Publications by authors named "Kiyoko Abe-Sandes"

23 Publications

  • Page 1 of 1

MLH1 intronic variants mapping to + 5 position of splice donor sites lead to deleterious effects on RNA splicing.

Fam Cancer 2020 10;19(4):323-336

Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB) [HIBA-IUHI-CONICET], C1199ABH, Buenos Aires, Argentina.

Germline pathogenic variants in the DNA mismatch repair genes (MMR): MLH1, MSH2, MSH6, and PMS2, are causative of Lynch syndrome (LS). However, many of the variants mapping outside the invariant splice site positions (IVS ± 1, IVS ± 2) are classified as variants of unknown significance (VUS). Three such variants (MLH1 c.588+5G>C, c.588+5G>T and c.677+5G>A) were identified in 8 unrelated LS families from Argentina, Brazil and Chile. Herein, we collected clinical information on these families and performed segregation analysis and RNA splicing studies to assess the implication of these VUS in LS etiology. Pedigrees showed a clear pattern of variant co-segregation with colorectal cancer and/or other LS-associated malignancies. Tumors presented deficient expression of MLH1-PMS2 proteins in 7/7 of the LS families, and MSI-high status in 3/3 cases. Moreover, RNA analyses revealed that c.588+5G>C and c.588+5G>T induce skipping of exon 7 whereas c.677+5G>A causes skipping of exon 8. In sum, we report that the combined clinical findings in the families and the molecular studies provided the evidences needed to demonstrate that the three MLH1 variants are causative of LS and to classify c.588+5G>C and c.677+5G>A as class 5 (pathogenic), and c.588+5G>T as class 4 (likely-pathogenic). Our findings underline the importance of performing clinical and family analyses, as well as RNA splicing assays in order to determine the clinical significance of intronic variants, and contribute to the genetic counseling and clinical management of patients and their relatives.
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http://dx.doi.org/10.1007/s10689-020-00182-5DOI Listing
October 2020

A snapshot of current genetic testing practice in Lynch syndrome: The results of a representative survey of 33 Latin American existing centres/registries.

Eur J Cancer 2019 09 20;119:112-121. Epub 2019 Aug 20.

Hospital de Especialidades Eugenio Espejo, Subproceso de Anatomía Patológica, Área de Genética Clínica, Quito, Ecuador.

We aimed to assess the current genetics practice to manage patients with Lynch syndrome (LS) across Latin America. A Latin American LS survey was sent out to 52 centres/registries, comprising a total of 12 countries from the region. Overall, 33 centres completed the survey, of which the oldest LS registry was established in 1992 in Sao Paulo (Brazil), and the youngest this year in San Jose (Costa Rica). In total, 87% (26/30) of the participating centres/registries belonging to the nine countries are performing genetic testing. Overall, 1352 suspected families were sequenced. Pathogenic variants were identified in 34% of the families, with slightly differing distribution of variants between females and males. Path_MLH1 variants were identified in 39% of females and 50% of males (p = 0.023), while path_MSH2 were identified in 37% of females and males, followed by path_PMS2 in 11% of females and 8% of males, path_MSH6 in 13% of females and 3% of males (p < 0.001) and path_EPCAM in 0.3% of females and 2% of males. In Latin America, 9 of 12 (75%) participating countries had implemented healthcare for LS. LS screening is inconsistently applied within Latin America healthcare systems because of structural differences in the healthcare systems between the countries.
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http://dx.doi.org/10.1016/j.ejca.2019.07.017DOI Listing
September 2019

From colorectal cancer pattern to the characterization of individuals at risk: Picture for genetic research in Latin America.

Int J Cancer 2019 07 5;145(2):318-326. Epub 2018 Dec 5.

AC Camargo Cancer Center, Sao Paulo, Brazil.

Colorectal cancer (CRC) is one of the most common cancers in Latin America and the Caribbean, with the highest rates reported for Uruguay, Brazil and Argentina. We provide a global snapshot of the CRC patterns, how screening is performed, and compared/contrasted to the genetic profile of Lynch syndrome (LS) in the region. From the literature, we find that only nine (20%) of the Latin America and the Caribbean countries have developed guidelines for early detection of CRC, and also with a low adherence. We describe a genetic profile of LS, including a total of 2,685 suspected families, where confirmed LS ranged from 8% in Uruguay and Argentina to 60% in Peru. Among confirmed LS, path_MLH1 variants were most commonly identified in Peru (82%), Mexico (80%), Chile (60%), and path_MSH2/EPCAM variants were most frequently identified in Colombia (80%) and Argentina (47%). Path_MSH6 and path_PMS2 variants were less common, but they showed important presence in Brazil (15%) and Chile (10%), respectively. Important differences exist at identifying LS families in Latin American countries, where the spectrum of path_MLH1 and path_MSH2 variants are those most frequently identified. Our findings have an impact on the evaluation of the patients and their relatives at risk for LS, derived from the gene affected. Although the awareness of hereditary cancer and genetic testing has improved in the last decade, it is remains deficient, with 39%-80% of the families not being identified for LS among those who actually met both the clinical criteria for LS and showed MMR deficiency.
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http://dx.doi.org/10.1002/ijc.31920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587543PMC
July 2019

The germline mutational landscape of BRCA1 and BRCA2 in Brazil.

