Autosomal dominant polycystic kidney disease: an update on epidemiological and molecular aspects

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of chronic kidney disease stage 5 and represents 3% to 10.3% among patients undergoing dialysis in Brazil. The ADPKD is caused by mutations in one of two genes, PKD1 or PKD2 encoding hence the polycystins 1 and 2 involved in cyst formation. The disease is characterized by progressive growth and development of multiple bilateral renal cysts which lead to loss of kidney function. The ADPKD presents several renal and extrarenal clinical manifestations, and comorbidities. Some diagnostic strategies are regarded as first choice for clinical and molecular investigation of the ADPKD. The knowledge of molecular aspects in association with the clinical manifestations presented by the epidemiology of the disease provides better understanding of the mechanisms of cystogenesis and greater diagnostic accuracyDoença renal policística autossômica dominante (DRPAD) é a causa hereditária mais comum da doença renal crônica estágio 5 e representa de 3% a 10,3% entre os doentes em diálise no Brasil. A DRPAD é causada por mutações em um de dois genes, PKD1 ou PKD2, que codificam, consequentemente, as policistinas 1 e 2 envolvidas na formação dos cistos. A doença é caracterizada pelo progressivo crescimento e desenvolvimento de múltiplos cistos renais bilaterais que levam à perda da função dos rins. A DRPAD apresenta diversas manifestações clínicas renais e extrarrenais, além de comorbidades. Algumas estratégias diagnósticas são consideradas de primeira escolha para a investigação clínica e molecular da DRPAD. O conhecimento de aspectos moleculares em associação com as manifestações clínicas apresentadas pela epidemiologia da doença proporciona melhor compreensão dos mecanismos de cistogênese e maior acurácia diagnóstic

HLA-DR and HLA-DQ alleles in patients from the south of Brazil: markers for leprosy susceptibility and resistance

<p>Abstract</p> <p>Background</p> <p>Many epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by <it>M. leprae</it>. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population.</p> <p>Methods</p> <p>One hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers(One Lambda^®, CA, USA).</p> <p>Results</p> <p>There was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy <it>per se </it>(7.3% <it>vs</it>. 3.2%, <it>P </it>= 0.01, OR = 2.52, CI = 1.26–5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% <it>vs</it>. 20.9%, <it>P </it>= 0.0424, OR = 1.61, CI = 1.09–2.39) was higher in patients, and HLA-DQA1*02 (3.0% <it>vs</it>. 7.5%, <it>P </it>= 0.0392, OR = 0.39, CI = 0.16 – 0.95) and HLA-DQA1*04 (4.0% <it>vs</it>. 9.1%, <it>P </it>= 0.0314, OR = 0.42, CI = 0.19 – 0.93) frequencies lower, <it>P</it>-values were not significant after the Bonferroni's correction. Furthermore, HLA-DRB1*1601 (9.0% <it>vs</it>. 1.8%; <it>P </it>= 0.0016; OR = 5.81; CI = 2.05–16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% <it>vs</it>. 1.2%; <it>P </it>= 0.0037; OR = 12.00; CI = 1.51 – 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection.</p> <p>Conclusion</p> <p>These data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy <it>per se</it>, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.</p

Analysis of the CCR5 gene coding region diversity in five South American populations reveals two new non-synonymous alleles in Amerindians and high CCR5*D32 frequency in Euro-Brazilians

The CC chemokine receptor 5 (CCR5) molecule is an important co-receptor for HIV. The effect of the CCR5*D32 allele in susceptibility to HIV infection and AIDS disease is well known. Other alleles than CCR5*D32 have not been analysed before, neither in Amerindians nor in the majority of the populations all over the world. We investigated the distribution of the CCR5 coding region alleles in South Brazil and noticed a high CCR5*D32 frequency in the Euro-Brazilian population of the Paraná State (9.3%), which is the highest thus far reported for Latin America. The D32 frequency is even higher among the Euro-Brazilian Mennonites (14.2%). This allele is uncommon in Afro-Brazilians (2.0%), rare in the Guarani Amerindians (0.4%) and absent in the Kaingang Amerindians and the Oriental-Brazilians. R223Q is common in the Oriental-Brazilians (7.7%) and R60S in the Afro-Brazilians (5.0%). A29S and L55Q present an impaired response to β-chemokines and occurred in Afro- and Euro-Brazilians with cumulative frequencies of 4.4% and 2.7%, respectively. Two new non-synonymous alleles were found in Amerindians: C323F (g.3729G > T) in Guarani (1.4%) and Y68C (g.2964A > G) in Kaingang (10.3%). The functional characteristics of these alleles should be defined and considered in epidemiological investigations about HIV-1 infection and AIDS incidence in Amerindian populations

Contrasting Patterns of Nuclear and mtDNA Diversity in Native American Populations

