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Manuel AP Vilela,1 Roberta K Menna Barreto,2 Pedro K Menna Barreto,1 Juliana MF Sallum,3 Vanessa S Mattevi1 1Department of Ophthalmology, Federal Health Sciences University of Porto Alegre, Porto Alegre, Brazil; 2Medical School, Federal University of Rio Grande do Sul, Rio Grande do Sul, Brazil; 3Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil Objective: To describe, in a multimodal way, a new RHO gene mutation with lysine-for-asparagine substitution in autosomal dominant retinitis pigmentosa.Methods: Case report. Retrospective data analysis.Results: The mutation is located within codon 15 of exon 1 of the RHO gene. A single base-pair transversion lead to a specific lysine-for-asparagine substitution (Asn15Lys). Hypoacusis, myopia, dyschromatopsis and diffuse retinitis pigmentosa were detected. Detailed multimodal images for the posterior segment are presented.Conclusion: We present a new mutation with a specific substitution that may cause eye disease and which has not been described previously. There is no description of this variant in the genetic databases. Keywords: tapetoretinal degeneration, rod-cone dystrophy, pigmentary retinopathy, opsins, retinal pigments

Thyroglobulin (Tg) is an important tool to evaluate the persistence and recurrence risk in differentiated thyroid cancer (DTC). We aimed to evaluate the correlation between pre-radioiodine therapy stimulated Tg (pre-RAI Tg) levels and the first response to treatment evaluation, and to establish a cut-off pre-RAI Tg threshold for predicting an initial excellent response. Retrospective cohort study of DTC patients who underwent total thyroidectomy and radioiodine therapy. Response to therapy was evaluated 6 to 24 months after initial therapy, and patients were classified as: excellent response (ER); indeterminate response (IndR) and incomplete response (IncR). Total patients: 166 among which 85.5% female with mean age of 47.6 ± 13 years. The ER had a significantly lower pre-RAI Tg in comparison to IndR (p<0.001) and IncR (p<0.001), and pre-RAI Tg were different between the IndR and IncR (p=0.02). A cut-off pre-RAI Tg value at 7.55ng/ml was obtained by receiver operating characteristics curve for differentiating ER from IndR and IncR. The area under curve was 0.832 (95% CI 0.76-0.91). In multivariate analysis, ATA low-risk (RR 1.61, 95% CI 1.06-2.43, p=0.025) and Tg below 7.55ng/ml (RR 2.17, 95% CI 1.52-3.10, p<0.001) were associated with ER. After a median of 7.4-year follow-up, 124 (74.7%) patients were allocated into ER, 22 (13.2%) into IndR, and 20 (12%) into IncR. In conclusion, pre-RAI Tg predicts first evaluation of treatment response. Pre-RAI Tg cut-off was a key predictor of initial excellent response to therapy and may be an important tool in the follow-up of DTC patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

We aimed to develop and validate a Loop-mediated Isothermal Amplification (LAMP) assay to Sporothrix brasiliensis. LAMP reaction was developed using six primers designed based on calmodulin gene. In the LAMP reaction, we tested twenty isolates of S. brasiliensis from animals and humans, along with ten tissue samples extracted from the left footpad of mice that had been experimentally infected with S. brasiliensis. In addition, it included DNA samples from various other fungal species for specificity evaluation. All S. brasiliensis isolates yielded positive results in the LAMP, and the limit of DNA detection was 1 ng/μL. All murine samples were positive in the test while DNA from other fungal species were all negative, resulting in 100% of sensitivity and specificity of primers. LAMP diagnosis technique is a promising alternative to sporotrichosis diagnosis, in a simple and cost-effective way. Further studies are warranted to validate this technique using animal model samples obtained from both humans and animals., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Objective: Prospective data on the accuracy of ultrasound (US) classification systems in thyroid nodules are still scarce. The aim of this study is to compare the accuracy of the American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) and European (EU)-TIRADS classification systems., Design and Patients: Consecutive patients with one or more thyroid nodule(s) who underwent fine-needle aspiration (FNA) under ultrasonographic guidance (FNA-US) were prospectively evaluated., Measurements: Clinical evaluation and US data were collected. The reference standard used for this study was FNA-US cytology and histopathological diagnosis., Results: A total of 186 thyroid nodules in 166 patients were evaluated, resulting in 168 nodules from 149 patients with conclusive benign or malignant results. Sensitivity, specificity, negative predictive value (NPV) and false negative (FN) were 100.0%, 28.7%, 100.0% and 0.0%, respectively, for ACR-TIRADS; and 90.0%, 19.1%, 96.8% and 9.1% (n = 1), respectively, for EU-TIRADS. The number of unnecessary FNA-US indicated by ACR-TIRADS was lower than EU-TIRADS (71.3% vs. 80.9%, p = .017), and the number of possibly avoided FNA-US was higher (26.7% vs. 17.8%). Using the same threshold of ACR-TIRADS to indicate FNA-US in EU-TIRADS 3 nodules (2.5 cm), there was an improvement in specificity (30.6%) and avoided FNA-US (28.6%). The best performance of both systems was demonstrated when FNA-US would be indicated only in highly suspicious nodules and/or in the presence of lymphadenopathy, with 85.7% and 89.3% of possibly avoided FNA-US for ACR-TIRADS and EU-TIRADS, respectively, without increasing FN., Conclusion: Both systems presented high sensitivity, but low specificity in selecting nodules for FNA-US. The use of nodular size for FNA-US selection is questioned., (© 2022 John Wiley & Sons Ltd.)

