Replicative Study in Performance-Related Genes of Brazilian Elite Soccer Players Highlights Genetic Differences from African Ancestry and Similarities between Professional and U20 Youth Athletes.

Classically, genetic association studies have attempted to assess genetic polymorphisms related to human physiology and physical performance. However, the heterogeneity of some findings drives the research to replicate, validate, and confirmation as essential aspects for ensuring their applicability in sports sciences. Genetic distance matrix and molecular variance analyses may offer an alternative approach to comparing athletes' genomes with those from public databases. Thus, we performed a complete sequencing of 44 genomes from male Brazilian first-division soccer players under 20 years of age (U20_BFDSC). The performance-related SNP genotypes were obtained from players and from the "1000 Genomes" database (European, African, American, East Asian, and South Asian). Surprisingly, U20_BFDSC performance-related genotypes had significantly larger FST levels (p < 0.00001) than African populations, although studies using ancestry markers have shown an important similarity between Brazilian and African populations (12-24%). U20_BFDSC were genetically similar to professional athletes, showing the intense genetic selection pressure likely to occur before this maturation stage. Our study highlighted that performance-related genes might undergo selective pressure due to physical performance and environmental, cognitive, and sociocultural factors. This replicative study suggests that molecular variance and Wright's statistics can yield novel conclusions in exercise science.

Investigation of associations of European, African, Amerindian genomic ancestries and MC4R, FTO, FAIM2, BDNF loci with obesity-related traits in Rio de Janeiro, Brazil.

A complex web of causation is involved in adiposity, including environmental, social and genetic factors. We aimed to investigate associations between genetic factors such as ancestry and single nucleotide polymorphisms, and obesity-related traits in a sampled Brazilian population. A sample of 501 unrelated adults participating in 2013 at the longitudinal Pró-Saúde Study (EPS) in Rio de Janeiro, Brazil was selected. We analysed 46 AIM-InDels (insertion/deletion) as genetic ancestry markers and four single nucleotide polymorphisms located in the genes MC4R (rs17782313), FTO (rs9939609), FAIM2 (rs7138803) and BDNF (rs4074134), previously described as associated with obesity. The selected obesity-related markers were anthropometric parameters such as body mass index, waist circumference and waist-to-hip ratio, and body composition measurements namely body fat percentage, android fat mass and gynoid fat mass. The sample showed greater European ancestry (57.20%), followed by African (28.80%) and lastly Amerindian (14%). Our results suggest that the rs4074134 (BDNF) CC genotype was directly associated with gynoid fat mass, whereas body fat percentage, android fat mass and the anthropometric parameters seem not to be associated with neither ancestry nor the four polymorphisms in this population sample, most likely due to a stronger role of social, behavioural and environmental determinants.

PDX1-MODY: A rare missense mutation as a cause of monogenic diabetes.

Maturity-Onset Diabetes of the Young type 4 is a rare form of diabetes mellitus, caused by mutations in the PDX1 gene. However, only a few mutations in this gene have been associated as a cause of monogenic diabetes up to date. It makes difficult to create a clinical manifestation profile of this disease and, consequently, to improve the therapeutic management for these patients. Here we report a normal weight woman, diagnosed with diabetes mellitus at 27 years old, during her first pregnancy. At the time of the recruitment, she was 40 years old and had a body mass index of 23.9 kg/m2, glycated hemoglobin level of 9.6%, and fasting plasma glucose (FPG) of 254 mg/dL. She presented no diabetic complications and she was being treated with insulin. She reported a family history of diabetes mellitus characteristic of an autosomal dominant mode of inheritance. Molecular analysis of the PDX1 gene revealed the missense variant c.532G > A (p.(Glu178Lys)) segregating from the patient to her son, reported as diabetic. It was absent in her healthy daughter. The c.532G > A seems to be a rare variant, absent in human variants databases, and among 86 normoglycemic controls. Eight in silico algorithms classified this variant as probably pathogenic. Additionally, analysis of the evolutionary conservation showed the glutamic acid in the position 178 of PDX-1 protein as conserved among several species. Our findings reinforce the importance of screening rare MODY genes among families with suspicion of monogenic diabetes to help better understand the clinical manifestations of this disease.

Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes.

Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations.

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: ß2-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.

Cytokine genes are associated with tuberculin skin test response in a native Brazilian population.

Tuberculosis was a major cause of population decline among Brazilian indigenous peoples and remains a leading cause of morbidity and mortality among them. Despite high BCG coverage, results of Tuberculin Skin Test (TST) reactivity have shown high rates of anergy in Amazonian Indians. Given the high prevalence of anergy in these populations and the fact that genetic host factors play an important role in susceptibility to Mycobacterium tuberculosis (MTB), the aim of this study was to evaluate the association of nineteen polymorphisms in fifteen genes related to immune response and anergy in the Xavante, an indigenous group from Brazil. A total of 481 individuals were investigated. TST anergy was observed in 69% of them. Polymorphisms in four genes showed absence or very low variability: SP110, PTPN22, IL12RB1 and IL6. IFNG +874 A/T heterozygotes and IL4-590 C/C homozygotes were more frequent in those individuals who presented a positive TST (prevalence ratios of 1.9 and 2.0 respectively). The risk of anergy was 1.5 in IL10-1082 G/G homozygotes when compared to carriers for the A allele. In indigenous groups such as the Xavante exposure to a variety of infections, associated with specific genetic factors, may disturb the T-helper 1 and T-helper 2 balance leading to increased immunological susceptibility.

Impact of variation in ADRB2, ADRB3, and GNB3 genes on body mass index and waist circumference in a Brazilian 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.

A resistin gene polymorphism is associated with body mass index in women.

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.