We report an integrated analysis of nuclear (autosomal, X- and Y-chromosome) short tandem repeat (STR) data and mtDNA D-loop sequences obtained in the same set of 22 Native populations from across the Americas. A north to south gradient of decreasing population diversity was observed, in agreement with a settlement of the Americas from the extreme northwest of the continent. This correlation is stronger with "least cost distances," which consider the coasts as facilitators of migration. Continent-wide estimates of population structure are highest for the Y-chromosome and lowest for the autosomes, consistent with the effective size of the different marker systems examined. Population differentiation is highest in East South America and lowest in Meso America and the Andean region. Regional analyses suggest a deviation from mutation-drift equilibrium consistent with population expansion in Meso America and the Andes and population contraction in Northwest and East South America. These data hint at an early divergence of Andean and non-Andean South Americans and at a contrasting demographic history for populations from these regions.Instituto Multidisciplinario de Biología Celula

Geographic Patterns of Genome Admixture in Latin American Mestizos

The large and diverse population of Latin America is potentially a powerful resource for elucidating the genetic basis of complex traits through admixture mapping. However, no genome-wide characterization of admixture across Latin America has yet been attempted. Here, we report an analysis of admixture in thirteen Mestizo populations (i.e. in regions of mainly European and Native settlement) from seven countries in Latin America based on data for 678 autosomal and 29 X-chromosome microsatellites. We found extensive variation in Native American and European ancestry (and generally low levels of African ancestry) among populations and individuals, and evidence that admixture across Latin America has often involved predominantly European men and both Native and African women. An admixture analysis allowing for Native American population subdivision revealed a differentiation of the Native American ancestry amongst Mestizos. This observation is consistent with the genetic structure of pre-Columbian populations and with admixture having involved Natives from the area where the Mestizo examined are located. Our findings agree with available information on the demographic history of Latin America and have a number of implications for the design of association studies in population from the region

Contrasting Patterns of Nuclear and mtDNA Diversity in Native American Populations

We report an integrated analysis of nuclear (autosomal, X- and Y-chromosome) short tandem repeat (STR) data and mtDNA D-loop sequences obtained in the same set of 22 Native populations from across the Americas. A north to south gradient of decreasing population diversity was observed, in agreement with a settlement of the Americas from the extreme northwest of the continent. This correlation is stronger with "least cost distances," which consider the coasts as facilitators of migration. Continent-wide estimates of population structure are highest for the Y-chromosome and lowest for the autosomes, consistent with the effective size of the different marker systems examined. Population differentiation is highest in East South America and lowest in Meso America and the Andean region. Regional analyses suggest a deviation from mutation-drift equilibrium consistent with population expansion in Meso America and the Andes and population contraction in Northwest and East South America. These data hint at an early divergence of Andean and non-Andean South Americans and at a contrasting demographic history for populations from these regions.Instituto Multidisciplinario de Biología Celula

KIR gene content in amerindians indicates influence of demographic factors

Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations

KIR gene content in amerindians indicates influence of demographic factors

Although the KIR gene content polymorphism has been studied worldwide, only a few isolated or Amerindian populations have been analyzed. This extremely diverse gene family codifies receptors that are expressed mainly in NK cells and bind HLA class I molecules. KIR-HLA combinations have been associated to several diseases and population studies are important to comprehend their evolution and their role in immunity. Here we analyzed, by PCR-SSP (specific sequencing priming), 327 individuals from four isolated groups of two of the most important Brazilian Amerindian populations: Kaingang and Guarani. The pattern of KIR diversity among these and other ten Amerindian populations disclosed a wide range of variation for both KIR haplotypes and gene frequencies, indicating that demographic factors, such as bottleneck and founder effects, were the most important evolutionary factors in shaping the KIR polymorphism in these populations

Butyrylcholinesterase genetic variability in Guarani Amerindians from the Brazilian state of Mato Grosso do Sul

Human butyrylcholinesterase (BChE; EC 3.1.1.8) is a polymorphic enzyme coded by the BCHE gene (3q26.1-q26.2) while the CHE2 gene (2q33-q35) determines a still not characterized substance that forms a complex with BChE (C5), being the CHE2 C5+ and CHE2 C5- phenotypes detected in electrophoresis. The present study investigated BCHE and CHE2 variability and the BChE activity of Brazilian Guarani Amerindians from the Kaiowá and Ñandeva sub-groups living in several indigenous territories in the Brazilian state of Mato Grosso do Sul. The frequency of the BCHE exon 2 D70G (A) allele was 0.60% &plusmn; 0.35% while that of the BCHE exon 2 G390V (F-2) allele, never before screened in Amerindians, was 8.82% &plusmn; 1.35%. This is the first time that the BCHE gene exon 4 A539T (K) allele has been surveyed in Brazilian Amerindians where it was found at a frequency of 3.69% &plusmn; 0.85%, similar to that found in Chilean Mapuche Amerindians. The BCHE gene variability seen in this survey differs from that of non-isolated populations in respect to both A539T and G390V allele frequency. The CHE2 C5+ phenotype frequency was 14.40% &plusmn; 2.22% and falls within the range of that found for other Brazilian Amerindian samples