Luciana F. Franco

Evaluation of body adiposity index (BAI) to estimate percent body fat in an indigenous population.

BACKGROUND & AIMS The aim of this study was to evaluate the usefulness of Body Adiposity Index (BAI) as a predictor of body fat in Xavante Indians and to investigate which anthropometric measures of adiposity best correlate with body fat in this population. METHODS We evaluated 974 individuals (476 male), aged 42.3 ± 19.5 years. Percentage of body fat (%BF) determined by bioimpedance analysis (BIA) was used as the reference measure of adiposity. Bland-Altman analysis was used to assess the agreement between the two methods: BAI and BIA. Associations between anthropometric measures of adiposity were investigated by Pearson correlation analysis. RESULTS BAI overestimates %BF (mean difference: 4.10%), mainly at lower levels of adiposity. Significant correlations were found between %BF and all measurements, being the strongest correlation with BAI. However, stratified analyses according to gender showed that among men waist circumference has the strongest correlation (r = 0.73, p < 0.001) and among women BAI (r = 0.71, p < 0.001), BMI (r = 0.69, p < 0.001) and waist circumference (r = 0.70, p < 0.001) performed similarly. CONCLUSION BAI can be a useful tool to predict %BF in Xavante Indians, although it has some limitations. However, it is not a better predictor of adiposity than waist circumference in men or BMI and waist circumference in women.

Genome-Wide Analysis in Brazilian Xavante Indians Reveals Low Degree of Admixture

Characterization of population genetic variation and structure can be used as tools for research in human genetics and population isolates are of great interest. The aim of the present study was to characterize the genetic structure of Xavante Indians and compare it with other populations. The Xavante, an indigenous population living in Brazilian Central Plateau, is one of the largest native groups in Brazil. A subset of 53 unrelated subjects was selected from the initial sample of 300 Xavante Indians. Using 86,197 markers, Xavante were compared with all populations of HapMap Phase III and HGDP-CEPH projects and with a Southeast Brazilian population sample to establish its population structure. Principal Components Analysis showed that the Xavante Indians are concentrated in the Amerindian axis near other populations of known Amerindian ancestry such as Karitiana, Pima, Surui and Maya and a low degree of genetic admixture was observed. This is consistent with the historical records of bottlenecks experience and cultural isolation. By calculating pair-wise Fst statistics we characterized the genetic differentiation between Xavante Indians and representative populations of the HapMap and from HGDP-CEPH project. We found that the genetic differentiation between Xavante Indians and populations of Ameridian, Asian, European, and African ancestry increased progressively. Our results indicate that the Xavante is a population that remained genetically isolated over the past decades and can offer advantages for genome-wide mapping studies of inherited disorders.

Variants of transcription factor 7-like 2 (TCF7L2) gene and incident glucose intolerance in Japanese-Brazilians

Common variants of the transcription factor 7-like 2 (TCF7L2) gene have been found to be associated with type 2 diabetes in different ethnic groups. The Japanese-Brazilian population has one of the highest prevalence rates of diabetes. Therefore, the aim of the present study was to assess whether two single-nucleotide polymorphisms (SNPs) of TCF7L2, rs7903146 and rs12255372, could predict the development of glucose intolerance in Japanese-Brazilians. In a population-based 7-year prospective study, we genotyped 222 individuals (72 males and 150 females, aged 56.2 ± 10.5 years) with normal glucose tolerance at baseline. In the study population, we found that the minor allele frequency was 0.05 for SNP rs7903146 and 0.03 for SNP rs12255372. No significant allele or genotype association with glucose intolerance incidence was found for either SNP. Haplotypes were constructed with these two SNPs and three haplotypes were defined: CG (frequency: 0.94), TT (frequency = 0.027) and TG (frequency = 0.026). None of the haplotypes provided evidence for association with the incidence of glucose intolerance. Despite no associations between incidence of glucose intolerance and SNPs of the TCF7L2 gene in Japanese-Brazilians, we found that carriers of the CT genotype for rs7903146 had significantly lower insulin levels 2 h after a 75-g glucose load than carriers of the CC genotype. In conclusion, in Japanese-Brazilians, a population with a high prevalence of type 2 diabetes, common TCF7L2 variants did not make major contributions to the incidence of glucose tolerance abnormalities.

