Validation of obesity susceptibility loci identified by genome-wide association studies in early childhood in South Brazilian children.

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.

Polymorphisms in adiponectin receptor genes are associated with lipodystrophy-related phenotypes in HIV-infected patients receiving antiretroviral therapy.

OBJECTIVES: Adiponectin is a circulating peptide secreted by mature adipocytes that may act as a regulator of glucose and lipid metabolism. This study aimed to investigate the association between genetic variability in the adiponectin receptor genes ADIPOR1 (adiponectin receptor 1) and ADIPOR2 and lipodystrophy and its related anthropometric and metabolic phenotypes in HIV-infected patients on highly active antiretroviral therapy (HAART). METHODS: We studied six single nucleotide polymorphisms (SNPs) in the adiponectin receptor genes ADIPOR1 (rs1342387 and rs10920533) and ADIPOR2 (rs11061925, rs10773983, rs929434 and rs767870) and their association with adiponectin plasma levels, lipodystrophy subtypes and other parameters linked to glucose and lipid metabolism involved in the lipodystrophic syndrome. The genotypes of 407 HIV-infected patients receiving HAART were investigated using real-time polymerase chain reaction. Mean biochemical and anthropometrical parameters were compared between the different genotypes using analysis of variance. RESULTS: Two ADIPOR2 SNPs (rs11061925 and rs929434) were associated with fasting plasma triglyceride concentrations in the entire sample. Stronger significant associations were found between these SNPs and biochemical parameters (levels of triglycerides, total cholesterol, adiponectin and glucose) in men. We did not find any significant associations with ADIPOR1 gene variants. CONCLUSIONS: SNPs in the ADIPOR2 gene appear to be involved in the metabolic alterations in HIV-infected men receiving HAART.

Lopinavir/ritonavir monotherapy as maintenance treatment in HIV-infected individuals with virological suppression: results from a pilot study in Brazil.

OBJECTIVE: The aim of the study was to evaluate the possibility of using lopinavir/ritonavir (LPV/RTV) alone as maintenance therapy in HIV-infected individuals with virological suppression. DESIGN: This was a single-armed single-centre pilot trial. METHODS: Asymptomatic HIV-infected patients on highly active antiretroviral therapy (HAART) including LPV/RTV, and with plasma HIV RNA <40 copies/mL for at least 6 months, were enrolled in the study, during which they continued with LPV/RTV alone. The intention was to recruit 25 patients to be followed for 2 years. Viral failure was defined as two consecutive HIV RNA measurements >40 copies/mL. Nadir and baseline CD4 cell counts, highest ever HIV RNA load, time with undetectable viraemia before monotherapy, number of previous antiretroviral (ARV) regimens, and gene polymorphism at CYP3A4 and CYP3A5 were evaluated. RESULTS: All patients (27) completed the study. Their median age was 43 years, and 66% were men. Ten patients (37%) failed to maintain virological suppression (the median time to HIV rebound was 10.5 months, with a range of 4-23 months). One patient developed full resistance to LPV and another developed neurocognitive impairment while on LPV/RTV which improved after HAART reintroduction. There were no differences between failures and nonfailures according to the analysed parameters. Patients with viral failure were successfully resuppressed. CONCLUSIONS: LPV/RTV maintenance therapy was associated with 37% failure, a higher than expected failure rate. In order to ensure that unnecessary risks are not being taken in patients on LPV/RTV, this finding should be further evaluated in large randomized trials for longer periods of follow-up.

Effects of a PPARG gene variant on obesity characteristics in Brazil.

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.

Effects of a PPARG gene variant on obesity characteristics in Brazil

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 (PPARGg), 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.

Association analysis of genes involved in the leptin-signaling pathway with obesity in Brazil.

OBJECTIVE: To investigate associations of polymorphisms in the LEP, LEPR and NPY genes with obesity-related traits in a Brazilian population of European descent. METHODS: A total of 183 women and 153 men (mean body mass index (BMI), 26.1+/-4.8 kg/m(2)) were genotyped using the PCR-RFLP procedure for the LEP A19G, LEPR Gln223Arg, LEPR PRO1019pro and NPY Leu7Pro polymorphisms. Frequencies were compared among normal-weight and overweight plus obese groups with chi-square tests, mean BMI and waist circumference were compared among genotypes by t-tests and analysis of variance. RESULTS: The genotype and allele frequencies of the LEPR Gln223Arg polymorphism were significantly different between normal-weight and overweight plus obese groups (P=0.013 and 0.009, respectively). Although there was no difference in the mean adjusted BMI among the three LEPRGln223Arg genotypes, a trend was observed for Arg/Arg individuals to have a higher mean BMI compared to Gln/Gln homozygotes, with heterozygote individuals presenting intermediate mean BMI between the two homozygote groups (ANOVA, P=0.063). However, in non-smokers, the LEPR Gln223Arg polymorphism showed a highly significant effect over BMI (P=0.009). When the analysis was restricted to premenopausal women, a highly significant effect of NPY was observed. Women bearing the Pro variant presented a lower BMI than wild-type homozygotes (P=0.001). CONCLUSION: Our findings suggest that genetic variability in the leptin receptor and neuropeptide Y genes is implicated in body weight regulation, the LEPR Gln223Arg variant being associated with a BMI increase in this Caucasian population, especially in non-smokers, while the NPY Leu7Pro polymorphism was associated with BMI reduction in premenopausal women.

Association of the low-density lipoprotein receptor gene with obesity in Native American populations.

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.

Beta-globin gene cluster haplotypes in two North American indigenous populations.

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.

D1S80 locus variability in South American Indians.

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.

Beta-globin gene cluster haplotype distribution in five Brazilian Indian tribes.

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.