Sci Rep 2018 06 15;8(1):9188. Epub 2018 Jun 15.

Centro de Paulista de Oncologia, Oncoclínicas, São Paulo, Brazil.

The detection of germline mutations in BRCA1 and BRCA2 is essential to the formulation of clinical management strategies, and in Brazil, there is limited access to these services, mainly due to the costs/availability of genetic testing. Aiming at the identification of recurrent mutations that could be included in a low-cost mutation panel, used as a first screening approach, we compiled the testing reports of 649 probands with pathogenic/likely pathogenic variants referred to 28 public and private health care centers distributed across 11 Brazilian States. Overall, 126 and 103 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-six novel variants were reported from both genes, and BRCA2 showed higher mutational heterogeneity. Some recurrent mutations were reported exclusively in certain geographic regions, suggesting a founder effect. Our findings confirm that there is significant molecular heterogeneity in these genes among Brazilian carriers, while also suggesting that this heterogeneity precludes the use of screening protocols that include recurrent mutation testing only. This is the first study to show that profiles of recurrent mutations may be unique to different Brazilian regions. These data should be explored in larger regional cohorts to determine if screening with a panel of recurrent mutations would be effective.
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http://dx.doi.org/10.1038/s41598-018-27315-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003960PMC
June 2018

Targeted Resequencing of Deafness Genes Reveals a Founder MYO15A Variant in Northeastern Brazil.

Ann Hum Genet 2016 Nov;80(6):327-331

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.

Identifying the genetic etiology in a person with hearing loss (HL) is challenging due to the extreme genetic heterogeneity in HL and the population-specific variability. In this study, after excluding GJB2 variants, targeted resequencing of 180 deafness-related genes revealed the causative variants in 11 of 19 (58%) Brazilian probands with autosomal recessive HL. Identified pathogenic variants were in MYO15A (10 families) and CLDN14 (one family). Remarkably, the MYO15A p.(Val1400Met) variant was identified in eight families from the city of Monte Santo in the northeast region of Brazil. Haplotype analysis of this variant was consistent with a single founder. No other cases with this variant were detected among 105 simplex cases from other cities of northeastern Brazil, suggesting that this variant is confined to a geographical region. This study suggests that it is feasible to develop population-specific screening for deafness variants once causative variants are identified in different geographical groups.
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http://dx.doi.org/10.1111/ahg.12177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127167PMC
November 2016

BRCA1 and BRCA2 rearrangements in Brazilian individuals with Hereditary Breast and Ovarian Cancer Syndrome.

Genet Mol Biol 2016 Apr-Jun;39(2):223-31

Laboratório de Medicina Genômica, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil.

Approximately 5-10% of breast cancers are caused by germline mutations in high penetrance predisposition genes. Among these, BRCA1 and BRCA2, which are associated with the Hereditary Breast and Ovarian Cancer (HBOC) syndrome, are the most frequently affected genes. Recent studies confirm that gene rearrangements, especially in BRCA1, are responsible for a significant proportion of mutations in certain populations. In this study we determined the prevalence of BRCA rearrangements in 145 unrelated Brazilian individuals at risk for HBOC syndrome who had not been previously tested for BRCA mutations. Using Multiplex Ligation-dependent Probe Amplification (MLPA) and a specific PCR-based protocol to identify a Portuguese founder BRCA2 mutation, we identified two (1,4%) individuals with germline BRCA1 rearrangements (c.547+240_5193+178del and c.4675+467_5075-990del) and three probands with the c.156_157insAlu founder BRCA2 rearrangement. Furthermore, two families with false positive MLPA results were shown to carry a deleterious point mutation at the probe binding site. This study comprises the largest Brazilian series of HBOC families tested for BRCA1 and BRCA2 rearrangements to date and includes patients from three regions of the country. The overall observed rearrangement frequency of 3.44% indicates that rearrangements are relatively uncommon in the admixed population of Brazil.
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http://dx.doi.org/10.1590/1678-4685-GMB-2014-0350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910561PMC
June 2016

Association of IFNL3 and IFNL4 polymorphisms with hepatitis C virus infection in a population from southeastern Brazil.

