mild, 34% were severe, 26% were critical, and 18% were deceased. Toll Like Receptor 7 (TLR7) single-nucleotide polymorphisms (rs3853839, rs179008, rs179009, and rs2302267) and MyD88 (rs7744) were genotyped using TaqMan OpenArray. The association of polymorphisms with disease outcomes was performed by logistic regression analysis adjusted by covariates. RESULTS: A significant association of rs3853839 and rs7744 of the TLR7 and MyD88 genes, respectively, was found with COVID-19 severity. The G/G genotype of the rs3853839 TLR7 was associated with the critical outcome showing an Odd Ratio = 1.98 (95% IC = 1.04-3.77). The results highlighted an association of the G allele of MyD88 gene with severe, critical and deceased outcomes. Furthermore, in the dominant model (AG + GG vs. AA), we observed an Odd Ratio = 1.70 (95% CI = 1.02-2.86) with severe, Odd Ratio = 1.82 (95% CI = 1.04-3.21) with critical, and Odd Ratio = 2.44 (95% CI = 1.21-4.9) with deceased outcomes. CONCLUSION: To our knowledge this work represents an innovative report that highlights the significant association of TLR7 and MyD88 gene polymorphisms with COVID-19 outcomes and the possible implication of the MyD88 variant with D-dimer and IFN-α concentrations.

A novel nonsense mutation in the insulin receptor gene in a patient with HAIR-AN syndrome and endometrial cancer.

Severe insulin resistance can be caused by rare genetic defects in the insulin receptor known as insulin receptoropathies. These genetic defects cause a wide spectrum of clinical manifestations ranging from mild syndromes to lethal disorders. Among those is the HAIR-AN an extreme subtype of polycystic ovary syndrome (PCOS). We present a case of a 29-year-old woman with amenorrhea, severe insulin resistance, hirsutism, and acanthosis nigricans who also developed endometrial cancer. She was found to carry a novel heterozygous nonsense mutation insulin receptor gene (INSR). The mutation was inherited from the mother. Levels of insulin receptor and AKT were measured using Western-Blot from peripheral blood mononuclear cells and were both decreased. Thus, we conclude that the identified mutation in the insulin receptor gene and lead to decreased activity of the downstream signaling of the insulin pathway.

Predictive factors and clinical effects of diabetic hand: A prospective study with 1-year follow-up.

AIMS: Diabetes mellitus is considered an etiological factor for hand-related conditions that are grouped under the term "diabetic hand" (DH), which includes limited joint mobility, Dupuytren's contracture, carpal tunnel syndrome, and trigger finger. This study aimed to identify predictive factors and the clinical effects of DH development among patients with diabetes. PATIENTS AND METHODS: Consecutive Japanese adults with diabetes were prospectively recruited at a single outpatient center. We assessed the presence of DH at baseline and at the 1-year follow-up, which was considered present if the patient exhibited one or more of the hand disorders at either examination. RESULTS: The 590 eligible subjects had a mean age of 57 years and included 155 patients (26%) with DH. Binary logistic regression analysis revealed that DH was significantly associated with older age, longer diabetes duration, and higher body mass index. Patients with DH had significantly lower hand function and quality of life (QOL) scores. We assessed 476 patients at the 1-year follow-up, including 96 patients (20%) who had DH at baseline. Although 25 of the 96 patients (26%) experienced resolution of DH without specific treatment, 83 of 380 patients (22%) without DH at baseline had developed new DH-related conditions. At the 1-year follow-up, the group with DH was significantly older than that without DH. CONCLUSION: Older age and prolonged duration of diabetes predicted the development of DH. Patients who are not old and do not have a prolonged duration of diabetes may experience DH resolution without specific treatment.

Occurrence of Klinefelter Syndrome Mosaic 45,X/46,XY/47,XXY/48,XXYY/48,XXXY and Primary Hyperparathyroidism.

OBJECTIVE: The presence of primary hyperparathyroidism (PHPT) and Klinefelter syndrome (KS) is rare, and its association with KS mosaicism is even rarer. We report an unusual combination of these entities with a mild phenotype of KS. METHODS: The patient was a 44-year-old male with a history of PHPT who had recurrent urolithiasis despite being treated with a successful parathyroidectomy. On examination, he had axillary hair growth, bilateral gynecomastia, a large port-wine stain at the right hemithorax and upper right limb, and genitalia and pubic hair corresponding to Tanner IV classification with small, normal consistency testicles. RESULTS: Laboratory findings were unremarkable except for a slightly elevated luteinizing hormone, which was normal on repeat testing. Because of the picture of unexplained gynecomastia, laboratory findings, and low-volume testis, a diagnosis of KS was considered. Chromosomal analysis revealed a rare 45,X/46,XY/47,XXY/48,XXYY/48,XXXY KS mosaic. CONCLUSIONS: KS phenotypes are largely variable, and their association with PHPT remains to be elucidated.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Contribution of Known Genetic Risk Variants to Dyslipidemias and Type 2 Diabetes in Mexico: A Population-Based Nationwide Study.