Chronic Myeloid Leukemia (CML) is a hematologic neoplasia, characterized as a proliferative disease of the hematopoietic system. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, is considered a first-line therapy for CML, indicated for both adult and pediatric patients presenting the Philadelphia chromosome (Ph + ). However, patients in treatment with IM may show different responses due to interindividual pharmacokinetic variability. Therapeutic drug monitoring should be routinely performed to identify treatment response profile, adherence to treatment, or possible drug interactions, thus supporting better treatment management. Volumetric absorptive microsampling (VAMS) are innovative devices for blood collection whose advantages include the possibility of home collection by the patient or at the physician's office. The assay was fully validated according to bioanalytical validation guidelines. Estimated plasma concentrations of IM were not statistically different between groups according to adherence (p = 0.15), with median of 789 ng ml -1 in the group with some level of non-adherence versus 1141.9 ng ml -1 in the group with adherence, classified with the Morisky-Green questionnaire. This study included 33 patients with CML in treatment with IM. These patients answered socioeconomic, sociodemographic, and adherence profile (Morisky-Green) questionnaires. Patients also received instructions for home blood collection with VAMS devices. Afterwards, the samples were analyzed by LC-MS/MS. The mean age of the patients was 52 years, 84.8% were ingesting doses of 400 mg/day and the majority were male (69.7%). IM and its metabolite NIM were extracted from VAMS with an aqueous solution with 0.1% formic acid, followed by protein precipitation with acetonitrile. The methodology developed in this study was satisfactory for the determination of IM and NIM in VAMS and can be used in hospital and office routines for the therapeutic monitoring of patients with CML., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of the present study was to verify whether the amount of sleep duration, screen time, and physical activity moderate the relationship between FTO rs9939609 polymorphism and waist circumference (WC) in children and adolescents. This is a cross-sectional study conducted with 1338 children and adolescents, aged between 6 and 17 years. Lifestyle habits were assessed through self-reported questionnaire. WC was measured on the narrowest part of the trunk between the last rib and the iliac crest. FTO rs9939609 polymorphism was genotyped by real time polymerase chain reaction. The PROCESS macro for the SPSS was used for moderation analyses, through multiple linear regression models. Results indicated significant interactions were found between sleep duration and screen time X FTO rs9939609, showing that these lifestyle behaviours are moderators in the relationship between a genetic predisposition for obesity and higher WC. For physical activity, there was no significant interaction. Therefore, sleeping more than 564 min a day (i.e. 9.4 h) and spending no more than 233 min in front of screen may counteract the genetic predisposition to obesity in children and adolescents. Highlights A healthy lifestyle may counteract the genetic predisposition to central obesity;Children and adolescents should sleep more than approximately 9 h (564 min) per day and spend less than approximately 4 h (233 min) per day in front of screens in order to counteract the genetic predisposition to central obesity conferred by the FTO gene variant.It is fundamental to promote actions for the adoption of a healthy lifestyle, including the importance of presenting adequate sleep habits and low screen time for a better cardiometabolic health and reduction of obesity.

Human Immunodeficiency Virus (HIV) infection dynamics is strongly influenced by the host genetic background. NKG2C is an activating receptor expressed mainly on Natural Killer (NK) cells, and a polymorphism of copy number variation in the gene coding for this molecule has been pointed as a potential factor involved in HIV infection susceptibility. We evaluated the impact of the NKG2C deletion on HIV-1 susceptibility, with or without HBV/HCV co-infection, in a total of 780 individuals, including 385 HIV-infected patients and 395 healthy blood donors. NKG2C deletion genotyping was performed by standard PCR. To our knowledge, this is the first study to access the impact of complete NKG2C deletion among HIV-infected Brazilian individuals. The frequency of NKG2C deletion (range: 19-22%) was similar in cases and controls. No association of NKG2C deletion with HIV-1 susceptibility or influence on clinical features, HBV or HCV co-infection was observed in the evaluated population. Our findings suggest that NKG2C deletion, and the consequent absence of this receptor expression, does not directly impact HIV susceptibility, HBV/HCV-co-infection in the studied population, suggesting that other signaling pathways might be triggered and perform similar functions in cell activity in the absence of this specific receptor, preventing the development of disadvantageous phenotypes. Larger cohorts and studies involving protein expression are necessary to confirm our findings., (© 2022. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Host genetic factors play a major role with respect to susceptibility to infections. Many polymorphisms of the Toll-like receptors (TLRs), members of the innate immune response, are directly associated with the clinical outcomes following infection. The 2848 G/A variant (rs352140) of the TLR9 gene is associated with increased TLR9 expression. However, the impact of the genotypes of this SNP on HIV+, HCV+, and HCV+/HIV+ individuals is still debated. Materials and Methods: This study investigated the 2848 G/A polymorphism in HCV infection, HIV infection, and HCV/HIV co-infection in a large sample of Brazilians ( n  = 1,182). Groups were initially compared without considering stratification by ethnicity and subsequently stratifying individuals between whites and non-whites. Results: Considering non-white individuals, a significant difference between the HIV+/HCV+ group and controls was observed with the GG genotype serving as a protective factor ( p  = 0.023). Additionally, significant allelic differences were observed between the HCV+ group and controls ( p  = 0.042); between the HIV+/HCV+ group and controls ( p  = 0.011); and between the HIV+/HCV+ group and HIV+ individuals ( p  = 0.047). However, all significant results were lost following adjustment for multiple comparisons ( p  > 0.05). Conclusion: Although our initial results indicated a potential influence of the rs352140 genotype on host altered susceptibility to viral infections, following correction for multiple comparisions the standard ( p  < 0.05) for statistical association was lost. This may be due to insufficient sample size as we were examining many different associations. Thus, a larger study is warranted to further pursue this topic.

Epigenetic modifications established during prenatal and early life, including DNA methylation, have been suggested as potential mediators of the interaction between environmental exposures during the perinatal period and adult metabolic health adverse outcomes, especially cardiometabolic complications and overweight. The effect of a dietary intervention in the first year of life on global methylation levels in leukocyte samples from a cohort of children born between 2001 and 2002 in southern Brazil was examined. Overall methylation measurements were performed using enzyme-linked immunosorbent assays on DNA samples from 237 children at 4 years old. Mean methylation values were higher in the intervention group (mean: 2.20 ± 1.31%) than in the control group (mean: 1.65 ± 1.11%; P = 0.001). It was observed that nutritional counseling in the first year increased breastfeeding duration and stimulated the development of healthier eating habits. Therefore, these factors might have contributed to increase global DNA methylation. The findings of the present study reinforce the notion that performing nutritional interventions in the early stages of life is important and provide further evidence of the interaction between the environment and epigenetic traits.

HIV-infected individuals on chronic use of highly active antiretroviral therapy (HAART) are more likely to develop adipose tissue and metabolic disorders, such as lipodystrophy (LD) and metabolic syndrome (MetS). The development of these phenotypes is known to be multifactorial. Thus, variants in genes implicated in adipogenesis and lipid metabolism may increase susceptibility to LD and MetS. Sirtuin 1 (SIRT1) may influence the outcome of these disturbances due to its role in the regulation of transcription factors involved in energy regulation. Therefore, we genotyped four polymorphisms located in SIRT1 (rs2273773 T>C, rs12413112 G>A, rs7895833 A>G, rs12049646 T>C) in 832 HIV-infected patients receiving HAART by real-time polymerase chain reaction. The prevalence of LD was 55.8% and MetS was 35.3%. Lipoatrophy was the most prevalent subtype in all samples (38.0%) and showed significant difference between white and non-white individuals (P = 0.002). None of the genetic variants investigated in SIRT1 was associated with LD and MetS. White individuals and those in longer time of HAART use were more likely to develop LD. We concluded that these SIRT1 polymorphisms are not predictive factors to the development of lipodystrophy and metabolic syndrome in HIV-infected individuals from Brazil.

