Publications by authors named "António Brehm"

57 Publications

Additional value of a combined genetic risk score to standard cardiovascular stratification.

Genet Mol Biol 2018 Oct-Dec;41(4):766-774

Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa-Portugal.

The utility of genetic risk scores (GRS) as independent risk predictors remains inconclusive. Here, we evaluate the additive value of a multi-locus GRS to the Framingham risk score (FRS) in coronary artery disease (CAD) risk prediction. A total of 2888 individuals (1566 coronary patients and 1322 controls) were divided into three subgroups according to FRS. Multiplicative GRS was determined for 32 genetic variants associated to CAD. Logistic Regression and Area Under the Curve (AUC) were determined first, using the TRF for each FRS subgroup, and secondly, adding GRS. Different models (TRF, TRF+GRS) were used to classify the subjects into risk categories for the FRS 10-year predicted risk. The improvement offered by GRS was expressed as Net Reclassification Index and Integrated Discrimination Improvement. Multivariate analysis showed that GRS was an independent predictor for CAD (OR = 1.87; p<0.0001). Diabetes, arterial hypertension, dyslipidemia and smoking status were also independent CAD predictors (p<0.05). GRS added predictive value to TRF across all risk subgroups. NRI showed a significant improvement in all categories. In conclusion, GRS provided a better incremental value in intermediate subgroup. In this subgroup, inclusion of genotyping may be considered to better stratify cardiovascular risk.
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http://dx.doi.org/10.1590/1678-4685-GMB-2017-0173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6415604PMC
June 2017

[Genetic Polymorphisms Associated with the Onset of Arterial Hypertension in a Portuguese Population].

Acta Med Port 2018 Oct 31;31(10):542-550. Epub 2018 Oct 31.

Unidade de Investigação. Hospital Doutor Nélio Mendonça. Funchal. Portugal.

Introduction: Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors.

Objective: Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology.

Material And Methods: Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0.

Results: The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018).

Discussion: According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology.

Conclusion: In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model.
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http://dx.doi.org/10.20344/amp.9184DOI Listing
October 2018

Genetic Risk Analysis of Coronary Artery Disease in a Population-based Study in Portugal, Using a Genetic Risk Score of 31 Variants.

Arq Bras Cardiol 2018 Jul 2;111(1):50-61. Epub 2018 Jul 2.

Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa - Portugal.

Background: Genetic risk score can quantify individual's predisposition to coronary artery disease; however, its usefulness as an independent risk predictor remains inconclusive.

Objective: To evaluate the incremental predictive value of a genetic risk score to traditional risk factors associated with coronary disease.

Methods: Thirty-three genetic variants previously associated with coronary disease were analyzed in a case-control population with 2,888 individuals. A multiplicative genetic risk score was calculated and then divided into quartiles, with the 1st quartile as the reference class. Coronary risk was determined by logistic regression analysis. Then, a second logistic regression was performed with traditional risk factors and the last quartile of the genetic risk score. Based on this model, two ROC curves were constructed with and without the genetic score and compared by the Delong test. Statistical significance was considered when p values were less than 0.05.

Results: The last quartile of the multiplicative genetic risk score revealed a significant increase in coronary artery disease risk (OR = 2.588; 95% CI: 2.090-3.204; p < 0.0001). The ROC curve based on traditional risk factors estimated an AUC of 0.72, which increased to 0.74 when the genetic risk score was added, revealing a better fit of the model (p < 0.0001).

Conclusions: In conclusion, a multilocus genetic risk score was associated with an increased risk for coronary disease in our population. The usual model of traditional risk factors can be improved by incorporating genetic data.
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http://dx.doi.org/10.5935/abc.20180107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078363PMC
July 2018

The genetic variant C825T of the beta 3 subunit of G protein is associated with hypertension in a Portuguese population.

Rev Port Cardiol 2018 06 28;37(6):499-507. Epub 2018 May 28.

Unidade de Investigação, Hospital Doutor Nélio Mendonça, Funchal, Portugal.

Introduction: Hypertension is an important public health problem, affecting about 25% of the adult population worldwide.1 Genetic and environmental factors contribute to its pathogenesis. The T allele of the C825T polymorphism of the beta 3 subunit of G protein (rs5443) leads to the production of a truncated variant that enhances intracellular signaling and may interfere with the regulation of blood pressure. This genetic variant has been described as a risk factor for hypertension, although study results are controversial.

Objective: The objective of this study was to analyze the association of the C825T polymorphism of the GNB3 gene with the occurrence of hypertension in a Portuguese population from the Madeira archipelago.