Unexpected finding of a whole HNF1B gene deletion during the screening of rare MODY types in a series of Brazilian patients negative for GCK and HNF1A mutations

Thirty-two patients with diabetes negative for point mutations in GCK and HNF1A underwent further molecular screening of GCK, HNF1A, HNF4A, and HNF1B by MLPA analysis. We described the first Brazilian case of MODY5 due to a heterozygous whole-gene deletion in HNF1B, who developed rapidly progressive renal failure and death.

Performance of glycated haemoglobin (HbA1c) as a screening test for diabetes and impaired glucose tolerance (IGT) in a high risk population—The Brazilian Xavante Indians

AIMS To examine the properties of HbA1c to detect diabetes and IGT in adult Brazilian Xavante Indians, a high risk population for diabetes. METHODS The survey was carried out between October 2010 and January 2012 and based on a 75 g oral glucose tolerance test (OGTT). Basal and 2h capillary glycaemia were measured by HemoCue Glucose 201+; HbA1c using an automated high-performance liquid chromatography analyzer (Tosoh G7). RESULTS 630 individuals aged ≥ 20 years were examined and 80 had a previous diagnosis of diabetes. Sensitivity, specificity and accuracy for HbA1c ≥ 6.5% (≥ 48 mmol/mol) were 71.3%, 90.5% and 87.2%. The areas under the ROC curve (AUC) was 0.88 (95%CI: 0.83-0.93). To identify IGT, HbA1c values between 5.7% and 6.4% (39-47 mmol/mol) presented sensitivity, specificity and accuracy of 87.2%, 24.7% and 51.4%, with an AUC of 0.62 (95%CI: 0.57-0.67). CONCLUSIONS The ADA/WHO proposed cut-off of 6.5% (48 mmol/mol) for HbA1c was adequate to detect diabetes among the Xavante. However, the performance of the ADA proposed cut-off points for pre-diabetes, when used to detect IGT was inadequate and should not be recommended.

Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data

AIMS Maturity-Onset Diabetes of the Young (MODY) comprises a heterogeneous group of monogenic forms of diabetes caused by mutations in at least 14 genes, but mostly by mutations in Glucokinase (GCK) and hepatocyte nuclear factor-1 homeobox A (HNF1A). This study aims to establish a national registry of MODY cases in Brazilian patients, assessing published and unpublished data. METHODS 311 patients with clinical characteristics of MODY were analyzed, with unpublished data on 298 individuals described in 12 previous publications and 13 newly described cases in this report. RESULTS 72 individuals had GCK mutations, 9 described in Brazilian individuals for the first time. One previously unpublished novel GCK mutation, Gly178Ala, was found in one family. 31 individuals had HNF1A mutations, 2 described for the first time in Brazilian individuals. Comparisons of GCK probands vs HNF1A: age 16±11 vs 35±20years; age at diagnosis 11±8 vs 21±7years; BMI 19±6 vs 25±6kg/m2; sulfonylurea users 5 vs 83%; insulin users 5 vs 17%; presence of arterial hypertension 0 vs. 33%, all p<0.05. No differences were observed in lipids and C-peptide. CONCLUSIONS Most MODY cases in Brazil are due to GCK mutations. In agreement with other studied populations, novel mutations are common. Only 14% of patients with familial diabetes carry a HNF1A mutation. Diagnosis of other rare forms of MODY is still a challenge in Brazilian population, as well as adequate strategies to screen individuals for molecular diagnosis.

Improving the identification of mody mutations by using mlpa technique in the molecular diagnostics routine

Background Maturity-onset diabetes of the young (MODY) represents about 3-5% of cases of diabetes mellitus (DM). Searching for mutations can be performed either by Sanger sequencing or Multiplex Ligation-dependent Probe Amplification (MLPA) technique. MLPA is a powerful molecular tool that identifies large genetic rearrangements such as deletions and insertions, even though these kinds of mutations seem to be rare in the majority of MODY subtypes.