To disclose the mechanisms surrounding obesity, we selected microRNAs (miRNAs) that target genes involved in adipogenesis, angiogenesis, and inflammation and compared their expression levels in the subcutaneous adipose tissue of 40 obese and nonobese women. Mature miRNAs were extracted from subcutaneous adipose tissue samples that were collected during surgery and quantified by real-time polymerase chain reaction. miR-16 was overexpressed in the nonobese group (n-expression ratio = - 151.1; P < 0.001). Furthermore, the expression levels of two other miRNAs were significantly correlated with waist circumference in nonobese women (miR-27b, r = 0.453; P = 0.027 and miR-424-5p, r = 0.502, P = 0.014). Central and total subcutaneous adipose tissue thicknesses were correlated with miR-424-5p levels (r = 0.506, P = 0.034 and r = 0.475, P = 0.046, respectively) in the nonobese group. In the obese group, miR-424-5p expression was correlated with body mass index (r = 0.582, P = 0.018). miR-16 and miR-424 have shown correlations with body-fat-mass-related parameters. Because these miRNAs have vascular endothelial growth factor (VEGF) and its receptors as target genes, they may be involved in the alterations of angiogenesis observed in obesity. In addition, higher levels of miR-27 and miR-424 were correlated with higher fat depot measurements in nonobese women. These results highlight the importance of miRNA expression in subcutaneous adipose tissue and encourage further investigation of miRNAs as prognostic markers.

The reward sensation after food intake may be different between individuals and variants in genes related to the dopaminergic system may indicate a different response in people exposed to the same environmental factors. This study investigated the association of TaqIA (rs1800497) and -141C InsDel (rs1799732) variants in DRD2/ANKK1 gene with food intake and adiposity parameters in a cohort of children. The sample consisted of 270 children followed until 7 to 8 years old. DNA was extracted from blood and polymorphisms were detected by PCR-RFLP analysis. Food intake and nutritional status were compared among individuals with different SNP genotypes. Children carrying the A1 allele (TaqIA) had higher energy of lipid dense foods (LDF) when compared with A2/A2 homozygous children at 7 to 8 years old (GLM p=0.004; Mann Whitney p=0.005). No association was detected with -141C Ins/Del polymorphism. To our knowledge, this is the first association study of the DRD2 TaqIA and -141C Ins/Del polymorphism with food intake and anthropometric parameters in children. DRD2 TaqIA polymorphism has been associated with a reduction in D2 dopamine receptor availability. Therefore, the differences observed in LDF intake in our sample may occur as an effort to compensate the hypodopaminergic functioning.

Although a potential involvement of the CCR5Δ32 variant has already been suggested in relation to susceptibility to hepatitis C virus (HCV) infection, data from the literature is still quite controversial. Thus, our study evaluated the influence of the CCR5Δ32 allele variant in HCV infection, HCV/HIV co-infection, and HCV-related diseases in individuals from southern Brazil. A total of 1352 individuals were included in this study, divided into the following groups: Control (n = 274); HCV+ (n = 674); HIV+ (n = 300); HCV+/HIV+ (n = 104). Individuals from the HCV+ group were further stratified according to clinical/histological criteria, as HCV+/control (n = 124); HCV+/fibrosis (n = 268); HCV+/cirrhosis (n = 190); HCV+/hepatocarcinoma (n = 92). Considering all individuals included in this study, the following genotype frequencies were observed: wild-type homozygous (wt/wt), 88.76%; heterozygous (wt/Δ32), 10.72%; variant homozygous (Δ32/Δ32), 0.52%. Genotypic frequencies were very similar between the groups. Of note, the frequency of the Δ32 homozygous was quite similar comparing control uninfected against the HCV+ individuals (p > 0.999). The overall Δ32 allele frequency was estimated at 5.88%. Considering the number of Δ32 allele carriers and non-carriers, no statistically significant differences (p > 0.05) between the groups were observed, suggesting that the CCR5Δ32 variant does not influence the susceptibility to HCV infection, HCV/HIV co-infection, or HCV-related diseases in individuals from southern Brazil., (Copyright © 2018. Published by Elsevier B.V.)

Our aim was to investigate if single nucleotide polymorphisms (SNPs) located in the 5' regions of leptin (LEP, -2548 G > A, rs7799039), resistin (RETN, -420 C > G, rs1862513) and adiponectin (ADIPOQ, -11391 G > A, rs17300539 and -11377 C > G, rs266729) genes were related to changes in body mass index (BMI) and metabolic variables after bariatric surgery in 60 extremely obese individuals. At baseline, ADIPOQ -11391 A-allele carriers showed higher plasma adiponectin and lower total cholesterol levels when compared to G/G homozygotes. Approximately 32 months post-surgery, a mean reduction of 35% in BMI and an important improvement in metabolic profiles were observed. In addition, for the ADIPOQ -11377 polymorphism, a higher decrease in lipid profile was associated to the C/C genotype. Moreover, individuals bearing the A-C haplotype for the two ADIPOQ SNPs were more prone to show a reduction in low-density lipoprotein levels after bariatric surgery (-43.0% A-C carriers vs. -18.1% G-G carriers, p = 0.019). We did not find any association of leptin and resistin SNPs with the clinical parameters analyzed. In summary, our results indicate that the A-C haplotype is a predictor of better lipid profile post-surgery and the studied SNPs in ADIPOQ gene are associated to changes in metabolic variables in obese individuals.

Background: Obesity is a worldwide prevalent disease and is an underlying factor of non-alcoholic fatty liver disease (NAFLD). It has been understood as a chronic inflammatory state, being associated with the production of adipokines. The aim of this study was to analyze the levels of adipokines in the serum, visceral, and subcutaneous fat and to compare them with hepatic histopathology in morbidly obese patients., Methods: This is a cross-sectional observational study, which analyzed the findings of liver biopsy in patients undergoing bariatric surgery and who had performed analysis of adipokines mRNA expression (adiponectin-ADIPOQ, leptin-LEP, and resistin-RETN) in subcutaneous and visceral adipose tissue and circulating adipokines in serum. Liver biopsies performed were evaluated according to Kleiner criteria., Results: The study analyzed 25 patients undergoing bariatric surgery. The sample was composed exclusively of women. There was a predominance of NAFLD, with 21 patients (84%) with intrahepatic fat accumulation. Twelve patients presented non-alcoholic steatohepatitis (NASH). Glycated hemoglobin levels (HbA1c) were elevated in NASH patients. ADIPOQ levels were directly correlated with high-density lipoprotein (HDL) cholesterol levels and inversely correlated with triglycerides and total cholesterol. LEP levels showed an inverse relationship with the degree of steatosis, and RETN levels showed an inverse relationship with fibrosis stages., Conclusion: Serum LEP levels were reduced in the presence of increased levels of intrahepatic fat, and serum levels of RETN were diminished in the presence of NASH. HbA1c levels were higher in the presence of NASH, indirectly reflecting insulin resistance. Moreover, ADIPOQ levels were related to blood lipid profile.

