Bilateral Peters' anomaly, aniridia and Wilms tumour (WAGR syndrome) in monozygotic twins.

AIM: This study reports the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins subsequently diagnosed with Wilms tumour (WAGR syndrome). METHODS: Two monozygotic female twins were referred at age 2 months with bilateral corneal opacity. A diagnosis of Peters' anomaly associated to aniridia was made in both eyes of both twins. Physical examination and ultrasonography were carried out at 12 months of age to explore the possibility of WAGR-related anomalies, specifically Wilms tumour. DNA were isolated and subjected to whole exome sequencing. RESULTS: Peters' anomaly associated to aniridia in both eyes as well as bilateral Wilms tumour in both children were diagnosed. Exome analyses showed a large heterozygous deletion encompassing 6 648 473 bp in chromosome 11p13, using Integrative Genomics Viewer and AnnotSV software. CONCLUSION: WAGR syndrome is a rare contiguous gene deletion syndrome with a greater risk of developing Wilms tumour associated with Peters' anomaly and congenital aniridia. However, co-occurrence of both anomalies was rarely reported in twins, and never in both eyes of monozygotic twins. Here, we report the bilateral association of Peters' anomaly and congenital aniridia in monozygotic twins with WAGR syndrome.

IFITM3 rs12252 polymorphism association with COVID-19 severity and mortality in a Brazilian sample: an update and a meta-analysis.

This study investigated the association between the IFITM3 rs12252 polymorphism and the severity and mortality of COVID-19 in hospitalized Brazilian patients. A total of 102 COVID-19 patients were included, and the outcomes of interest were defined as death and the need for mechanical ventilation. Genotypes were assessed using Taqman probes. No significant associations were found between the rs12252 polymorphism and COVID-19 outcomes in the original sample, both for death and the need for mechanical ventilation. A meta-analysis, incorporating previous studies that used death as a severity indicator, revealed no association in the allelic and C-recessive models. However, due to the rarity of the T allele and its absence in the sample, further replication studies in larger and more diverse populations are needed to clarify the role of rs12252 in COVID-19 prognosis.

Chronic rhinosinusitis with nasal polyps does not harbor KRAS, BRAF, and EGFR mutations.

BACKGROUND: Chronic rhinosinusitis is a chronic inflammation of the nasal mucosa and nasal polyps are present in ~25%-30% of cases (chronic rhinosinusitis with nasal polyps [CRSwNP]). CRSwNP is associated with significant morbidity and decreased quality of life, making it clinically important. Inflammation leads to DNA damage and DNA mutations occur in some inflammatory diseases. Notably, mutations in KRAS, BRAF, and EGFR have been reported in different human benign and malignant neoplastic lesions. In addition, KRAS mutations have also been reported in non-neoplastic tissues under chronic inflammatory conditions. Importantly, KRAS mutations have been reported in oncocytic sinonasal papillomas and sinonasal squamous cell carcinoma associated with oncocytic sinonasal papilloma and EGFR mutations have been reported in sinonasal adenocarcinoma, inverted sinonasal papilloma, and sinonasal squamous cell carcinoma associated with inverted sinonasal papilloma. The molecular pathogenesis of nasal polyps remains unclear. Therefore, the present study aimed to investigate the presence of KRAS, BRAF, and EGFR pathogenic mutations in CRSwNP. METHODS: Fourteen chronic rhinosinusitis-associated nasal polyp samples were direct sequenced, targeting KRAS exons 2, 3, and 4 (encompassing important hotspot mutations, including codons 12, 13, 61 and 146), BRAF exons 11 and 15, and EGFR exons 19 and 20. RESULTS: No pathogenic mutations were detected in the sequenced regions of KRAS, BRAF, and EGFR genes. CONCLUSION: This finding suggests that mutations in these genes are not a frequent event in CRSwNP, and, if they occur, they might represent marginal events at best.