Methods: A case-control study was performed with 1641 Caucasian individuals (mean age 50.6±8.1 years), 848 with hypertension and 793 controls. Blood was collected from all participants for biochemical and genetic analysis, including genotyping of the C825T polymorphism. Logistic regression analysis was performed to determine which variables were significantly associated with the onset of hypertension. Statistical analyses were performed using IBM SPSS version 19.0 and p-values <0.05 were considered statistically significant.

Results: In our study, there was a significant association between the C825T polymorphism of the GNB3 gene and the occurrence of hypertension (odds ratio 1.275; 95% confidence interval 1.042-1.559; p=0.018) in the dominant model, after multivariate analysis.

Conclusion: We conclude that the C825T polymorphism of the beta 3 subunit of G protein is significantly and independently associated with the occurrence of hypertension in the study population.
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http://dx.doi.org/10.1016/j.repc.2017.09.018DOI Listing
June 2018

Relationship between ADD1 Gly460Trp gene polymorphism and essential hypertension in Madeira Island.

Medicine (Baltimore) 2017 Oct;96(42):e7861

Funchal Hospital Center, Research Unit, Avenida Luís de Camões, n° 57, Funchal, Madeira Faculty of Medical Sciences, New University of Lisbon, Campo dos Mártires da Pátria, Lisboa Laboratory of Human Genetics, Madeira University, Campus da Penteada, Funchal-Madeira, Portugal.

Essential hypertension (EH) is a complex disease in which physiological, environmental, and genetic factors are involved in its genesis. The genetic variant of the alpha-adducin gene (ADD1) has been described as a risk factor for EH, but with controversial results.The objective of this study was to evaluate the association of ADD1 (Gly460Trp) gene polymorphism with the EH risk in a population from Madeira Island.A case-control study with 1614 individuals of Caucasian origin was performed, including 817 individuals with EH and 797 controls. Cases and controls were matched for sex and age, by frequency-matching method. All participants collected blood for biochemical and genotypic analysis for the Gly460Trp polymorphism. We further investigated which variables were independently associated to EH, and, consequently, analyzed their interactions.In our study, we found a significant association between the ADD1 gene polymorphism and EH (odds ratio 2.484, P = .01). This association remained statistically significant after the multivariate analysis (odds ratio 2.548, P = .02).The ADD1 Gly460Trp gene polymorphism is significantly and independently associated with EH risk in our population. The knowledge of genetic polymorphisms associated with EH is of paramount importance because it leads to a better understanding of the etiology and pathophysiology of this pathology.
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http://dx.doi.org/10.1097/MD.0000000000007861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662351PMC
October 2017

Synergistic Association of Genetic Variants with Environmental Risk Factors in Susceptibility to Essential Hypertension.

Genet Test Mol Biomarkers 2017 Oct 5;21(10):625-631. Epub 2017 Sep 5.

3 Faculty of Medical Sciences, New University of Lisbon , Lisboa, Portugal .

Aims: Essential hypertension (EH) is a disease in which both environment and genes have an important role. This study was designed to identify the interaction model between genetic variants and environmental risk factors that most highly potentiates EH development.

Methods: We performed a case-control study with 1641 participants (mean age 50.6 ± 8.1 years), specifically 848 patients with EH and 793 controls, adjusted for gender and age. Traditional risk factors, biochemical and genetic parameters, including the genotypic discrimination of 14 genetic variants previously associated with EH, were investigated. Multifactorial dimensionality reduction (MDR) software was used to analyze gene-environment interactions. Validation was performed using logistic regression analysis with environmental risk factors, significant genetic variants, and the best MDR model.

Results: The best model indicates that the interactions among the ADD1 rs4961 640T allele, diabetes, and obesity (body mass index ≥30) increase approximately four-fold the risk of EH (odds ratio = 3.725; 95% confidence interval: 2.945-4.711; p < 0.0001).

Conclusion: This work showed that the interaction between the ADD1 rs4961 variant, obesity, and the presence of diabetes increased the susceptibility to EH four-fold. In these circumstances, lifestyle adjustment and diabetes control should be intensified in patients who carry the ADD1 variant.
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http://dx.doi.org/10.1089/gtmb.2017.0048DOI Listing
October 2017

Genetic characterization of Guinea-Bissau using a 12 X-chromosomal STR system: Inferences from a multiethnic population.

Forensic Sci Int Genet 2017 11 24;31:89-94. Epub 2017 Aug 24.