Arch Virol 2016 Jun 14;161(6):1477-84. Epub 2016 Mar 14.

Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated complications such as liver cirrhosis and hepatocellular carcinoma (HCC). Viral and host factors are known to be predictors for antiviral therapy. Host factors that are predictors of sustained viral response (SVR) were discovered by genome-wide association studies (GWAS), including single-nucleotide polymorphisms (SNPs) in or near the interferon lambda gene (rs8099917, rs12979860 and rs368234815). The aim of the present study was to verify the genotype frequencies of SNPs rs8099917, rs12979860 and rs368234815 and to evaluate the association between SNPs and the outcome of HCV infection, taking into account the population ancestry. In this study, there was an association of the three polymorphisms with both clinical outcome and response to treatment with PEG-IFN and RBV. The polymorphisms rs12979860 and rs368234815 were associated with increased sensitivity (97.7 %, 95 % CI 87.2-100, and 93.3 %, 95 % CI 81.3-98.3; respectively) and with a greater predictive value of a positive response to treatment. In multivariable analysis adjusted by gender, age and ancestry, the haplotype G/T/ΔG was related to non-response to treatment (OR = 21.09, 95 % CI 5.33-83.51; p < 0.001) and to a higher chance of developing chronic infection (OR = 5.46, 95 % CI 2.06-14.46; p = 0.001) when compared to the haplotype T/C/TT. These findings may help to adjust our treatment policies for HCV infection based on greater certainty in studies with populations with such genetic characteristics, as well as allowing us to get to know the genetic profile of our population for these polymorphisms.
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http://dx.doi.org/10.1007/s00705-016-2809-8DOI Listing
June 2016

Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal.

World J Hepatol 2015 Jun;7(10):1433-8

Lourianne Nascimento Cavalcante, Andre Castro Lyra, Gastro-Hepatology Department, Hospital Sao Rafael, Salvador BA 41253-190, Brazil.

Aim: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal.

Methods: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P < 0.05).

Results: In the Brazilian sample, NASH was significantly more frequent among the elderly patients with diabetes (NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old, P = 3.7 x 10(-9)), dyslipidemia (NASH 63% vs S. Steatosis 37%, P = 0.009), higher fasting glucose levels (NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3, P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups.

Conclusion: There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort.
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http://dx.doi.org/10.4254/wjh.v7.i10.1433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450207PMC
June 2015

Lymphocyte subset reference intervals in blood donors from northeastern Brazil.

An Acad Bras Cienc 2015 Apr-Jun;87(2):1019-25. Epub 2015 Apr 28.

Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, BA, Brasil.

Unlabelled: The reference intervals for leukocytes and lymphocytes currently used by most clinical laboratories present limitations as they are primarily derived from individuals of North American and European origin. The objective this study was to determine reference values for peripheral blood B lymphocytes, T lymphocyte subsets (CD4+, CD8+, naïve, memory, regulatory, TCRαβ and TCRγδ+) and NK cells from blood donors in Salvador-Bahia, Brazil.

Results: The proportion of included male subjects was 73.7% and the median ages of males (34) and females (35) were found to be similar. Absolute counts total lymphocytes subsets to both gender was 1,956 (1,060-4,186) cells and relative values 34%. The T CD4+ and T CD8+ lymphocytes relative values was 51% (20-62) and 24% (9-28), respectively. The most statistically significant finding observed was a higher percentage of B lymphocytes (p=0.03) in females. Commonly cited subset reference intervals were found to be consistent with values in several populations from different geographic areas.
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http://dx.doi.org/10.1590/0001-3765201520130114DOI Listing
December 2015

A community-based study of mucopolysaccharidosis type VI in Brazil: the influence of founder effect, endogamy and consanguinity.

Hum Hered 2014 29;77(1-4):189-96. Epub 2014 Jul 29.

Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.

Mucopolysaccharidosis type VI (MPS VI - Maroteaux-Lamy syndrome) is a globally rare lysosomal storage disease caused by a deficiency of arylsulfatase B. However, in Monte Santo, a poor and isolated rural region in Northeast Brazil with large family sizes and high rates of community endogamy and parental consanguinity (α = 0.00483), 9 living and 4 now deceased individuals in 11 kindreds have been diagnosed with MPS VI, all with the same p.H178L missense founder mutation. A further 33 deceased persons have been identified by family members as exhibiting the disease phenotype. Detailed pedigrees were constructed for the 13 genomically confirmed MPS VI patients, with blood samples collected from 236 unaffected family members to determine the prevalence of the p.H178L mutation. A total of 98 (20.8%) mutant alleles and 374 (79.2%) normal alleles were identified, with 41.5% of the individuals heterozygous for the p.H178L mutation and 58.5% homozygous for the normal allele. A significant number of other family members with a 50 or 25% chance of being heterozygous for the p.H178L mutation were unavailable for testing. The data indicate a compelling case for community-based neonatal screening in conjunction with further initiatives among MPS VI family members to promote genetic education and genetic counselling.
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http://dx.doi.org/10.1159/000358404DOI Listing
March 2015

Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population.