Association of 3p21.31 Locus (CXCR6 and LZTFL1) with COVID-19 Outcomes in Brazilian Hospitalyzed Subjects.

The 3p21.31 locus has been associated with severe COVID-19 prognosis in GWAS studies. Here, we evaluated whether three polymorphisms (LZTFL1 rs10490770, CXCR6 rs2234355 and rs2234358) in the reported locus were associated with the need for mechanical ventilation, hospitalization length and death in 102 COVID-19 hospitalized Brazilian subjects. No genetic association was found with the need for mechanical ventilation and hospitalization length. CXCR6 rs2234355 was associated with mortality under the codominance model, with carriers of the A/A genotype having a greater chance of death than A/G (OR: 10.5; 95% CI: 1.55-70.76). Our results further suggest that the CXCR6 genetic variant contributes to COVID-19 outcomes.

Adenoid ameloblastoma harbors beta-catenin mutations.

Adenoid ameloblastoma is a very rare benign epithelial odontogenic tumor characterized microscopically by epithelium resembling conventional ameloblastoma, with additional duct-like structures, epithelial whorls, and cribriform architecture. Dentinoid deposits, clusters of clear cells, and ghost-cell keratinization may also be present. These tumors do not harbor BRAF or KRAS mutations and their molecular basis appears distinct from conventional ameloblastoma but remains unknown. We assessed CTNNB1 (beta-catenin) exon 3 mutations in a cohort of 11 samples of adenoid ameloblastomas from 9 patients. Two of the 9 patients were female and 7 male and in 7/9 patients the tumors occurred in the maxilla. Tumors of 4 of these 9 patients harbored CTNNB1 mutations, specifically p.Ser33Cys, p.Gly34Arg, and p.Ser37Phe. Notably, for one patient 3 samples were analyzed including the primary tumour and two consecutive recurrences, and results were positive for the mutation in all three tumors. Therefore, 6/11 samples tested positive for the mutation. In the 6 mutation-positive samples, ghost cells were present in only 2/6, indicating beta-catenin mutations are not always revealed by ghost cell formation. Dentinoid matrix deposition was observed in 5/6 mutation-positive samples and clear cells in all 6 cases. None of the cases harbored either BRAF or KRAS mutations. Beta-catenin immunoexpression was assessed in the samples of 8 patients. Except for one wild-type case, all cases showed focal nuclear expression irrespective of the mutational status. Together with the absence of BRAF mutation, the detection of beta-catenin mutation in adenoid ameloblastomas supports its classification as a separate entity, and not as a subtype of ameloblastoma. The presence of this mutation may help in the diagnosis of challenging cases.

Whole-exome sequencing reveals novel vacuolar ATPase genes' variants and variants in genes involved in lysosomal biology and autophagosomal formation in oral granular cell tumors.

BACKGROUND: Granular cell tumors (GCTs) are rare neuroectodermal soft tissue neoplasms that mainly affect the skin of the upper limbs and trunks and the oral cavity. GCTs are derived from Schwann cells and, ultrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation. METHODS: In this study, a convenience set of 22 formalin-fixed, paraffin-embedded samples of oral GCTs, all but one sample located at the tongue, was screened for mutations by whole-exome (WES) or targeted sequencing. RESULTS: WES revealed two novel variants in genes of the vacuolar ATPase (V-ATPase) complex: ATP6AP1 frameshift c.746_749del, leading to p.P249Hfs*4, and ATP6V1A non-synonymous c.G868A, leading to p.D290N. Each of these mutations occurred in one case. With regard to the samples that were wild type for these V-ATPase variants, at least two samples presented variants in genes that are part of endosomal/lysosomal/autophagosomal networks including ABCA8, ABCC6, AGAP3, ATG9A, CTSB, DNAJC13, GALC, NPC1, SLC15A3, SLC31A2, and TMEM104. CONCLUSION: Although the mechanisms involved in oral GCT initiation and progression remain unclear, our results suggest that oral GCTs have V-ATPase variants similarly to GCTs from other tissues/organs, and additionally show variants in lysosomes/endosomes/autophagosomal genes.