Human Genetics Laboratory, University of Madeira, Campus of Penteada, 9020-105 Funchal, Portugal. Electronic address:

A male West African sample from Guinea-Bissau (West-African coast) was genetically analyzed using 12 X chromosomal short tandem repeats that are grouped into four haplotype groups. Linkage disequilibrium was tested (p≤0.0008) and association was detected for the majority of markers in three out of the four studied haplotype clusters. The sample of 332 unrelated individuals analyzed in this study belonged to several recognized ethnic groups (n=18) which were used to evaluate the genetic variation of Guinea-Bissau's population. Pairwise genetic distances (F) did not reveal significant differences among the majority of groups. An additional 110 samples from other countries also belonging to West Africa were as well compared with the sample of Guinea-Bissau. No significant differences were found between these two groups of West African individuals, supporting the genetic homogeneity of this region on the X chromosome level. The generation of over 100 DNA West African sequences provided new insights into the repeat sequence structure of some of the present X-STRs. Parameters for forensic evaluation were also calculated for each X-STR, supporting the potential application of these markers in typical kinship scenarios. Also, the high power of discrimination values for samples of female and male origin observed in this study, confirms the usefulness of the present X-STRs in identification analysis.
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http://dx.doi.org/10.1016/j.fsigen.2017.08.016DOI Listing
November 2017

The Genetic Background of Metabolic Trait Clusters in Children and Adolescents.

Metab Syndr Relat Disord 2017 09 20;15(7):329-336. Epub 2017 Jul 20.

2 Department of Physical Education and Sport, University of Madeira , Funchal, Portugal .

Background: It is well known that metabolic risk factors of cardiovascular diseases are correlated, but the background of this clustering in children is more poorly known than in adults. Thus, we studied the contribution of genetic and environmental factors to the clustering of metabolic traits in childhood and adolescence.

Data And Methods: Nine metabolic traits were measured in 214 complete twin pairs aged 3-18 years in the Autonomous Region of Madeira, Portugal, in 2007 and 2008. The variation of and covariations between the traits were decomposed into genetic and environmental components by using classical genetic twin modeling.

Results: A model, including additive genetic and environmental factors unique for each twin individual, explained the variation of metabolic factors well. Under this model, the heritability estimates varied from 0.47 (systolic blood pressure in children under 12 years of age) to 0.91 (high-density lipoprotein [HDL] cholesterol in adolescents 12 years of age or older). The most systematic correlations were found between adiposity (body mass index and waist circumference) and blood lipids (HDL cholesterol, low-density lipoprotein cholesterol, and triglycerides), as well as blood pressure. These correlations were mainly explained by common genetic factors.

Conclusions: Our results suggest that obesity, in particular, is behind the clustering of metabolic factors in children and adolescents. Both general and abdominal obesity partly share the same genetic background as blood lipids and blood pressure. Obesity prevention early in childhood is important in reducing the risk of metabolic diseases in adulthood.
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http://dx.doi.org/10.1089/met.2017.0013DOI Listing
September 2017

Genetic risk score and cardiovascular mortality in a southern european population with coronary artery disease.

Int J Clin Pract 2017 Jun 15;71(6). Epub 2017 May 15.

Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, Lisboa, Portugal.

Several genetic risk scores (GRS) have been associated with cardiovascular disease; their role, however, in survival from proven coronary artery disease (CAD) have yielded conflicting results.

Objective: The objective of this study was to evaluate long-term cardiovascular mortality according to the genetic risk score in a Southern European population with CAD.

Methods: A cohort of 1464 CAD patients with angiographic proven CAD were followed up prospectively for up to 58.3 (interquartile range: 25.8-88.1) months. Genotyping of 32 single-nucleotide polymorphisms previously associated with CAD was performed using oligonucleotides probes marked with fluorescence for each allele. GRS was constructed according to the additive model assuming codominance and categorised using the median (=26). Cox Regression analysis was performed to determine independent multivariate predictors of cardiovascular mortality. Kaplan-Meier survival curves compared high vs low GRS using log-rank test. C-index was done for our population, as a measure of discrimination in survival analysis model.

Results: During a mean follow-up of 58.3 months, 156 patients (10.7%) died, 107 (7.3%) of CV causes. High GRS (≥26) was associated with reduced cardiovascular survival. Survival analysis with Cox regression model adjusted for 8 variables showed that high GRS, dyslipidemia, diabetes and 3-vessel disease were independent risk factors for cardiovascular mortality (HR=1.53, P=.037; HR=3.64, P=.012; HR=1.75, P=.004; HR=2.97, P<.0001, respectively). At the end of follow-up, the estimated survival probability was 70.8% for high GRS and 80.8% for low GRS (Log-rank test 5.6; P=.018). C-Index of 0.71 was found when GRS was added to a multivariate survival model of diabetes, dyslipidemia, smoking, hypertension and 3 vessel disease, stable angina and dual antiplatelet therapy.