Background: The 5-HTT gene contains polymorphisms in its promoter region, the insertion/deletion (5-HTTLPR) that creates long (L) or short (S) alleles (biallelic approach) and SNP (rs25531) in L allele (triallelic approach)., Objectives: The aim of this study is to investigate the association of the 5-HTTLPR and rs25531 polymorphisms, using bi- and triallelic approach, with dietary intake and anthropometric parameters in children followed until 8 years old., Methods: The sample were 303 children who were recruited at birth and examined at 1, 3 to 4 and 7 to 8 years old. The polymorphisms were analyzed by polymerase-chain-reaction-based methods., Results: In the biallelic approach, children with the S/S genotype presented a higher body mass index Z-score in the three developmental stages and higher sum of skinfolds at 3 to 4 and 7 to 8 years old than carriers of the L allele. In the triallelic approach, S/S, Lg/S plus Lg/Lg genotypes were associated with higher energy intake daily at 1 year old and with waist circumference at 3 to 4 years old., Conclusions: In the biallelic approach, the 5-HTTLPR polymorphism is associated with food intake, body mass index Z-score and sum of skinfolds in children, reinforcing the role of the serotonin transporter in childhood obesity. Our data indicate that the biallelic approach is more sensible than the triallelic approach for detected associations with food intake and nutritional status in childhood. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent children to become obese adults., (Copyright © 2017. Published by Elsevier Inc.)

Taste perception plays a key role in determining individual food preferences and dietary habits and may influence nutritional status. This study aimed to investigate the association of TAS1R2 (Ile191Val - rs35874116) and TAS1R3 (-1266 C/T - rs35744813) variants with food intake and nutritional status in children followed from birth until 7.7 years old. The nutritional status and food intake data of 312 children were collected at three developmental stages (1, 3.9 and 7.7 years old). DNA was extracted from blood samples and the polymorphisms were analyzed by real-time polymerase chain reactions (qPCR) using hydrolysis probes as the detection method. Food intake and nutritional status were compared among individuals with different single nucleotide polymorphism (SNP) genotypes. At 3.9 years old, children homozygous (Val/Val) for the TAS1R2 Ile191Val polymorphism ingested less sugar and sugar-dense foods than children who were *Ile carriers. This finding demonstrated that a genetic variant of the T1R2 taste receptor is associated with the intake of different amounts of high sugar-content foods in childhood. This association may provide new perspectives for studying dietary patterns and nutritional status in childhood.

Background: The prevalence of childhood obesity has been dramatically increasing in developing countries as it has been reported for developed nations. Identifying susceptibility genes in early life could provide the foundations for interventions in lifestyle to prevent obese children to become obese adults., Objectives: The objective of this study was to evaluate the influence of genetic variants related to obesity identified by genome-wide association studies (MC4R, TMEM18, KCTD15, SH2B1, SEC16B, BDNF, NEGR1, OLFM4 and HOXB5 genes) on anthropometric and dietary phenotypes in two Brazilian cohorts followed-up since birth., Methods: There were 745 children examined at birth, after 1 year and after 3.5 years of follow-up. Ten single nucleotide polymorphisms were genotyped. Anthropometric and dietary parameters were compared among genotypes. Children were classified as overweight when body mass index Z-score was >+1., Results: Overweight prevalence was 30.7% at 3.5 years old. Significant associations were identified at 3.5 years old for TMEM18 rs6548238, NEGR1 rs2815752, BDNF rs10767664 and rs6265 (1 year old and 3.5 years old) with anthropometric phenotypes and at 3.5 years old for SEC16B rs10913469 with dietary parameters., Conclusions: Our results indicate that genetic variants in/near these genes contribute to obesity susceptibility in childhood and highlight the age at which they begin to affect obesity-related phenotypes., (© 2016 World Obesity Federation.)

The genetic background of human populations can influence the susceptibility and outcome of infection diseases. Toll-like receptors (TLRs) have been previously associated with susceptibility to human immunodeficiency virus (HIV) infection, disease progression and hepatitis C, virus (HCV) co-infection in different populations, although mostly in Europeans. In this study, we investigated the genetic role of endosomal TLRs on susceptibility to HIV infection and HCV co-infection through the analysis of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and TLR9 rs352140 polymorphisms in 789 Brazilian individuals (374 HIV+ and 415 HIV-), taking into account their ethnic background. Amongst the 357 HIV+ individuals with available data concerning HCV infection, 98 were positive. In European descendants, the TLR9 rs5743836 C carriers displayed a higher susceptibility to HIV infection [dominant, Odds Ratio (OR)=1.53; 95% CI: 1.05-2.23; P=0.027]. In African descendants, TLR9 rs5743836 CT genotype was associated with protection to HIV infection (codominant, OR=0.51; 95% CI: 0.30-0.87; P=0.013). Also, the TLR9 rs352140 AA variant genotype was associated with susceptibility to HIV+/HCV+ co-infection in African descendants (recessive, OR=2.92; 95% CI: 1.22-6.98, P=0.016). These results are discussed in the context of the different ethnic background of the studied individuals highlighting the influence of this genetic/ethnic background on the susceptibility to HIV infection and HIV/HCV co-infection in Brazilian individuals., (Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

After the introduction of highly active antiretroviral therapy in the 1990s, the perception of the diagnosis of HIV infection gradually shifted from a 'death sentence' to a chronic disease requiring long-term treatment. The host genetic variability has been shown to play a relevant role in both antiretroviral drugs bioavailability and adverse effects susceptibility. Knowledge about pharmacogenetics role in HIV infection treatment has largely increased over the last years, and is reviewed in the present report, as well as future perspectives for the inclusion of pharmacogenetics information in the directing of HIV infection treatment.