Hum Genome Var 2014 16;1:14012. Epub 2014 Oct 16.

Laboratório de Imunologia e Biologia Molecular, Instituto de Ciências da Saúde, Universidade Federal da Bahia, Salvador, Brazil; Laboratório Avançado de Saúde Pública, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

Considering the importance of BRCA1, BRCA2, CHEK2 and TP53 in the development of hereditary early-onset breast and ovarian cancer and that the genetic susceptibility profile of the Northeast population from Brazil has never been analyzed, this study aimed to verify the frequency of mutations of clinical significance in these genes in high-risk hereditary breast and ovarian cancer (HBOC) syndrome patients from that region. DNA samples from 106 high-risk unrelated patients mostly from Bahia, the biggest state in the Northeast region, were analyzed. These patients underwent full BRCA1 gene sequencing, screening for common founder mutations in the BRCA2, CHEK2 and TP53 genes and genetic ancestry analysis with nine ancestry informative markers. The positive results were confirmed by two sequencing reactions. Three mutations of clinical significance were found: BRCA1 p.R71G (4.71%), 3450del4 (3.77%) and TP53 p.R337H (0.94%). The genetic ancestry analysis showed a high European ancestry contribution (62.2%) as well as considerable African (31.2%) and Amerindian (6.6%) ancestry contributions (r (2)=0.991); this degree of heterogeneity was also significant in the population structure analysis (r=0.604). This population is highly admixed with a different spectrum of genetic susceptibility, with the Galician founder mutation BRCA1 p.R71G accounting for 50% of all identified mutations in high-risk HBOC patients. TP53 p.R337H was also significantly frequent; thus, the combined screening of BRCA1/2 and TP53 should be offered to high-risk HBOC patients from Northeast Brazil.
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http://dx.doi.org/10.1038/hgv.2014.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785545PMC
April 2016

Myxovirus resistance, osteopontin and suppressor of cytokine signaling 3 polymorphisms predict hepatitis C virus therapy response in an admixed patient population: comparison with IL28B.

Clinics (Sao Paulo) 2013 Oct;68(10):1325-32

Laboratory of Immunology, Federal University of Bahia, SalvadorBA, Brazil.

Objectives: Suppressor of cytokine signaling 3, myxovirus resistance protein and osteopontin gene polymorphisms may influence the therapeutic response in patients with chronic hepatitis C, and an association with IL28 might increase the power to predict sustained virologic response. Our aims were to evaluate the association between myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 gene polymorphisms in combination with IL28B and to assess the therapy response in hepatitis C patients treated with pegylated-interferon plus ribavirin.

Method: Myxovirus resistance protein, osteopontin, suppressor of cytokine signaling 3 and IL28B polymorphisms were analyzed by PCR-restriction fragment length polymorphism, direct sequencing and real-time PCR. Ancestry was determined using genetic markers.

Results: We analyzed 181 individuals, including 52 who were sustained virologic responders. The protective genotype frequencies among the sustained virologic response group were as follows: the G/G suppressor of cytokine signaling 3 (rs4969170) (62.2%); T/T osteopontin (rs2853744) (60%); T/T osteopontin (rs11730582) (64.3%); and the G/T myxovirus resistance protein (rs2071430) genotype (54%). The patients who had ≥3 of the protective genotypes from the myxovirus resistance protein, the suppressor of cytokine signaling 3 and osteopontin had a greater than 90% probability of achieving a sustained response (p<0.0001). The C/C IL28B genotype was present in 58.8% of the subjects in this group. The sustained virological response rates increased to 85.7% and 91.7% by analyzing C/C IL28B with the T/T osteopontin genotype at rs11730582 and the G/G suppressor of cytokine signaling 3 genotype, respectively. Genetic ancestry analysis revealed an admixed population.

Conclusion: Hepatitis C genotype 1 patients who were responders to interferon-based therapy had a high frequency of multiple protective polymorphisms in the myxovirus resistance protein, osteopontin and suppressor of cytokine signaling 3 genes. The combined analysis of the suppressor of cytokine signaling 3 and IL28B genotypes more effectively predicted sustained virologic response than IL28B analysis alone.
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http://dx.doi.org/10.6061/clinics/2013(10)06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798553PMC
October 2013

Non-syndromic hearing impairment in a multi-ethnic population of Northeastern Brazil.