Conclusions: Besides the classical risk factors management, this work highlights the relevance of the genetic profile in survival from CAD. It is expected that new therapies will be dirsected to gene targets with proven value in cardiovascular survival.
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http://dx.doi.org/10.1111/ijcp.12956DOI Listing
June 2017

Genetic Polymorphism of Drug-Metabolizing Enzymes CYP2C9 and CYP2C19 in Moroccan Population.

Genet Test Mol Biomarkers 2017 May 10;21(5):298-304. Epub 2017 Mar 10.

1 Cellular Biology and Molecular Genetics Laboratory, Faculty of Sciences, University Ibn-Zohr , Agadir, Morocco .

Background: The polymorphic cytochrome P450 isoenzymes CYP2C9 and CYP2C19 are involved in the biotransformation of a wide variety of clinical drugs. Their major alleles occur with varying frequencies among different populations worldwide and have been associated with a varied capacity to degrade important therapeutic agents. This gives rise to important individual and interethnic variability in drug metabolism and may be the cause for different clinical responses regarding drug administration. In this study we aimed to analyze the distribution of the CYP2C9 and CYP2C19 major alleles associated with the impaired metabolism, and that account for the "poor metabolizer" phenotype in our study population.

Methods: A sample of 290 healthy subjects living in South Morocco was genotyped using a restriction fragment length polymorphism-polymerase chain reaction genotyping method.

Results: The CYP2C9*3 and CYP2C19*3 mutations were not found in our population. The CYP2C9*2 and CYP2C19*2 were the most common alleles, respectively with frequencies of 8% and 11.4%. Regarding CYP2C9*2 and CYP2C19*2, approximately 16% and 22% of Moroccans are respectively deficient metabolizers, and thus largely lack this enzymatic activity. Our results suggest that only CYP2C9*2 and CYP2C19*2 are likely to substantially contribute to individual and interethnic variability of CY2C9-19 activity in our population.

Conclusions: The distribution of clinically relevant alleles of the CYP2C19 and CYP2C9 genes among our population follows the patterns commonly found in other Mediterranean populations, and suggests a certain degree of African influence. This population study provides relevant information on polymorphisms within the CYP2C19 and CYP2C9 genes. In the future, these results could be used in prognosis and for predicting response to drug treatments as well as to help develop personalized medicine studies in the Moroccan population.
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http://dx.doi.org/10.1089/gtmb.2016.0304DOI Listing
May 2017

New sequence variants detected at DXS10148, DXS10074 and DXS10134 loci.

Forensic Sci Int Genet 2016 Jan 28;20:112-116. Epub 2015 Oct 28.

Institute of Legal Medicine, Faculty of Medicine, University of Cologne, Cologne, Germany.

A great amount of population and forensic genetic data are available for X-STRs supporting the need for having a common and accurate nomenclature among laboratories allowing for better communication, data exchange, and data comparison. DXS10148, DXS10074 and DXS10134 are commonly used X-STRs particularly due to their inclusion in the commercial kit Investigator Argus X-12 (Qiagen). Samples from West Africa and Iraq were sequenced for all three X-STRs allowing the detection of new DNA sequence variants. At DXS10148, variation was detected at four bases downstream from the flanking region from the repeat motif. The sequence AAGG-AAAG has been detected for the first time as a varying (AAGG-AAAG)1-3 motif, in the present work. One additional string when compared to the common one (AAGG-AAAG)2 adds eight bases to the fragment size of the tetranucleotide STR. This means that 2 repeats are added in these cases to the fragment size of the allele, while the presence of only one copy will reduce the expected allele size by 2 repeats. At DXS10074 two varying stretches consisting of AC and AG dinucleotide repeats were observed in the upstream flanking region, six bases from the main repeat core that also influence the expected allele size. DXS10134 revealed a simpler nomenclature in the Guinea-Bissau sample set when compared to the previously described allele nomenclature. This detected new hidden variation also has impact on the actual allele nomenclature at this locus as it contributes to a new class of short alleles so far undetected in other studies.
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http://dx.doi.org/10.1016/j.fsigen.2015.10.005DOI Listing
January 2016

Asthma-snapshot or motion picture?

Front Genet 2013 30;4:73. Epub 2013 Apr 30.

Human Genetics Laboratory, University of Madeira Funchal, Portugal.

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http://dx.doi.org/10.3389/fgene.2013.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3639421PMC
May 2013

RTTN mutations link primary cilia function to organization of the human cerebral cortex.