Background: Imatinib (IM) is a first choice drug for treatment of chronic myeloid leukemia (CML), with a widely accepted concentration threshold of 1000ng/ml being used as a target for therapeutic drug monitoring. Once adherence to the pharmacotherapeutic regimen is of paramount importance during the long treatment course of CML, the measurement of hair IM concentrations could be a surrogate of the patient's exposure to the drug., Methods: IM was extracted from a 5mg hair sample by a liquid-liquid extraction with ethyl acetate, and IM-d8 was used as internal standard (IS). After evaporation, and reconstitution in acetonitrile, the extract was injected into a LC-MS/MS system. Compounds were eluted on a C8 column in isocratic mode. IM and IS were identified in positive electrospray ionization mode using ion transitions of m/z 494.5>394.5 and 503.0>394.3 respectively. The method was applied to 102 paired hair and samples obtained from CML patients. Treatment response was evaluated according to the European LeukemiaNet recommendations., Results: The assay was validated in the concentration range of 0.5-25ng/mg, with intra- and inter-assay imprecisions of <13.1% and <9.3%, respectively. The limits of quantification and detection were 0.5 and 0.15ng/mg, respectively. Median hair IM concentrations are significantly smaller in patients with therapeutic failure when compared with patients with partial or optimal response (4.63 vs. 7.93, p=0.040), the same trend presented by median plasma IM concentrations (629.5 vs. 1084.8, p=0.009). An IM hair concentration below 5.8ng/mg has 83% sensibility and 70% specificity to identify patients with therapeutic failure., Conclusions: A fast, sensitive, and selective LC-MS/MS method allowing quantification of IM in hair samples was developed and validated. CML patients with therapeutic failure had significantly lower hair IM concentrations when compared with patients with optimal response. These preliminary findings may support the use of hair as a matrix for IM monitoring in clinical settings, with significant logistic advantages over the collection of venous blood, particularly in developing countries., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Variants of dopamine system genes such as the DRD4 and the SLC6A3 genes may be involved in food intake regulation because the dopaminergic system influences food reward. We investigated an association of polymorphisms in the DRD4 (exon 3 VNTR) and SLC6A3 (3'UTR VNTR, rs2550948, rs2652511 and rs1048953) genes with food intake and nutritional status in children. This prospective cohort study recruited 359 children at birth. Dietary data and nutritional status were collected at 1 year, 3-4 years, and 7-8 years of age. The polymorphisms were analyzed using polymerase chain reaction based techniques. Food intake and nutritional status were compared among the different SNP genotypes. In the first year of life, DRD4.7R- children showed higher BMI Z-scores (P=.019) than the DRD4.7R+ cohort. At 3-4 years old, DRD4.7R- and SLC6A3.10R/10R children showed a higher intake of palatable foods (P=.024) and a higher waist circumference (P=.017). The rs1048953 SLC6A3 polymorphism was associated with average daily energy intake (P=.003) at 3-4 years and with a waist-to-height ratio of children at 7-8 years (P=.041). Carriers of high dopamine activity alleles of the VNTRs studied in DRD4 and SLC6A3 genes and carriers of T/T genotype of the variant rs1048953 SLC6A3 can present an increased risk for obesity related to overeating because high dopamine activity can increase the perceived incentive value of food reward., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Serotonin plays a critical role in the regulation of food intake. The solute carrier family 6 member 14 (SLC6A14) and serotonin receptor 2C (5-HTR2C) genes are involved in the bioavailability and action of this neurotransmitter., Objective: Evaluation of the association of six polymorphisms in these genes with food intake and nutritional status in children followed to 7-8years of age., Design: Blood samples and the biodemographic data of 344 children were collected at three development stages, in a cross-sectional study undertaken with the cohort from a randomized trial. Polymorphisms were analyzed using polymerase chain reaction-based techniques., Results: At 7 to 8years of age, carriers of the A alleles for both the SLC6A14 rs2312054 and SLC6A14 rs12391221 polymorphisms showed higher food intake, except for the sugar-dense food (SDF) intake parameter, than T/T and C/C homozygotes, respectively. Boy carriers of the C allele of rs2071877 had a higher sum of triceps and subscapular folds than T allele carriers at 7 to 8years old. For 5-HTR2C gene variants, A allele carriers (rs3813928) and T allele carriers (rs3813929) had higher food intake at 3 to 4years old than G/G and C/C homozygotes, respectively, except for SDF. At this age, the intake of energy-dense foods was higher in carriers of the T allele (rs3813929) than in C/C homozygotes., Conclusion: This study provides evidence that genetic variants of these proteins might be involved in the determination of food intake and nutritional status in children., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: This study evaluated the impact of seven single nucleotide polymorphisms in five candidate genes (ABCB1, ABCC2, ABCC4, SLC22A6, and SLC22A11) in relation to nephrotoxicity associated with highly active antiretroviral therapy (HAART) in HIV-infected individuals., Methods: The following single nucleotide polymorphisms were genotyped by real-time PCR: ABCB1 rs1045642, ABCC2 rs717620 and rs2273697, ABCC4 rs1751034 and rs3742106, SLC22A6 rs11568626, and SLC22A11 rs11231809 in 507 HIV-infected patients from the city of Porto Alegre, Southern Brazil, receiving HAART for, at least, 1 year., Results: From the 507 HIV-infected patients recruited, 19.1% presented a reduction in estimated glomerular filtration rate (eGFR). A total of 16 (3.2%) patients fulfilled the criteria for chronic kidney disease (defined as eGFR<60 ml/min/1.73 m). Individuals carrying at least one T allele of ABCC2 -24 C>T (rs717620) presented lower eGFR than C/C homozygotes (104 ± 22 vs. 108 ± 22 ml/min/1.73 m, independent-samples t-test, P=0.040). In multivariate analysis, the predictors associated with decreased eGFR were time of treatment, tenofovir use, atazanavir/ritonavir use, and carrying one T allele of ABCC2 -24 C>T., Conclusion: Our data support the importance of genetic factors in the etiology of nephrotoxicity in patients treated with HAART. Studies to verify treatment implications of genotyping before HAART initiation may be advisable to guide the selection of an appropriate antiretroviral therapy regimen.

Background: Imatinib (IM) is widely used in treatment of chronic myeloid leukemia with target trough plasma concentrations above 1000 ng ml(-1). DBS can increase access to IM therapeutic drug monitoring., Results: IM was measured in the range 50-4000 ng ml(-1) by UHPLC-MS/MS using one 6 mm DBS in a fully validated method. IM was stable at DBS maintained at 40°C for 36 days. Plasma and DBS concentrations were highly correlated (r > 0.96). The use of a IM concentration target of 765 ng ml(-1) in DBS identified 93% of patients with plasma concentration below 1000 ng ml(-1)., Conclusion: IM can be measured in DBS using UHPLC-MS/MS with results comparable to those obtained in blood plasma.

The Metabolic Syndrome (MetS) is defined as a pattern of metabolic disturbances, which include central obesity, insulin resistance and hyperglycemia, dyslipidemia, and hypertension. Milk has been promoted as a healthy beverage that can improve the management of MetS. Most human adults, however, down-regulate the production of intestinal lactase after weaning. Lactase encoded by the LCT gene is necessary for lactose digestion. The -13910C > T SNP (rs4988235) is responsible for the lactase persistence phenotype in European populations. We herein investigated whether the lactase persistence genotype is also associated with the MetS in subjects from a Brazilian population of European descent. This study consisted of 334 individuals (average age of 41 years) genotyped by PCR-based methods for the -13910C > T SNP. Clinical data were assessed and the genotypes were tested for their independent contribution to the MetS using chi-square tests and multiple logistic regression analysis. Univariate analyses showed that hypertension and MetS prevalence were higher in individuals with the lactase non-persistence genotype than in lactase persistence subjects. Furthermore, lactase persistence was associated with a lower risk for MetS (OR = 0.467; 95% CI 0.264-0.824; p = 0.009). These results suggest that LCT genotypes can be a valuable tool for the management of MetS treatment.