Int J Pediatr Otorhinolaryngol 2013 Jul 15;77(7):1077-82. Epub 2013 May 15.

Advanced Laboratory of Public Health/Gonçalo Moniz Research Center (CPqGM), Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil.

Objective: There are many hearing impaired individuals in Monte Santo, a rural municipality in the state of Bahia, Brazil, including multiple familial cases strongly suggestive of a genetic aetiology.

Methods: The present study investigated 81 subjects with hearing impairment (HI) recruited from 36 families. Mutations often associated with HI, i.e. the DFNB1 mutations c.35delG in GJB2, deletions del(GJB6-D13S1830) and del(GJB6-D13S1854), and A1555G in the mitochondrial gene MTRNR1 were initially analyzed, with additional mutations in GJB2 identified by sequencing the coding region of the gene.

Results: Seven different mutations were present in GJB2 with mutations c.35delG and p.Arg75Gln, which are known to be pathogenic, identified in 37.0% of the subjects. Individuals homozygous for the c.35delG mutation were diagnosed in eight families, corresponding to 24.7% of unrelated individuals with nonsyndromic hearing impairment (NSHI), and an additional heterozygote for this mutation was present in a single family. Ten individuals (12.4%) in another family were heterozygous for the mutation p.Arg75Gln.

Conclusions: Significant heterogeneity was observed in the alleles and patterns of NSHI inheritance among the subjects studied, probably due to the extensive inter-ethnic admixture that characterizes the peoples of Brazil, together with a high prevalence of community endogamy and consanguineous marriage.
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http://dx.doi.org/10.1016/j.ijporl.2013.04.001DOI Listing
July 2013

Does celiac disease occur in Afro-derived Brazilian populations?

Am J Hum Biol 2012 Sep-Oct;24(5):710-2. Epub 2012 Apr 17.

Faculdade de Medicina, Centro de Pesquisa em Doença Celíaca, Universidade de Brasília, Distrito Federal, Brazil.

Background: Celiac disease is an autoimmune disorder that occurs in genetically susceptible individuals in whom the ingestion of dietary gluten induces intestinal mucosa inflammation. Previous studies suggest that celiac disease may either be very rare or underdiagnosed in African and/or African-derived population.

Aim: Determine the prevalence of celiac disease in Sub-Saharan African-derived Brazilian communities using serological screening.

Subjects And Methods: Inhabitants from 10 African-derived communities from Northeastern of Brazil were screened for celiac disease. All sera were tested for endomysial class IgA antibody using indirect immunofluorescence.

Results: No positive test for IgA-endomysial was observed in the 860 individuals tested.

Conclusion: Our data suggests a low prevalence of celiac disease in African-derived Brazilian populations.
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http://dx.doi.org/10.1002/ajhb.22271DOI Listing
January 2013

IL28B polymorphisms are markers of therapy response and are influenced by genetic ancestry in chronic hepatitis C patients from an admixed population.

Liver Int 2012 Mar 3;32(3):476-86. Epub 2011 Oct 3.

Department of Medicine, Federal University of Bahia, Salvador, Bahia, Brazil.

Background: IL28B polymorphisms are predictors of therapy response in hepatitis C virus (HCV) patients. We do not know whether they are markers of treatment response in admixed populations or not.

Aims: To determine whether IL28B polymorphisms are predictors of therapy response in patients with HCV from an admixed population and are influenced by genetic ancestry.

Methods: rs12979860 and rs8099917 were genotyped in 222 HCV patients treated with pegylated interferon and ribavirin. Ancestry was determined using genetic markers.

Results: IL28B rs12979860 C/C was associated with sustained virological response (SVR), whereas C/T and T/T were associated with failure to therapy (P = 1.12 × 10(-5) ). IL28B rs8099917 T/T was associated with SVR, and G/G and G/T were associated with nonresponse/relapse (NR/R) (P = 8.00 × 10(-3) ). Among HCV genotype 1 patients with C/C genotype, genomic ancestry did not interfere with therapy response. Among patients with rs12979860 T/T genotype, African genetic contribution was greater in the NR/R group (P = 1.51 × 10(-3) ), whereas Amerindian and European genetic ancestry contribution were higher in the SVR group (P = 3.77 × 10(-3) and P = 2.16 × 10(-2) respectively). Among HCV type 1 patients with rs8099917 T/T, African genetic contribution was significantly greater in the NR/R group (P = 5.0 × 10(-3) ); Amerindian and European ancestry genetic contribution were greater in the SVR group.