Am J Hum Genet 2012 Sep 30;91(3):533-40. Epub 2012 Aug 30.

Department of Clinical Genetics, Erasmus University Medical Center (Erasmus MC), P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.
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http://dx.doi.org/10.1016/j.ajhg.2012.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511998PMC
September 2012

Distribution of polymorphisms IL4-590 C/T and IL4 RP2 in the human populations of Madeira, Azores, Portugal, Cape Verde and Guinea-Bissau.

Int J Mol Epidemiol Genet 2012 10;3(2):179-83. Epub 2012 May 10.

Human Genetics Laboratory, University of Madeira, 9000-390 Funchal, Portugal, Central Hospital of Funchal, 9000-514 Funchal, Portugal.

The IL4 gene is located on chromosome 5q23.3-31.2. Polymorphisms within this cytokine gene, like the derivative allele T of IL4-590, have been reported as being associated to elevated IgE serum levels and asthma. In the present work, the allelic and genotypic frequency of the IL4-590 and IL4 RP2 polymorphisms was carried out in 599 individuals from Madeira, Azores, Portugal mainland, Cape Verde and Guinea-Bissau and in a sample of 101 asthmatics from Madeira population. In all populations the polymorphisms were in LD and presented a significant dissimilar allelic and genotypic distribution (p<0.05) except between mainland Portugal and Madeira when compared to Azores. Significant differences regarding both loci were found between Madeira population and the group of asthmatics. Genotype 183183TT frequency is higher for African populations while 253253CC prevails in Caucasian populations. The existence of a Hardy-Weinberg Disequilibrium in Guinea-Bissau population not observed in neutral markers leads to the hypothesis of natural selection occurring in these loci probably associated to a rapid population growth an hypothesis strengthened by neutral STRs D5S818 and CSF1PO gene diversity.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376918PMC
August 2012

Independent association of the variant rs1333049 at the 9p21 locus and coronary heart disease.

Rev Port Cardiol 2011 Jun;30(6):575-91

Unidade de Investigação e Serviço de Cardiologia do Hospital Nélio de Mendonça (SESARAM), Funchal, Portugal.

Introduction: Recent genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). Among them, the SNP rs1333049 has demonstrated a consistent association with CAD, which has been successfully replicated in several populations.

Aim: To investigate whether the SNP rs1333049 located on the 9p21 chromosome is an independent risk factor for CAD in a Portuguese population.

Methods: We performed a case-control study which included 1406 individuals, 723 consecutive coronary patients (mean age 53.71 +/- 8.9 years, 79.9% male and 683 controls without coronary disease (mean age 53.3 +/- 10.5 years, 73.9% male). Cases and controls were selected so as not to be significantly different in terms of gender and age. We studied the SNP rs1333049 at the 9p21 locus in all individuals, using standard PCR combined with the TaqMan technique (Applied Biosystems). The allelic and genotype distribution (C/G), odds ratios and corresponding confidence intervals for CAD risk were determined. A forward Wald logistic regression analysis model was constructed, adjusted for age, gender, conventional risk factors, biochemical markers and the genotypes under study, in order to determine which variables were linked significantly and independently with CAD.

Results: The C allele was found in 60% of the CAD patients and 53% of the controls, with OR = 1.33; p = 0.0002. The CC genotype appeared in 35.7% of CAD patients, with OR = 1.34, p = 0.010. The heterozygous CG genotype was present in 48.1% of the CAD patients and 47% of the controls, and did not present vascular risk (OR = 1.05, p = 0.670). After logistic regression analysis, the CC genotype remained in the equation with OR = 1.7; p = 0.018 and CG with OR = 1.5, p = 0.048.

Conclusion: In the present study we replicated the coronary risk linked to the recently discovered variant rs1333049 on the 9p21 chromosome in a Portuguese population. Although the mechanism underlying the risk is still unknown, the robustness of this risk allele in risk stratification for CAD has been consistent, even in very different populations. The presence of the CC or CG genotype may thus prove to be useful for predicting the risk of developing CAD in the Portuguese population.
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June 2011

Signatures of the preagricultural peopling processes in sub-Saharan Africa as revealed by the phylogeography of early Y chromosome lineages.

Mol Biol Evol 2011 Sep 4;28(9):2603-13. Epub 2011 Apr 4.

Institute of Evolutionary Biology, Universitat Pompeu Fabra-Institut de Biologia Evolutiva, Consejo Superior de Investigationes Cientificas, Barcelona, Spain.