Definition of Late Onset Alzheimer's Disease and Anticipation Effect of Genome-Wide Significant Risk Variants: Pilot Study of the APOE e4 Allele.

BACKGROUND/OBJECTIVES: This study aims to investigate the role of apolipoprotein E (APOE) e4 influencing the age at onset (AAO) of Alzheimer's disease (AD). In AD, the AAO of dementia varies from 40 to 90 years. Usually, AD patients who develop symptoms before the age of 65 are considered as early-onset AD (EOAD). However, considering the heterogeneity of the AD onset, the definition of late-onset AD (LOAD) cannot rely on an arbitrary cut-off. Thus, we aim to validate the anticipation effect of the APOE e4 allele in LOAD. Methods/Overview: Firstly, the optimal number of AAO subgroups was determined using MCLUST for 3 AD samples from Italy, Brazil, and from the ADNI consortium. MCLUST selects the best-fitting model based on the Bayesian information criterion (BIC), and the ideal cut-off for separating early onset from late onset in each sample. Then, when the AAO was modeled for each sample, the finite mixture model (FMM) analysis was used to analyze the effect of the APOE e4 in determining the risk for anticipated onset in LOAD. For the Brazilian sample, the ancestry was incorporated as a covariate. The FMM results from the 3 samples were meta-analyzed using METAL. RESULTS: We performed the AAO analysis on the APOE e4 in 474 Italian patients enrolled at the IRCCS Santa Lucia Foundation in Italy, 135 AD from the Outpatients Reference Center for Geriatrics from the Federal University of Minas Gerais in Brazil, and 376 from the ADNI consortium. Using this distribution model, we found that the specific LOAD cut-off was ≥64 for the Italian sample, ≥67 for the ADNI sample, and ≥74 for the Brazilian sample. The APOE e4 showed a significant anticipatory effect specific for LOAD in all 3 samples. The METAL analysis for the anticipatory e4 effect was genome-wide significant when analyzing the LOAD effect size under the fixed model (beta = -8.1; p < 0.0001). However, when analyzing EOAD there was no genome-wide significant anticipation effect (beta = 1.9244; p = 0.0219). CONCLUSIONS: This study showed that the mixture analysis can refine the ideal cut-off for defining LOAD as a homogeneous genetic entity. We also validated the e4 allele anticipatory effect only in LOAD. In summary, the tool developed in this study is a sophisticated statistical pipeline to analyze the AAO in genome-wide association studies of AD, to find new molecular targets as a new line of translational research to foster drug discovery.

Ocular alterations, molecular findings, and three novel pathological mutations in a series of NF2 patients.

PURPOSE: To evaluate ophthalmological and molecular findings in eight patients with a clinical diagnosis of neurofibromatosis type 2 (NF2). New pathological mutations are described and variability in the ophthalmic phenotype and NF2 allelic heterogeneity are discussed. METHODS: Eye examination was performed in eight NF2 patients, and it included the measurement of the visual acuity, biomicroscopy, dilated fundus examination, color fundus photography, infrared photography, and spectral domain optical coherence tomography (SD-OCT). Molecular analysis was performed with whole-exome sequencing using DNA derived from peripheral blood mononuclear cells from each individual. RESULTS: Ophthalmological features were present in all patients, ranging from subtle retinal alterations identified only using SD-OCT to severe ocular damage present at birth. Six mutations were observed: two patients with stop codon mutation as shown on table 1 and result section, three patients with frameshift mutation as shown on table 1 and result section. Three novel mutations were found among them. CONCLUSIONS: It is a descriptive study of a rare disease, with poor previous literature. Clinical and genetic data are shown, reviving the need to further studies to clarify the genotype-phenotype correlations in NF2.

Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.

Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.

The In Vitro and In Vivo Antiangiogenic Effects of Flavokawain B.