Conclusion: IL28B rs12979860 and rs8099917 polymorphisms were predictors of therapy response in HCV genotypes 1, 2 and 3 subjects from an admixed population. Genomic ancestry did not interfere with response to therapy in patients with rs12979860 C/C, whereas it interfered in patients with C/T and T/T genotypes. Among HCV genotype 1 rs8099917 T/T patients, genomic ancestry interfered with response to therapy.
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http://dx.doi.org/10.1111/j.1478-3231.2011.02653.xDOI Listing
March 2012

Genetic studies in a cluster of mucopolysaccharidosis type VI patients in Northeast Brazil.

Mol Genet Metab 2011 Dec 20;104(4):603-7. Epub 2011 Sep 20.

Medical Genetics Service, Hospital de Clínicas, Porto Alegre, RS, Brazil.

Mucopolysaccharidosis type VI (MPS VI, Maroteaux-Lamy syndrome) is a lysosomal storage disease caused by deficiency of arylsulphatase B. The incidence of MPS VI is very low, usually less than 1 case for every 1,000,000 newborns. In Northeast Brazil we identified in the county of Monte Santo (52,360 inhabitants) thirteen patients with MPS VI. The aim of this work was to identify the mutation(s) present in these patients and analyze intragenic SNPs to define possible haplotypes. The 13 MPS VI patients were found to be homozygous for the p.H178L mutation. All patients have the same haplotype for the intragenic SNPs. Based on current data, the prevalence of MPS VI in this region is estimated as 1:5,000 newborns. These results, together with pedigree analysis, strongly suggest a founder effect accounting for the high frequency of p.H178L mutation in this area. This reinforces the need of a comprehensive community genetics program for this area.
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http://dx.doi.org/10.1016/j.ymgme.2011.09.017DOI Listing
December 2011

Who were the male founders of rural Brazilian Afro-derived communities? A proposal based on three populations.

Ann Hum Biol 2011 Mar 15;38(2):237-40. Epub 2010 Jul 15.

Departamento de Genética e Morfologia, Instituto de Ciências Biológicas, Universidade de Brasília, DF, Brazil.

Background: Brazilian Quilombos are Afro-derived communities founded mainly by fugitive slaves between the 16(th) and 19(th) centuries; they can be recognized today by ancestral and cultural characteristics. Each of these remnant communities, however, has its own particular history, which includes the migration of non-African derived people.

Methods: The present work presents a proposal for the origin of the male founder in Brazilian quilombos based on Y-haplogroup distribution. Y haplogroups, based on 16 binary markers (92R7, SRY2627, SRY4064, SRY10831.1 and .2, M2, M3, M09, M34, M60, M89, M213, M216, P2, P3 and YAP), were analysed for 98 DNA samples from genetically unrelated men from three rural Brazilian Afro-derived communities-Mocambo, Rio das Rãs and Kalunga-in order to estimate male geographic origin.

Results: Data indicated significant differences among these communities. A high frequency of non-African haplogroups was observed in all communities.

Conclusions: This observation suggested an admixture process that has occurred over generations and directional mating between European males and African female slaves that must have occurred on farms before the slaves escaped. This means that the admixture occurred before the slaves escaped and the foundation of the quilombo.
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http://dx.doi.org/10.3109/03014460.2010.500471DOI Listing
March 2011

Investigation of Neospora caninum, Hammondia sp., and Toxoplasma gondii in tissues from slaughtered beef cattle in Bahia, Brazil.

Parasitol Res 2010 Jan 27;106(2):457-61. Epub 2009 Nov 27.

Departamento de Patologia e Clínicas, Universidade Federal da Bahia, Escola de Medicina Veterinária, Avenida Ademar de Barros 500, Ondina, Salvador, Bahia 40170-110, Brazil.

Neospora caninum, Hammondia sp., and Toxoplasma gondii are parasites with morphological and genetic similarities. N. caninum and T. gondii are important abortive agents of cattle and sheep, respectively, and may infect numerous animal species. Hammondia sp. is not known to induce disease in animals, but may cause confusion in the identification of closely related coccidia. The aim of this study was to investigate infection rates caused by N. caninum, Hammondia sp., and T. gondii in beef cattle using a nested PCR for Toxoplasmatinae rDNA, followed by sequencing of the PCR products. Antibodies to N. caninum and T. gondii were also investigated in the tested animals. Brains and hearts were obtained from 100 beef cattle in a slaughterhouse in Bahia. Seven samples from brain tested positive for Toxoplasmatinae DNA. No positive reactions were found in heart tissues. After sequencing of the PCR products from all positive tissues, five sequences matched with N. caninum and two matched with T. gondii. Antibodies to N. caninum and T. gondii were found in 20% and 26% of the animals, respectively. The confirmation of N. caninum and the absence of Hammondia heydorni in the tested animals is suggestive that cattle are not efficient intermediate hosts of H. heydorni; however further studies need to be performed using a greater variety of tissues and a higher sample size. The detection of T. gondii DNA in bovine tissues reinforces the potential risk of transmission of this parasite to humans and other animals through the consumption of bovine meat.
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http://dx.doi.org/10.1007/s00436-009-1686-4DOI Listing
January 2010