Dyslipidemias are common risk factors for the development of chronic disorders including type 2 diabetes (T2D). Over 100 associated loci have been identified but few reports have evaluated the population attributable fraction captured by them in population-based nationwide surveys. Therefore, we determined the population contribution of a set of known genetic risk variants to the development of dyslipidemias and T2D in Mexico. This study included 1665 participants from a Mexican National Health Survey carried out in the year 2000. It is a probabilistic complex sample survey of households, which comprises representative data at a national level. 103 previously reported SNPs associated with different dyslipidemias or T2D were genotyped and used to compute polygenic risk scores. We found that the previously known variants associated with dyslipidemias explain at most 7% of the total risk variance of lipid levels. In contrast, the known genetic risk component for T2D explained a negligible amount of variance (0.1%). Notably, variants derived from the Native-American ancestry have the strongest effect and contribute with a high proportion of the variance. These results support the need for additional studies aimed to identify specific genetic risk variants for Mexican population.

A Loss-of-Function Splice Acceptor Variant in IGF2 Is Protective for Type 2 Diabetes.

Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the IGF2 gene associated with ∼20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between IGF2 exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of IGF2 isoform 2. In individuals who do not carry the protective allele, expression of IGF2 isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in IGF2 isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing IGF2 isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.

The panorama of familial hypercholesterolemia in Latin America: a systematic review.

The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.

Trypanosoma cruzi: multiple actin isovariants are observed along different developmental stages.

The expression and biological role of actin during the Trypanosoma cruzi life cycle remains largely unknown. Polyclonal antibodies against a recombinant T. cruzi actin protein were used to confirm its expression in epimastigotes, trypomastigotes, and amastigotes. Although the overall levels of expression were similar, clear differences in the subcellular distribution of actin among the developmental stages were identified. The existence of five actin variants in each developmental stage with distinct patterns of expression were uncovered by immunoblotting of protein extracts separated 2D-SDS gels. The isoelectric points of the actin variants in epimastigotes ranged from 4.45 to 4.9, whereas they ranged from 4.9 to 5.24 in trypomastigotes and amastigotes. To determine if the actin variants found could represent previously unidentified actins, we performed a genomic survey of the T.cruzi GeneDB database and found 12 independent loci encoding for a diverse group of actins and actin-like proteins that are conserved among trypanosomatids.

Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families.

CONTEXT: Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset and a primary insulin secretion defect. Certain MODY gene sequence variants may be involved in polygenic forms of type 2 diabetes. OBJECTIVE: We assessed the contribution of MODY genes to the etiology of type 2 early-onset diabetes in 23 Mexican families, including five with apparently autosomal dominant inheritance. PATIENTS: Twenty-three unrelated Mexican families with early-onset type 2 diabetes previously screened for the presence of glucokinase mutations, were studied. DESIGN: We screened MODY genes for sequence variants by PCR-SSCP analysis and automated sequencing. We performed a functional analysis of the HNF-1alpha P379H recombinant protein in vitro in both HeLa and RINm5f beta-cell lines. MAIN OUTCOME MEASURES: MODY gene mutation screening and P379H mutant protein transactivation assay. RESULTS: No mutations were detected in the HNF-4alpha, IPF-1, NEUROD1 or HNF-1beta genes in any of the families studied. A new mutation (P379H) of the HNF-1alpha gene was identified in one MODY family. RINm5f and HeLa cell transfection assays revealed decreased transactivation activity of the mutant protein on the human insulin promoter. CONCLUSIONS: All known MODY genes were screened for abnormalities in this cohort of early-onset diabetes families which included 5 MODY pedigrees. We identified a new HNF-1alpha MODY mutation (P379H) and demonstrated that it reduces the transactivation potential of the mutant protein on the human insulin promoter. No other mutation was identified in this cohort indicating that abnormalities in MODY genes are generally not a common cause of early-onset diabetes and this includes MODY families in Mexico.