Angiogenesis is implicated in the development of a variety of pathological processes, most commonly cancer. It is essential for tumor growth and metastasis, making it an important cancer therapeutic target. Naturally occurring substances have led to the discovery of anticancer agents. Flavokawain B (FKB), a chalcone isolated from the root extracts of kava-kava plant, inhibits proliferation and causes apoptosis in vitro and in vivo of various cancer cell lines. The antimetastatic potential of FKB has also been suggested. In our study, we confirm the antiangiogenic action of FKB in vitro and, for the first time, demonstrate its strong antiangiogenic activity in vivo, using a zebrafish model. Our data show that FKB inhibits human brain endothelial cell (HUVEC) migration and tube formation even at very low and non-toxic concentrations. Moreover, FKB blocks angiogenesis process in zebrafish, with a dramatic reduction of subintestinal vein formation in a dose-dependent manner. Flavokawain B at the concentration of 2.5 µg/mL did not exhibit any toxic effects in zebrafish larvae and caused a markedly or complete obliteration of subintestinal vein formation. Our findings along with previously published data confirm that FKB may form the basis for creating an additional tool in the treatment of cancer and other neovascularization-related diseases. Copyright © 2017 John Wiley & Sons, Ltd.

Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1.

BACKGROUND: Paraganglioma syndrome type 1 (PGL1) is a rare autosomal dominant syndrome associated with multiple, overwhelmingly benign, pheochromocytomas and paragangliomas, attributed to SDHD gene mutations. OBJECTIVE: Clinically and molecularly characterize a family with uncommon malignant phenotype of paragangliomas attributed to two seemingly pathogenic SDHD germline mutations. MATERIALS & METHODS: The proband presented with large bilateral carotid body tumours and family history of cervical masses in his five siblings. All family members underwent clinical examination, imaging studies (18F-FDG PET/CT) and genotyping of relevant genes. The proband was diagnosed with locally advanced paraganglioma; his hypertensive, otherwise asymptomatic father, had locally advanced pheochromocytoma and his three siblings showed multiple head and neck masses, confirmed to be paragangliomas with local metastasis. All affected patients carried two germline mutations in the SDHD gene; a previously reported nonsense mutation in exon 1 (p.Trp5X) and a novel missense mutation in exon 2 (p.Pro53Leu), highly deleterious by in silico analysis. Allelic loss at the SDHD locus was not shown for any of the analysed tumours. CONCLUSIONS: This is a rare case of malignant PGL1 with seemingly double pathogenic mutations in the SDHD gene, highlighting the possibility that the presence of both mutations is associated with the more aggressive phenotype.

Spectrum of somatic EGFR, KRAS, BRAF, PTEN mutations and TTF-1 expression in Brazilian lung cancer patients.

Lung cancer is the leading global cause of cancer-related mortality. Inter-individual variability in treatment response and prognosis has been associated with genetic polymorphisms in specific genes: EGFR, KRAS, BRAF, PTEN and TTF-1. Somatic mutations in EGFR and KRAS genes are reported at rates of 15-40% in non-small cell lung cancer (NSCLC) in ethnically diverse populations. BRAF and PTEN are commonly mutated genes in various cancer types, including NSCLC, with PTEN mutations exerting an effect on the therapeutic response of EGFR/AKT/PI3K pathway inhibitors. TTF-1 is expressed in approximately 80% of lung adenocarcinomas and its positivity correlates with higher prevalence of EGFR mutation in this cancer type. To determine molecular markers for lung cancer in Brazilian patients, the rate of the predominant EGFR, KRAS, BRAF and PTEN mutations, as well as TTF-1 expression, was assessed in 88 Brazilian NSCLC patients. EGFR exon 19 deletions (del746-750) were detected in 3/88 (3·4%) patients. Activating KRAS mutations in codons 12 and 61 were noted in five (5·7%) and two (2·3%) patients, respectively. None of the common somatic mutations were detected in either the BRAF or PTEN genes. TTF-1 was overexpressed in 40·7% of squamous-cell carcinoma (SCC). Our findings add to a growing body of data that highlights the genetic heterogeneity of the abnormal EGFR pathway in lung cancer among ethnically diverse populations.

Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients.

AIM: The angiotensin type 2 (AT2 ) receptor takes part in the process of ureteric bud during kidney development. Therefore, the gene encoding AT2 receptor, the AGTR2 gene located in the X chromosome, is a potential candidate for genetic association with Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). This study aimed to investigate whether AGTR2 gene polymorphisms are associated with CAKUT in general or even with common phenotypes of CAKUT in a Brazilian sample of paediatric patients. METHODS: We analyzed 290 paediatric patients with CAKUT and 262 healthy controls from the same geographic area. TaqMan single-nucleotide polymorphism (SNP) genotyping assays for AGTR2 gene at rs1403543, rs3736556, rs35474657, rs5193 and rs5194 were performed. The sample was in Hardy-Weinberg Equilibrium for all five SNPs. RESULTS: The presence of CAKUT in general was not significantly associated with the SNPs included in this study. However, when patients were segregated according to major phenotypes, the diagnosis of Ureteropelvic Junction Obstruction (UPJO) was significantly associated with AGTR2 gene polymorphisms at rs3736556 and at rs5194. On the other hand, the diagnoses of vesicoureteral reflux and of multicystic dysplastic kidney were not associated with AGTR2 gene polymorphisms. CONCLUSION: Our results support that the AGTR2 gene may contribute to the pathogenesis of UPJO and the genetic origin of CAKUT could vary according to phenotype expression.

Sociodemographic characteristics, clinical factors, and genetic polymorphisms associated with Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) has a multifactorial etiology involving an interaction of genetic and environmental factors. The Apolipoprotein E ε4 (ApoE ε4) is the single most important genetic risk factor for sporadic AD. Our aim was to study the association between sociodemographic, clinical data and gene polymorphisms in patients with sporadic AD in a heterogeneous genomic Brazilian population with low educational levels. METHODS: We selected 169 sporadic AD patients and 97 controls older than 65 years and compared co-variables between them: age, years of education, vascular risk factors, genomic ancestry, and functional polymorphisms of ApoE, BDNF, COMT, and 5-HTTLPR. We also determined the genomic ancestry of all individuals. RESULTS: The average years of education was significantly smaller in the patient's group (p = 0.003), and they had a history of depression when compared with controls (p < 0.001). The carriers of ApoE ε4 have an earlier onset of the disease (76.9 years) (p = 0.001) than ApoE ε3 (79.5 years) (p = 0.024). Patients with Met allele of Val66Met have a tendency to later onset of disease (p = 0.056). There were no differences in the genomic ancestry between groups. CONCLUSION: Low level of education and history of depression were associated with AD. Public policies and intensive observation of old-age patients with lifetime history of depression, especially APOE ε4 carriers, could improve the well-being of our population.

Association analysis of CFH and ARMS2 gene polymorphisms in a Brazilian cohort with age-related macular degeneration.

PURPOSE: To investigate the association between the CFH and ARMS2 gene polymorphisms and age-related macular degeneration (AMD) in a Brazilian cohort. METHODS: We examined 163 individuals with AMD and 154 controls recruited at the Department of Ophthalmology of the Universidade Federal de Minas Gerais, at the Instituto da Visão, and at the Centro Especializado em Olhos, in Brazil, between 2007 and 2012. Genotyping for CFH rs1061170 and ARMS2 rs10490924 single-nucleotide polymorphisms was performed. The odds ratios (OR) for all of the studied genotypes (heterozygous and homozygous) of both genes were calculated compared to homozygous ancestral alleles. RESULTS: Homozygosity for the CFH and ARMS2 at-risk allele was 33.3 and 23.6%, respectively, for AMD individuals and 10.3 and 7.1%, respectively, for controls (p < 0.0001). The OR was 7.2 (95% CI 3.6-14.5; p < 0.001) for the CFH at-risk genotype (CC) and 5.5 (95% CI 2.6-11.8; p < 0.0001) for ARMS2 (TT). Subjects homozygous for both polymorphisms had a much higher risk of developing AMD (n = 14 patients, OR 33.3, 95% CI 12.8-86.4). The proportion of ancestry in each group indicated that AMD patients had a higher European (Caucasian) component than controls. CONCLUSION: CFH and ARMS2 polymorphisms were strongly associated with AMD in this Brazilian cohort.