Toxoplasma gondii and Neospora caninum in sparrows (Passer domesticus) in the Northeast of Brazil.

Vet Parasitol 2010 Feb 9;168(1-2):121-4. Epub 2009 Oct 9.

Departamento de Patologia e Clínicas, Universidade Federal da Bahia, Escola de Medicina Veterinária, Avenida Ademar de Barros, Bahia, Brazil.

Toxoplasma gondii is a cosmopolitan protozoan parasite of warm-blooded animals that causes high rates of infection in mammals and birds. Sparrows (Passer domesticus) are synantropic birds which are distributed worldwide. They serve as intermediate hosts for the parasite but are quite resistant to toxoplasmosis. The aims of this study were to determine the frequency of T. gondii infection in sparrows using serologic and molecular tests, and to investigate related parasites, such as Neospora caninum and Hammondia sp., using a nested PCR for Toxoplasmatinae DNA followed by sequence analysis of the PCR amplicons. A total of 293 sparrows were trapped at the states of Bahia and Pernambuco, Brazil. Tissues of 40 animals were available for molecular tests. Antibodies to T. gondii were found in 1.02% (3/293) of animals using a hemagglutination test, with titers ranging from 1:32 to 1:128. Toxoplasmatinae DNA was detected in 10/40 (25%) sparrows; after nucleotide sequencing, T. gondii was confirmed in 7/40 (17.5%) birds and N. caninum in 3/40 (7.5%) animals. Sparrows from Brazil were confirmed as intermediate hosts of T. gondii, that reinforces the potential importance of these birds on the transmission of the parasite to cats and other animals that may predate sparrows. In addition, N. caninum was detected for the first time in sparrows. To the authors' knowledge, this is the first wild synantropic bird species identified as intermediate host of N. caninum. These findings seem to have a great epidemiologic impact because of the cosmopolitan distribution of sparrows and due to their increasing population in urban and rural areas.
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http://dx.doi.org/10.1016/j.vetpar.2009.09.055DOI Listing
February 2010

Detection of Hammondia heydorni and related coccidia (Neospora caninum and Toxoplasma gondii) in goats slaughtered in Bahia, Brazil.

Vet Parasitol 2009 May 12;162(1-2):156-9. Epub 2009 Feb 12.

Departamento de Patologia e Clínicas, Escola de Medicina Veterinária, Universidade Federal da Bahia, Salvador, Bahia, Brazil.

Hammondia heydorni is a coccidian parasite with an obligatory two host life cycle, with dogs and foxes as definitive hosts, and a number of intermediate hosts, including goats. While infection by this parasite seems to be unassociated with any clinical signs, infection by the closely related parasites Neospora caninum and Toxoplasma gondii can result in abortion, stillbirths and low yielding in caprine herds. The aim of this work was to investigate the frequency of goats infected with H. heydorni using a nested PCR, specific to Toxoplasmatinae internal transcribed spacer 1 (ITS1) of the rDNA, followed by sequencing of the purified PCR fragments. The same molecular techniques were used to determine the frequencies of N. caninum and T. gondii-infected animals. A total frequency of 13.72% (14/102) was obtained for Toxoplasmatinae DNA in goat tissues. After sequencing the PCR products from all positive tissues, a frequency of 3.92% (4/102), 1.96% (2/102) and 7.84% (8/102) were obtained for H. heydorni, N. caninum and T. gondii, respectively. All sequences shared 98-100% identity with sequences from other strains of these coccidia present in GenBank. To the authors' knowledge, this is the first report of H. heydorni DNA in tissues from naturally infected intermediate hosts.
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http://dx.doi.org/10.1016/j.vetpar.2009.02.007DOI Listing
May 2009

Knops blood group haplotypes among distinct Brazilian populations.

Transfusion 2007 Jan;47(1):147-53

Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, SP, Brazil.

Background: The Knops blood group system consists of antigens encoded by exon 29 of complement receptor 1 (CR1) gene. To better elucidate the complexity of Knops group system, the frequency of six single-nucleotide polymorphisms (SNPs) in three Brazilian populations is determined.