The study of Y chromosome variation has helped reconstruct demographic events associated with the spread of languages, agriculture, and pastoralism in sub-Saharan Africa, but little attention has been given to the early history of the continent. In order to overcome this lack of knowledge, we carried out a phylogeographic analysis of haplogroups A and B in a broad data set of sub-Saharan populations. These two lineages are particularly suitable for this objective because they are the two most deeply rooted branches of the Y chromosome genealogy. Their distribution is almost exclusively restricted to sub-Saharan Africa where their frequency peaks at 65% in groups of foragers. The combined high-resolution single nucleotide polymorphism analysis with short tandem repeats variation of their subclades reveals strong geographic and population structure for both haplogroups. This has allowed us to identify specific lineages related to regional preagricultural dynamics in different areas of sub-Saharan Africa. In addition, we observed signatures of relatively recent contact, both among Pygmies and between them and Khoisan speaker groups from southern Africa, thus contributing to the understanding of the complex evolutionary relationships among African hunter-gatherers. Finally, by revising the phylogeography of the very early human Y chromosome lineages, we have obtained support for the role of southern Africa as a sink, rather than a source, of the first migrations of modern humans from eastern and central parts of the continent. These results open new perspectives on the early history of Homo sapiens in Africa, with particular attention to areas of the continent where human fossil remains and archaeological data are scant.
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http://dx.doi.org/10.1093/molbev/msr089DOI Listing
September 2011

Interaction of paraoxonase-192 polymorphism with low HDL-cholesterol in coronary artery disease risk.

Rev Port Cardiol 2010 Apr;29(4):571-80

Unidade de Investigação e Serviço de Cardiologia do Hospital Dr. Nélio Mendonça (Hospital Central do Funchal), Funchal, Madeira, Portugal.

Introduction: Coronary artery disease (CAD) is the main cause of mortality in developed countries. Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidant enzyme bound to high-density lipoprotein (HDL), which protects against lipid peroxidation and coronary artery disease. PON1 activity is under genetic control and its molecular basis is a polymorphism in the PON1 gene that shows two common isoforms: the wild Q form (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and the mutated R (Arg) form with lower ability.

Aim: To explore the interaction of the R allele of the paraoxonase gene and low HDL-cholesterol concentrations in CAD risk.

Methods: The study population consisted of 818 individuals, 298 coronary patients, aged 55.0 +/- 10.3 years, 78.9% male, and 520 age and gender matched healthy controls, aged 53.3 +/- 11.7 years, 72.5% male. Low HDL-cholesterol was defined as < 0.90 mmol/l in men and < 1.11 mmol/l in women. Comparisons of genotypes between cases and controls were performed by a chi-square test. Statistical significance was accepted at p < 0.05. Odds ratios and 95% confidence intervals for the RR genotypes and HDL-deficient subjects were computed using univariate analysis (2 x 2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used 4 x 2 epidemiologic tables and synergy measures: the additive model (Rothman's synergy index, SI) and multiplicative model (Khoury's synergy index, SIM). The relative excess risk due to interaction (RERI) and the attributable proportion (AP) due to interaction (Rothman) were calculated.

Results: The PON1 RR192 polymorphism was associated with coronary heart disease (OR = 1.61; p = 0.043) in the whole population. HDL-deficient subjects with the RR192 genotype showed increased risk for CAD (OR = 17.38; p < 0.0001) compared to those with normal HDL and RR192 (OR = 1.39; p = 0.348) and HDL-deficient subjects not carrying the RR genotype (OR = 7.79; p < 0.0001). Synergy measures were SI = 2.3, SIM = 1.6; RERI = 9.2.

Conclusion: These data suggest the existence of a synergistic effect of the PON1 RR192 genotype (with lower antioxidant ability) and HDL-deficient subjects in risk for development of CAD. The AP due to this interaction was 0.53, meaning that 53% of CAD was explained by this interaction.
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April 2010

Prevalence of H63D, S65C, and C282Y hereditary hemochromatosis gene variants in Madeira Island (Portugal).

Ann Hematol 2011 Jan 17;90(1):29-32. Epub 2010 Aug 17.

Human Genetics Laboratory, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.

Hereditary HFE Hemochromatosis is an inherited disorder of iron metabolism that results from mutations in the HFE gene. Almost all patients with hereditary hemochromatosis show a C282Y mutation in homozygosity or in compound heterozygosity with H63D. Also, the mutation S65C has been shown to be associated to a milder iron overload. Since allele and genotype frequencies of these three variants of the HFE gene vary between populations, the determination of their prevalence in Madeira Island will clarify the population susceptibility to hereditary hemochromatosis. One hundred and fifty-four samples from Madeira Island were genotyped for the three most common HFE gene mutations, H63D, C282Y, and S65C, by polymerase chain reaction followed by restriction fragment length polymorphism analysis. Results have shown a prevalence of 20.5%, 0.33%, and 1% for H63D, C282Y, and S65C, respectively. Accordingly to our estimates, both genotypes associated to hereditary hemochromatosis, C282Y homozygotes and C282/H63D compound heterozygotes, could be present in Madeira Island population in 1,648 individuals, which represents 0.65% of the total population.
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http://dx.doi.org/10.1007/s00277-010-1034-xDOI Listing
January 2011

Alpha-1-antitrypsin deficiency in the Cape Verde islands (Northwest Africa): High prevalence in a sub-Saharan population.