Evaluation of clinical and genetic factors in obstructive sleep apnoea.

Purpose: To evaluate the correlation between several presumed candidate genes for obstructive sleep apnoea (OSA) and clinical OSA phenotypes and propose a predictive comprehensive model for diagnosis of OSA. Methods: This case-control study compared polysomnographic patterns, clinical data, morbidities, dental factors and genetic data for polymorphisms in PER3, BDNF, NRXN3, APOE, HCRTR2, MC4R between confirmed OSA cases and ethnically matched clinically unaffected controls. A logistic regression model was developed to predict OSA using the combined data. Results: The cohort consisted of 161 OSA cases and 81 controls. Mean age of cases was 53.5 ± 14.0 years, mostly males (57%) and mean body mass index (BMI) of 27.5 ± 4.3 kg/m2. None of the genotyped markers showed a statistically significant association with OSA after adjusting for age and BMI. A predictive algorithm included the variables gender, age, snoring, hypertension, mouth breathing and number of T alleles of PER3 (rs228729) presenting 76.5% specificity and 71.6% sensitivity. Conclusions: No genetic variant tested showed a statistically significant association with OSA phenotype. Logistic regression analysis resulted in a predictive model for diagnosing OSA that, if validated by larger prospective studies, could be applied clinically to allow risk stratification for OSA.

Whole-exome identifies germline variants in families with obstructive sleep apnea syndrome.

Background: Obstructive sleep apnea syndrome (OSAS) (OMIM #107650) is characterized by complete or partial obstruction of the upper airways, resulting in periods of sleep associated apnea. OSAS increases morbidity and mortality risk from cardiovascular and cerebrovascular diseases. While heritability of OSAS is estimated at ∼40%, the precise underlying genes remain elusive. Brazilian families with OSAS that follows as seemingly autosomal dominant inheritance pattern were recruited. Methods: The study included nine individuals from two Brazilian families displaying a seemingly autosomal dominant inheritance pattern of OSAS. Whole exome sequencing of germline DNA were analyzed using Mendel, MD software. Variants selected were analyzed using Varstation® with subsequent analyses that included validation by Sanger sequencing, pathogenic score assessment by ACMG criteria, co-segregation analyses (when possible) allele frequency, tissue expression patterns, pathway analyses, effect on protein folding modeling using Swiss-Model and RaptorX. Results: Two families (six affected patients and three unaffected controls) were analyzed. A comprehensive multistep analysis yielded variants in COX20 (rs946982087) (family A), PTPDC1 (rs61743388) and TMOD4 (rs141507115) (family B) that seemed to be strong candidate genes for being OSAS associated genes in these families. Conclusion: Sequence variants in COX20, PTPDC1 and TMOD4 seemingly are associated with OSAS phenotype in these families. Further studies in more, ethnically diverse families and non-familial OSAS cases are needed to better define the role of these variants as contributors to OSAS phenotype.

The contribution of FTO and UCP-1 SNPs to extreme obesity, diabetes and cardiovascular risk in Brazilian individuals.