Study Design And Methods: A total of 118 individuals descendant from Europe, Asia, and Africa were studied. The genomic fragment of CR1 was amplified by polymerase chain reaction, and the SNPs and haplotypes were determined after DNA sequence analysis.

Results: Among the six polymorphisms characterized, one of them was described for the first time. The analysis of allele frequency showed that these six SNPs did not differ between the European and Asian groups. The African group presented a higher frequency of alleles McC(b), Sl2, and KAM+. The six polymorphisms gave origin to 12 haplotypes that were defined for the first time. The haplotypes 1 (4646A, Kn(a), McC(a), Sl1, Sl4, KAM+), 2 (4646A, Kn(a), McC(a), Sl1, KAM-), and 3 (4646A, Kn(a), McC(a), Sl2, Sl4, KAM-) are the most frequent in all populations. The H2 presents similar frequency in all populations; however, whereas the H1 presented a higher prevalence in the European and Asian groups, in the African group H3 was present in a higher prevalence.

Conclusions: In this study, a new SNP substituting serine for asparagine at amino acid 1540 was identified. Moreover 12 haplotypes were identified. The differences in haplotype frequencies strongly suggest that the H1 and H2 might be the ancestral one while the H3 may have originated in Africa and may have fixed there by positive selection.
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http://dx.doi.org/10.1111/j.1537-2995.2007.01077.xDOI Listing
January 2007

Heterogeneity of the Y chromosome in Afro-Brazilian populations.

Hum Biol 2004 Feb;76(1):77-86

Centro de Terapia Celular, Hemocentro de Ribeirão Preto, Rua Tenente Catão Roxo, 2501, 14051-140 Ribeirão Preto, Brazil.

Sixteen biallelic markers (SRY10831a, SRY10831b, SRY4064, SRY2627, 92R7, P2, P3, M34, M9, M3, M2, YAP, M60, M89, M213, M216) located in the nonrecombinant region of the Y chromosome were analyzed in 209 individuals belonging to six Brazilian populations: four Afro-Brazilian populations, one population of white European descendants, and one population of Japanese descendants. The results showed that most of the Y chromosomes of the Afro-Brazilians were from sub-Saharan Africa and that the proportion of Y chromosomes of European origin was greater than that of Y chromosomes of Amerindian origin. No typical African or Amerindian haplogroup was detected among Japanese individuals, and only one white individual showed a typical African haplogroup. Haplogroup P-92R7, which is highly frequent in the Portuguese and Italian populations, was the most frequent among whites (54%), and haplogroup K-M9, which shows wide geographic distribution and is absent in Africa, was the most frequent among Japanese individuals (65.6%). The two semi-isolated Afro-Brazilian populations showed the highest and the lowest genetic diversity, respectively. These differences probably reflect the effect of greater or smaller gene flow between a small isolated group and other populations. These findings show that the process of admixture does not occur homogeneously, with a tendency toward preferential marriages within the ethnic group and a clear direction in unions between European men and Amerindian or African women in the past. The results agree with historical and social data about the formation of the Brazilian population and reveal some of the factors that contribute to its heterogeneity.
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http://dx.doi.org/10.1353/hub.2004.0014DOI Listing
February 2004

Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America.

Am J Hum Genet 2002 Jul 17;71(1):187-92. Epub 2002 May 17.

Center for Cell Therapy and Regional Blood Center, University of São Paulo, Ribeirão Preto, Brazil.

There is general agreement that the Native American founder populations migrated from Asia into America through Beringia sometime during the Pleistocene, but the hypotheses concerning the ages and the number of these migrations and the size of the ancestral populations are surrounded by controversy. DNA sequence variations of several regions of the genome of Native Americans, especially in the mitochondrial DNA (mtDNA) control region, have been studied as a tool to help answer these questions. However, the small number of nucleotides studied and the nonclocklike rate of mtDNA control-region evolution impose several limitations to these results. Here we provide the sequence analysis of a continuous region of 8.8 kb of the mtDNA outside the D-loop for 40 individuals, 30 of whom are Native Americans whose mtDNA belongs to the four founder haplogroups. Haplogroups A, B, and C form monophyletic clades, but the five haplogroup D sequences have unstable positions and usually do not group together. The high degree of similarity in the nucleotide diversity and time of differentiation (i.e., approximately 21,000 years before present) of these four haplogroups support a common origin for these sequences and suggest that the populations who harbor them may also have a common history. Additional evidence supports the idea that this age of differentiation coincides with the process of colonization of the New World and supports the hypothesis of a single and early entry of the ancestral Asian population into the Americas.
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http://dx.doi.org/10.1086/341358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC384978PMC
July 2002