Respir Med 2010 Jul 11;104(7):1069-72. Epub 2010 Mar 11.

Human Genetics Laboratory, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.

Alpha-1-antitrypsin (AAT) deficiency results from mutations on the Protease Inhibitor (PI) locus located in chromosome 14 and has been associated with pulmonary early-onset emphysema and chronic obstructive pulmonary disease (COPD). African populations show a lower prevalence of AAT deficiency compared to Europeans. Two hundred and two (202) unrelated samples from the Cape Verde archipelago (Northwest Africa) were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using PCR - Mediated Site-Directed Mutagenesis. PI*S mutation in Cape Verde (3.2%) presents one of the highest frequencies in sub-Saharans, similar to South Africa (3.3%) but lower than Angolans (18.8%), Namibians (14.7%), Nigerians (6.4%) and Botswains (4.5%). The PI*Z mutation shows lower values (0.2%) than other sub-Saharan populations, namely Somalia (1.15%), Mali (0.98%)or Nigeria (0.36%). However, many other sub-Saharan populations, like Botswana, Congo, Cameroon, Angola, Gambia, South Africa, Mozambique and Namibia, lack the PI*Z mutation. The frequency of all the AAT deficiency genotypes in the Cape Verde archipelago (PI*ZZ, PI*SS, and PI*SZ) was estimated to be one of the highest in sub-Saharans (15 per 1000), only lower than Angola (54 per 1000) and Namibia (22 per 1000). The results obtained show a high prevalence of the AAT deficiency in Cape Verdeans when compared to other sub-Saharans a condition that can be explained by a heavy European genetic influence, characteristic of that population.
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http://dx.doi.org/10.1016/j.rmed.2010.02.012DOI Listing
July 2010

Gene-gene interaction affects coronary artery disease risk.

Rev Port Cardiol 2009 Apr;28(4):397-415

Unidade de Investigção, Hospital Central do Funchal, Funchal, Portugal.

Introduction: Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature.

Objective: Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in differen genes.

Methods: We evaluated the risk associated with ACE DD, ACE 8 CC, ACT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD.

Results: Isolated polymorphisms including ACE DD(p < 0.0001), ACE 8 gg (p=0.023), and MTHFR 1298AA (p = 0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CA fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the, model and proved to be independent predictors of CAD.

Conclusions: The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.
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April 2009

Alpha-1-antitrypsin deficiency in Madeira (Portugal): the highest prevalence in the world.

Respir Med 2009 Oct 17;103(10):1498-502. Epub 2009 May 17.

Human Genetics Laboratory, University of Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.

Alpha-1-antitrypsin (AAT) deficiency is a common genetic disease which affects both lung and liver. Early diagnosis can help asymptomatic patients to adjust their lifestyle choices in order to reduce the risk of Chronic Obstructive Pulmonary Disease (COPD). The determination of this genetic deficiency prevalence in Madeira Island (Portugal) population is important to clarify susceptibility and define the relevance of performing genetic tests for AAT on individuals at risk for COPD. Two hundred samples of unrelated individuals from Madeira Island were genotyped for the two most common AAT deficiency alleles, PI*S and PI*Z, using Polymerase Chain Reaction-Mediated Site-Directed Mutagenesis. Our results show one of the highest frequencies for both mutations when compared to any already studied population in the world. In fact, PI*S mutation has the highest prevalence (18%), and PI*Z mutation (2.5%) was the third highest worldwide. The frequency of AAT deficiency genotypes in Madeira (PI*ZZ, PI*SS, and PI*SZ) is estimated to be the highest in the world: 41 per 1000. This high prevalence of AAT deficiency on Madeira Island reveals an increased genetic susceptibility to COPD and suggests a routine genetic testing for individuals at risk.
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http://dx.doi.org/10.1016/j.rmed.2009.04.012DOI Listing
October 2009

Human paraoxonase gene polymorphisms and coronary artery disease risk.

Rev Port Cardiol 2008 Dec;27(12):1539-55

Unidade de Investigação do Hospital Central do Funchal, Madeira, Portugal.