BACKGROUND: Obesity has become a common human disorder associated with significant morbidity and mortality and adverse effects on quality of life. Sequence variants in two candidate genes, FTO and UCP-1, have been reported to be overrepresented in obese Caucasian population. The association of these genes polymorphisms with the obesity phenotype in a multiethnic group such as the Brazilian population has not been previously reported. METHODS: To assess the putative contribution of both FTO and UCP-1 to body mass index (BMI) and cardiovascular risk we genotyped SNPs rs9939609 (FTO) and rs6536991, rs22705565 and rs12502572 (UCP-1) from 126 morbidly obese subjects (BMI 42.9 ± 5.6 kg/m2, mean ± SE) and 113 normal-weight ethnically matched controls (BMI 22.6 ± 3.5 kg/m2, mean ± SE). Waist circumference, blood pressure, glucose and serum lipids were also measured. Each sample was also genotyped for 40 biallelic short insertion/deletion polymorphism (indels) for ethnic assignment and to estimate the proportion of European, African and Amerindian biogeographical ancestry in the Brazilian population. RESULTS: Cases did not differ from controls in the proportions of genomic ancestry. The FTO SNP rs9939609 and UCP-1 SNP rs6536991 were significantly associated with BMI (p= 0.04 and p<0.0001 respectively). An allele dose dependent tendency was observed for BMI for rs6536991 sample of controls. No other significant associations between any SNP and hypertension, hyperlipidemia and diabetes were noted after correction for BMI and no significant synergistic effect between FTO and UCP-1 SNPs with obesity were noted. There was not an association between rs9939609 (FTO) and rs6536991 (UCP-1) in with maximum weight loss after 1 year in 94 obese patients who underwent bariatric surgery. CONCLUSION: Our data are consistent with FTO rs9939609 and UCP-1 rs6536991 common variants as contributors to obesity in the Brazilian population.

Genetic association of the PERIOD3 (PER3) Clock gene with extreme obesity.

BACKGROUND: Obesity has reached epidemic proportions worldwide, affecting life quality and span. Susceptibility to obesity is partly mediated by genetic differences. Indeed, several genes from the clock gene family have already been shown to be intimately associated with obesity in diverse ethnic groups. In the present study, an association between BMI and the rs707467, rs228697 and rs228729 PER3 (Period Circadian Clock 3) polymorphisms in subjects with class II (BMI ≥ 35.0-39.9 kg/m2) and class III obesity (>40 kg/m2, extreme obesity) were carried out using TaqMan real-time PCR. Overall, 259 Brazilian adults were genotyped, of whom 122 had class II or III obesity (BMI ≥ 35.0 kg/m2) and 137 were controls having normal weight (BMI > 18.5 and <24.9 kg/m2). RESULTS: PER3 tag SNP (rs228729) shows a significant association with extreme obesity (1000 permutation p = 0.03 and p = 0.04), for genotype and allele frequency respectively) and a haplotype among the three assessed SNPs (alleles G/T/A, rs228697, rs228729, and rs707467, respectively, 1000 permutation p = 0.03) was significantly more prevalent in the group with obesity. CONCLUSION: This exploratory association study suggests that PER3 rs228729 may be associated with extreme obesity in Brazilian adults, however, replication is needed.

Germline Mutations in Familial Papillary Thyroid Cancer.

Thyroid cancer, predominantly of papillary histology (PTC), is a common cancer mostly diagnosed sporadically. Hereditary PTC is encountered in ~ 5% of cases and may present at an earlier age, with greater risks of metastasis and recurrence, compared with sporadic cases. The molecular basis of hereditary PTC is unknown in most cases. In this study, the genetic basis of hereditary PTC in three Brazilian families was investigated. Whole exome sequencing (WES) was carried out for probands in each family, and validated, pathogenic/likely pathogenic sequence variants (P/LPSVs) were genotyped in additional family members to establish their putative pathogenic role. Overall, seven P/LPSVs in seven novel genes were detected: p.D283N*ANXA3, p.Y157S*NTN4, p.G172W*SERPINA1, p.G188S*FKBP10, p.R937C*PLEKHG5, p.L32Q*P2RX5, and p.Q76*SAPCD1. These results indicate that these novel genes are seemingly associated with hereditary PTC, but extension and validation in other PTC families are required.