Objective: This study aimed to investigate the role of Human Leukocyte Antigen (HLA)-G in the susceptibility to HIV-1 infection through the analysis of the HLA-G 3' untranslated region (UTR) polymorphisms 14 bp insertion/deletion (rs66554220) and +3142C>G (rs1063320)., Design: We analyzed 582 HIV-1 infected patients and 626 uninfected individuals from Brazil and Italy in a case-control study., Methods: HLA-G polymorphisms were genotyped using PCR, PCR-RFLP assays or direct sequencing. All analyses were stratified by ethnicity. Genotypic, allelic and diplotypic frequencies were compared between HIV-1 infected subjects and controls using Chi-square or Fischer exact tests. Also, haplotypic frequencies were estimated using MLocus software., Results: African-derived HIV-infected individuals presented a higher frequency of the 14 bp insertion allele as compared to non-infected individuals (0.468 versus 0.373, respectively; p(Bonf) = 0.010). A higher frequency of the 14 bp insertion +3142G (insG) haplotype (0.456 versus 0.346, p<0.001) and the insG/insG diplotype (OR=1.88, 95%CI = 1.08-3.23, p=0.021) was observed among African-derived patients as compared to uninfected controls. Also, we observed a higher frequency of the ins/ins genotype among African-derived HIV patients co-infected with HCV (OR=2.78, 95%CI = 1.20-6.49, p = 0.008)., Conclusions: Our data point out to an increased frequency of alleles and genotypes associated with low HLA-G expression among African-derived patients, suggesting a potential role for HLA-G in the susceptibility to HIV-1 infection and HCV co-infection in those individuals., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To assess the association of single nucleotide polymorphisms (SNPs) in five genes - leptin, leptin receptor (LEPR), adiponectin (APM1), peroxisome proliferator-activated receptor gamma (PPARG) and uncoupling protein 1 - with anthropometric, metabolic, and dietary parameters in a Southern Brazilian cohort of 325 children followed up from birth to 4 years old., Materials and Methods: SNPs were analyzed using polymerase chain reaction-based procedures, and their association with phenotypes was evaluated by t-test, analysis of variance, and general linear models., Results: LEPR223Arg allele (rs1137101) was associated with higher daily energy intake at 4 years of age (P = 0.002; Pcorrected = 0.024). PPARG 12Ala-carriers (rs1801282) presented higher glucose levels than Pro/Pro homozygotes (P = 0.007; Pcorrected = 0.042)., Conclusions: Two of the six studied SNPs presented consistent associations, showing that it is already possible to detect the influences of genetic variants on susceptibility to overweight in 4-year-old children.

This study evaluated the impact of 9 single nucleotide polymorphisms (SNPs) in 6 candidate genes (APOB, APOA5, APOE, APOC3, SCAP, and LDLR) over dyslipidemia in HIV-infected patients on stable antiretroviral therapy (ART) with undetectable viral loads. Blood samples were collected from 614 patients at reference services in the cities of Porto Alegre, Pelotas, and Rio Grande in Brazil. The SNPs were genotyped by conventional polymerase chain reaction (PCR) and real-time PCR. The prevalence of dyslipidemia was particularly high among the protease inhibitors-treated patients (79%). APOE (rs429358 and rs7412) genotypes and APOA5 -1131T>C (rs662799) were associated with plasma triglycerides (TG) and low-density-lipoprotein cholesterol levels (LDL-C). The APOA5 -1131T>C (rs662799) and SCAP 2386A>G (rs12487736) polymorphisms were significantly associated with high-density-lipoprotein cholesterol levels. The mean values of the total cholesterol and LDL-C levels were associated with both the APOB SP Ins/Del (rs17240441) and APOB XbaI (rs693) polymorphisms. In conclusion, our data support the importance of genetic factors in the determination of lipid levels in HIV-infected individuals. Due to the relatively high number of carriers of these risk variants, studies to verify treatment implications of genotyping before HAART initiation may be advisable to guide the selection of an appropriate antiretroviral therapy regimen.

Background: Our goal was to analyze the association of the fat mass and obesity- associated (FTO) gene rs9939609 variant (T/A) with the anthropometric and dietary intake phenotypes related to obesity in Brazilian children., Methods: We analyzed the association of this single nucleotide polymorphism (SNP) with phenotypes related to the accumulation of body mass in a cohort of 348 children followed from the time of birth until 8 years old and then replicated the main findings in an independent schoolchildren sample (n = 615)., Results: At the age of 4, we observed a significant association between the A/A genotype and a higher mean BMI Z-score (P = 0.036). At the age of 8, the A/A individuals still presented with a higher BMI Z-score (P = 0.011) and with marginal differences in the volume of subcutaneous fat (P = 0.048). We replicated these findings in the schoolchildren sample, which showed that those with at least one copy of the A allele presented with a higher BMI Z-score (P = 0.029) and volume of subcutaneous fat (P = 0.016)., Conclusion: Our results indicate that this FTO variant is associated with increased body mass and subcutaneous fat in Brazilian children beginning at the age of 4.

Highly active antiretroviral therapy (HAART) has increased the survival of HIV-infected patients. However, adverse effects play a major role in adherence to HAART. Some protease inhibitors (mainly atazanavir and indinavir) act as inhibitors of uridine diphosphate-glucuronosyltransferase (UGT1A1), the enzyme responsible for hepatic conjugation of bilirubin. Variations in the promoter region of the UGT1A1 gene (UGT1A1*28, rs8175347) can influence bilirubin plasma levels, modulating the susceptibility to hyperbilirubinemia. Aiming to analyze the association between UGT1A1*28 allele and hyperbilirubinemia in individuals exposed to HAART, we evaluated 375 HIV-positive individuals on antiretroviral therapy. Individuals carrying the UGT1A1*28 allele had a higher risk of developing severe hyperbilirubinemia [prevalence ratio (PR)=2.43, 95% confidence interval (CI) 1.08-5.45, p=0.032] as well as atazanavir users (PR=7.72, 95% CI=3.14-18.98, p<0.001). This is the first description of such an association in Brazilian HIV patients, which shows that in African-American and Euroamerican HAART users, the UGT1A1*28 allele also predisposes to severe hyperbilirubinemia, especially in those exposed to atazanavir.

Background: Polymorphisms in the oestrogen receptor 1 (ESR1) and oestrogen receptor 2 (ESR2) genes are associated with intermediate or endpoint markers of cardiovascular disease and with the efficacy of postmenopausal hormone therapy (HT). Contradictory findings have been described in the past and the role of these genetics variants remains unclear., Methods: A cross-sectional study was carried out with 266 postmenopausal women, of whom 115 received oral HT (HT+) and 151 did not receive any HT (HT-). We analysed three single-nucleotide polymorphisms (SNPs) in ESR1 (rs1801132, rs7757956 and rs2813544) and two in ESR2 (rs3020450 and rs7154455) and derived haplotypes with three additional polymorphisms that had been previously investigated by our group (ESR1 rs2234693 and ESR2 rs1256049 and rs4986938)., Results: The ESR1 rs2813544 polymorphism was associated with low-density lipoprotein cholesterol (LDL-C) in HT+ postmenopausal women (p = 0.044; pC = 0.388), while one ESR2 gene haplotype was associated with total cholesterol (T-chol) (p = 0.015; pC = 0.090) and LDL-C in HT+ postmenopausal women (p = 0.021; pC = 0.126)., Conclusion: Our findings suggest that, in HT+ postmenopausal women, the rs2813544 polymorphism may influence LDL-C levels and, as previously described, ESR2 rs1256049 is associated with T-chol and LDL-C. No previous study has investigated the association of this SNP set with lipoprotein levels in women while taking into account the hormonal status of the patients.