CLL: chromosomal abnormalities (FISH) and their relation with clinical stage, CD38 and ZAP-70

Chronic lymphocytic leukemia is the most prevalent type of leukemia in the West. It is characterized by an extremely variable clinical course. The aim of the study was to detect the most frequent chromosomal abnormalities in patients with CLL using FISH, and assess them regarding age, gender, clinical stage and CD38 and ZAP-70 expressions. We found 51.7% of the patients with chromosome abnormalities. The most frequent one was del 13q14 in 34.5% of cases. It was associated to other alterations in 17.2%. 17p13 deletions were found in 17.2% and trisomy 12 in 13.8% (in isolation in 6.9% and associated to del 13q14, in 6.9% of the cases). An 11q22 deletion was found in one case associated to a 13q14 deletion. To better evaluate the relationship between chromosome aberrations and other prognostic factors in CLL, two cytogenetics groups were considered: favorable (13q deletion in isolation and no alteration) and unfavorable outcomes (trisomy 12, 17p13 deletion, 11q22 deletion and two simultaneous alterations).The unfavorable alterations were more frequently seen among young individuals (<60y). There were more females (70%) than males in this group (p=0.04). In relation to the Binets staging system, patients with unfavorable cytogenetic alterations, tended to be B and C stages, while in the favorable group prevailed patients in stage A. Additionally, patients with poor prognostic cytogenetics tended to express CD38 and ZAP-70 proteins.

Cardiovascular Risk in Xavante Indigenous Population

Background The prevalence of cardiovascular risk factors is little known in Brazilian indigenous populations. In the last two decades, important changes have occurred in the lifestyle and epidemiological profile of the Xavante people. Objective to assess the prevalence of cardiovascular risk factors in Xavante adults in São Marcos and Sangradouro/Volta Grande reserves, in the state of Mato Grosso, Brazil. Methods Cross-sectional study carried out with 925 Xavante people aged ≥ 20 years between 2008 and 2012. The following indicators were assessed: triglycerides (TG), total, LDL and HDL-cholesterol, Castelli index I and II, TG/HDL-cholesterol ratio, apo B / Apo A1 ratio, Framingham risk score, C-reactive protein, body mass index (BMI), waist circumference (WC), hypertriglyceridemic waist (HW), glycemia and blood pressure. Kolmogorov-Smirnov, Students t test and Chi-square test (χ2) were used for statistical analysis, and significance level was set at 5%. Results High prevalence of elevated cardiovascular risk was observed in men and women according to HDL-cholesterol (66.2% and 86.2%, respectively), TG (53.2% and 51.5%), TG/HDL-cholesterol ratio (60.0% and 49.1%), C-reactive protein (44.1% and 48.1%), BMI (81.3% and 81.7%), WC (59.1% and 96.2%), HW (38.0% and 50,6%) and glycemia (46.8% and 70.2%). Individuals aged 40 to 59 years had the highest cardiovascular risk. Conclusions The Xavante have a high cardiovascular risk according to several indicators evaluated. The present analysis of cardiovascular risk factors provides support for the development of preventive measures and early treatment, in attempt to minimize the impact of cardiovascular diseases on this population.

More than kin, less than kind: one family and the many faces of diabetes in youth

Identification of the correct etiology of diabetes brings important implications for clinical management. In this report, we describe a case of a 4-year old asymptomatic girl with diabetes since age 2, along with several individuals in her family with different etiologies for hyperglycemia identified in youth. Genetic analyses were made by Sanger sequencing, laboratory measurements included HbA1c, lipid profile, fasting C-peptide, pancreatic auto-antibodies (glutamic acid decarboxylase [GAD], Islet Antigen 2 [IA-2], and anti-insulin). We found a Gly178Ala substitution in exon 5 of GCK gene in three individuals co-segregating with diabetes, and type 1 diabetes was identified in two other individuals based on clinical and laboratory data. One individual with previous gestational diabetes and other with prediabetes were also described. We discuss difficulties in defining etiology of hyperglycemia in youth in clinical practice, especially monogenic forms of diabetes, in spite of the availability of several genetic, laboratory, and clinical tools.