Objective: To investigate genetic single nucleotide polymorphisms (SNPs) in estrogen receptor-α (ERα) (ESR1, rs2234693, rs1801132, rs7757956 and rs2813544) and ERβ (ESR2, rs3020450, rs7154455 and rs4986938) genes and relate them to the adverse effects lipodystrophy, dyslipidemia and metabolic syndrome as well as to differences in their prevalence between sexes in HIV-infected individuals on HAART., Design: Cross-sectional study., Methods: Blood samples and anthropometric measurements were collected from 614 patients at reference services in the cities of Porto Alegre, Pelotas and Rio Grande in Brazil. The SNPs were genotyped by real-time PCR., Results: The lipodystrophy subtype frequencies in patients of different sexes showed statistically significant differences; the atrophic pattern was more prevalent in men, and the hypertrophic pattern was more prevalent in women. Furthermore, metabolic syndrome prevalence was higher in women than in men. The ESR1 rs2813544 G-allele was associated with higher measurements of several anthropometric variables in women: BMI, total subcutaneous fat and subcutaneous fat of limbs. Additionally, patients who were AA homozygous for ESR2 rs3020450 presented an increased risk for developing lipoatrophy (prevalence ratio 1.37, 95% confidence interval 1.09-1.73, P = 0.007)., Conclusion: Significant differences in lipodystrophy and metabolic syndrome prevalence were detected between sexes. Moreover, the ESR1 gene (rs2813544) presented significant sex-specific associations with anthropometric variables, and the ESR2 gene (rs3020450) was associated with an increased risk of developing lipoatrophy. Our results suggest that these genes are in part responsible for the sexual dimorphism in fat tissue redistribution and patterns of lipodystrophy.

Objectives: This study investigates the role of mannose-binding lectin (MBL) in susceptibility and clinical expression of systemic lupus erythematosus (SLE), through the analysis of promoter region and exon 1 polymorphisms of the MBL2 gene., Methods: We analysed 325 SLE patients from the Hospital de Clínicas de Porto Alegre and 344 controls. All individuals were grouped according to ethnic origin. Genotyping of the promoter and exon 1 variants were performed by PCR-SSP and PCR-RFLP, respectively. Polymorphisms frequencies between patients and controls were compared by Chi-square or Fisher's exact tests., Results: A statistically significant difference was observed among the frequencies of both promoter haplotypes (p=0.005) and haplotypic combinations (p=0.004) in African-derived patients, with a higher incidence of HY haplotype and LY/HY combination in SLE patients when compared to controls. These results showed a tendency to higher frequencies of genotypes related to high MBL levels in African-derived patients. A joint analysis of data from the promoter and exon 1 polymorphisms showed an increased frequency of genotypes conferring a deficient of MBL levels in European-derived patients (p<0.001)., Conclusions: Our data suggest a possible influence of MBL deficiency in SLE European-derived although we did not observe any involvement of MBL2 variants in SLE clinical progression. The conflicting results shown by the analysis of patients grouped by ethnicity emphasise the need for studies considering this variable.

We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African-derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity-related phenotypes were investigated: β2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-γ (PPARG) (Pro12Ala), and resistin (RETN) (-420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI ≥ 25 kg/m2), risk of obesity alone (BMI ≥ 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in the genetic component of obesity.

Objective: This study investigates the role of mannose-binding lectin (MBL) in the susceptibility to HIV-1 infection analyzing polymorphisms located at the MBL2 promoter and exon 1 regions., Materials and Methods: The prevalence of MBL2 variant alleles was investigated in 410 HIV-1-infected patients from the South Brazilian HIV cohort and in 345 unexposed uninfected healthy individuals. The promoter variants were genotyped using polymerase chain reaction with sequence-specific primers (PCR-SSP) and exon 1 variants were analyzed by real-time PCR using a melting temperature assay and were confirmed by PCR-restriction fragment length polymorphism (RFLP). MBL2 genotypic and allelic frequencies were compared between HIV-1-infected patients and controls using the chi-squared tests., Results: The analyses were performed subdividing the individuals according to their ethnic origin. Among Euro-derived individuals a higher frequency of the LX/LX genotype was observed in patients when compared to controls (P < 0.001). The haplotypic analysis also showed a higher frequency of the haplotypes associated with lower MBL levels among HIV-1-infected patients (P = 0.0001). Among Afro-derived individuals the frequencies of LY/LY and HY/HY genotypes were higher in patients when compared to controls (P = 0.009 and P = 0.02)., Conclusions: An increased frequency of MBL2 genotypes associated with low MBL levels was observed in Euro-derived patients, suggesting a potential role for MBL in the susceptibility to HIV-1 infection in Euro-derived individuals.

Objective: This study aimed to investigate the association between 4 polymorphisms in the leptin, leptin receptor, and adiponectin (APM1) genes and the occurrence of lipodystrophy and dyslipidemia in HIV-infected patients receiving highly active antiretroviral therapy (HAART)., Materials and Methods: Genotypes of 410 HIV-infected patients on HAART were investigated. Anthropometric (weight, height, waist circumference and skinfolds thickness) and biochemical (blood lipids, glucose, leptin, and adiponectin levels) parameters were evaluated. Genotype frequencies were compared between patients with or without lipodystrophy. Mean biochemical and anthropometric parameters were compared between the different genotypes., Results: Lipodystrophy prevalence was 53.4%. Genotype frequencies were not different between patients with or without lipodystrophy. Carriers of the A allele for the APM1-11391 G.A and of the C allele for APM1-11377 C.G presented higher adiponectin levels compared to other genotypes, and carriers of the -11391A-11377C haplotype when compared with carriers of other haplotypes., Conclusions: SNPs in APM1 gene are associated with adiponectin levels in HIV-infected patients receiving HAART and may thus affect the occurrence of metabolic alterations in these patients. No influence of the leptin and leptin receptor gene polymorphisms on the occurrence of lipodystrophy and dyslipidemia was observed.

The CB1 cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in energy balance control, stimulating appetite and increasing body weight in wasting syndromes. Different studies have investigated the relationship between polymorphisms of the cannabinoid receptor 1 (CNR1) gene and obesity with conflicting results. In the present study, we investigated the 1359G/A (rs1049353), 3813A/G (rs12720071) and 4895A/G (rs806368) polymorphisms in the CNR1 gene in a Brazilian population of European descent. To verify the association between these variants and obesity-related traits in this population, 756 individuals were genotyped by PCR-RFLP methods. The 4895G allele was associated with waist to hip ratio (WHR) (P = 0.014; P = 0.042 after Bonferroni correction). An additive effect with the GAA haplotype was associated with WHR (P = 0.028), although this statistical significance disappeared after Bonferroni correction (P = 0.084). No significant association was observed between the genotypes of the 1359G/A and 3813A/G polymorphisms and any of the quantitative variables investigated. Our findings suggest that CNR1 gene polymorphism is associated with central obesity in this Brazilian population of European ancestry.

The contribution of genetic factors to the development of obesity has been widely recognized, but the identity of the genes involved has not yet been fully clarified. Variation in genes involved in adipocyte differentiation and energy metabolism is expected to have a role in the etiology of obesity. We assessed the potential association of a polymorphism in one candidate gene, peroxisome proliferator-activated receptor-gamma (PPARGgamma), involved in these pathways and obesity-related phenotypes in 335 Brazilians of European descent. All individuals included in the sample were adults. Pregnant women, as well as those individuals with secondary hyperlipidemia due to renal, liver or thyroid disease, and diabetes, were not invited to participate in the study; all other individuals were included. The gene variant PPARG Pro12Ala was studied by a PCR-based method and the association between this genetic polymorphism and obesity-related phenotypes was evaluated by analysis of covariance. Variant allele frequency was PPARG Ala12 = 0.09 which is in the same range as described for European and European-derived populations. No statistically significant differences were observed for mean total cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels among PPARG genotypes in either gender. In the male sample, an association between the PPARG Pro12Ala variant and body mass index was detected, with male carriers of the Ala variant presenting a higher mean body mass index than wild-type homozygotes (28.3 vs 26.2 kg/m2, P = 0.037). No effect of this polymorphism was detected in women. This finding suggests that the PPARG gene has a gender-specific effect and contributes to the susceptibility to obesity in this population.

The potential effect of variants in three catecholaminergic pathway genes (ADRB2, ADRB3, and GNB3) on obesity-related traits was investigated in an European-derived Brazilian population. Three-hundred and thirty-five individuals were screened for the ADRB2 Arg16Gly and Gln27Glu, ADRB3 Trp64Arg, and GNB3 814G-->A and 825C-->T polymorphisms using PCR-based methods. The association of the polymorphisms with quantitative variables was tested separately in each sex by analysis of covariance using general linear models, including age as a covariate. Only the ADRB2 Arg16Gly polymorphism was associated with higher body mass index and waist circumference. This association was restricted to the male sample. As the number of studies increases, it becomes clear that the genetic bases of obesity are complex, with sex-specific effects a playing an important role in its etiology. In the context of this European-derived population, the ADRB2 gene accounts for a significant part of obesity-related phenotypes in males., (Am. J. Hum. Biol. 18:182-186, 2006. (c) 2006 Wiley-Liss, Inc.)

The potential association of resistin (RETN) gene variability with obesity-related phenotypes was investigated in 585 non-diabetic individuals of European descent. The polymorphism studied (-420 C>G) is located in the RETN gene 5'-flanking region. A significant association between the polymorphism and body mass index and waist circumference was observed in the women subsample (n = 356), where the G allele was somewhat less frequent in the overweight/obese group than in normal-weight individuals (0.25 vs. 0.32; p = 0.040; OR=0.70 [0.50-0.98]). Female carriers of the G-allele presented a lower mean BMI than C/C homozygotes (25.5 vs. 26.8 kg/m(2); p = 0.010). Furthermore, when women were stratified by menopausal status, the association was restricted to premenopausal women (C/C homozygotes, mean BMI = 26.3 kg/m2; G-carriers, 24.4 kg/m2; p = 0.014). Our findings suggest that RETN gene variation has gender-specific effects on BMI and warrants further investigation of its implications for the development of obesity., (Copyright 2004 Springer-Verlag)

Haplotypes derived from five polymorphic restriction sites were determined in 50 Carrier-Sekani and 70 Mvskoke chromosomes, and the results were integrated with those previously obtained for 11 South American Indian populations. Eleven haplotypes were identified in the Mvskokes, while five were observed in the Carrier-Sekani. As in South American natives, haplotype 2 (+----) and 6 (-++ -+) were the most prevalent among the Mvskoke (46% and 30%, respectively). In the Carrier-Sekani, haplotype 2 was also the most common, but haplotype 5 (-+ -++) was somewhat more frequent (18%) than 6 (12%). High heterozygosities, as well as genetic differentiation, were observed among these two North American and two other South American groups (Mapuche and Xavante). They could be due to non-Indian admixture in the Mvskoke and Mapuche, but the findings in the other two populations require some other type of explanation., (Copyright 2000 Wiley-Liss, Inc.)

Five low-density lipoprotein receptor gene (LDLR) restriction fragment length polymorphisms (RFLPs: TaqI, intron 4; HincII, exon 12; AvaII, exon 13; MspI and NcoI, exon 18) were investigated in 131 individuals from five Brazilian Indian tribes. All markers were polymorphic in this ethnic group. In the whole sample of Amerindians, 13 (41%) of the 32 expected haplotypes were identified, but only three were shared by all tribes. The Xavante, Suruí, Zoró, and Gavião tribes, who had been studied for anthropometry, were grouped according to their genotypes, and the corresponding mean values were examined. Significant associations were observed between HincII *H-, AvaII *A+, MspI *M-, and NcoI *N+ and the body mass index (BMI), triceps and subscapular skinfolds, and the arm fat index (AFI). Haplotypes were derived for these four RFLPs, and (*H-/*A+/*M-/*N+) haplotype carriers were compared with noncarriers of this haplotype with equally significant results for the three parameters (BMI, P=0.021; skinfold thickness, P<0.001; AFI, P=0.005). These results suggest that the LDLR gene has some influence over adipose tissue deposition.

We have studied the hypervariable D1S80 locus in 185 individuals from five South American Indian tribes, integrating these results with previous investigations. Three alleles (*18, *24 and *30) were common to all tribes, but their frequencies varied between northern and southern populations. Brazilian tribes have a high frequency of *30 (average 35%) while in Argentinian and Chilean Indian populations this allele is present, on average, in 7% of the chromosomes only. Allele *24, the most common in other ethnic groups, was observed in 10% and 25% of northern and southern Amerindians respectively. Genetic distance and dendrogram analyses placed the Argentinian and Chilean tribes closer to Brazilian Caucasians, suggesting non-Indian admixture among them.

Haplotypes derived from five polymorphic restriction sites in the beta-globin gene cluster were investigated in 139 individuals from five different Brazilian Indian tribes by the polymerase chain reaction (PCR). Eight haplotypes were identified. Haplotypes 2 ((+)----) and 6 (-)++(-)+) were the most frequent and were common to all tribes. Their prevalences ranged from 60% to 93% and from 3% to 18%, respectively. Average heterozygosity measured by the Gini-Simpson index is markedly reduced among these Brazilian Indians when compared with Europeans (56%), but much less (8%) in relation to Asiatics, suggesting the absence of an important bottleneck effect in the early colonization of South America. The coefficient of gene differentiation (GST') was estimated as 0.082 among six Brazilian Indian tribes, but when only three Tupi-Mondé-speaking tribes were considered, this estimate was reduced to 0.030.