Background: Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results.

Aims: 1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes.

Methods: We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD.

Results: We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p<0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018.

Conclusion: When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.
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December 2008

RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population.

BMC Cardiovasc Disord 2008 Jul 17;8:15. Epub 2008 Jul 17.

Human Genetics Laboratory, University of Madeira, Portugal.

Background: Several polymorphisms within the renin-angiotensin system cluster of genes have been associated with the advent of coronary artery disease (CAD) or related pathologies. We investigated the distribution of 5 of these polymorphisms in order to find any association with CAD development and distinguish if any of the biochemical and behavioural factors interact with genetic polymorphisms in the advent of the disease.

Methods: ACE I/D (rs4340), ACE A11860G (rs4343), AT1R A1166C (rs5186), AGT T174M (rs4762) and AGT M235T (rs699) gene polymorphisms were PCR-RFLP analysed in 298 CAD patients and 510 controls from Portugal. Several biochemical and behavioural markers were obtained.

Results: ACE I/D DD and ACE11860 GG genotypes are risk factors for CAD in this population. The simultaneous presence of ACE I/D I and ACE11860 A alleles corresponds to a significant trend towards a decrease in CAD incidence. We found several synergistic effects between the studied polymorphisms and classical risk factors such as hypertension, obesity, diabetes and dyslipidaemia: the presence of the DD genotype of ACE I/D (and also ACE11860 GG) increases the odds of developing CAD when associated to each one of these classical risk factors, particularly when considering the male and early onset CAD subgroup analysis; AGT235 TT also increases the CAD risk in the presence of hypertension and dyslipidaemia, and AT1R1166 interacts positively with hypertension, smoking and obesity.

Conclusion: ACE polymorphisms were shown to play a major role in individual susceptibility to develop CAD. There is also a clear interaction between RAS predisposing genes and some biochemical/environmental risk factors in CAD onset, demonstrating a significant enhancement of classical markers particularly by ACE I/D and ACE11860.
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http://dx.doi.org/10.1186/1471-2261-8-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483949PMC
July 2008

Discrepancies in HLA typing by PCR-SSOP and SBT techniques: a case study.

Hum Biol 2007 Oct;79(5):537-43

Human Genetics Laboratory, University of Madeira, Campus of Penteada, 9000-399 Funchal, Portugal.

Six hundred twenty-one samples from Portugal, the Cabo Verde archipelago, and Guinea-Bissau were typed for HLA-A, HLA-B, and HLA-DRB1 using the polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) method and the sequence-based typing (SBT) method to characterize and compare discrepancies between the two methods. Fifty-three alleles (4.27% of 1242 chromosomes typed) identified by the PCR-SSOP method were not concordant with the results obtained using the SBT method. Thirty-four (2.74% of total chromosomes typed) PCR-SSOP mistyping results were discrepancies inside the same allele group and 19 others (1.53% of total chromosomes typed) were relative to nonconcordant results between different groups. PCR-SSOP allele mistyping is the result of interpretation difficulties resulting from less intense, absent, or dubious hybridization patterns. Noncommercial PCR-SSOP procedures are highly exigent on the technicians' experience and the availability of properly calibrated high-precision equipment.
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http://dx.doi.org/10.1353/hub.2008.0001DOI Listing
October 2007

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal).

Thromb Res 2008 1;122(5):648-56. Epub 2008 Apr 1.

Human Genetics Laboratory, University of Madeira, Funchal, Portugal.

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.
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http://dx.doi.org/10.1016/j.thromres.2008.02.005DOI Listing
December 2008

Evaluation of two methods for computational HLA haplotypes inference using a real dataset.

BMC Bioinformatics 2008 Jan 29;9:68. Epub 2008 Jan 29.

Hospital Santo Espírito de Angra do Heroísmo, SEEBMO, Angra do Heroísmo, Azores, Portugal.

Background: HLA haplotype analysis has been used in population genetics and in the investigation of disease-susceptibility locus, due to its high polymorphism. Several methods for inferring haplotype genotypic data have been proposed, but it is unclear how accurate each of the methods is or which method is superior. The accuracy of two of the leading methods of computational haplotype inference--Expectation-Maximization algorithm based (implemented in Arlequin V3.0) and Bayesian algorithm based (implemented in PHASE V2.1.1)--was compared using a set of 122 HLA haplotypes (A-B-Cw-DQB1-DRB1) determined through direct counting. The accuracy was measured with the Mean Squared Error (MSE), Similarity Index (IF) and Haplotype Identification Index (IH).

Results: None of the methods inferred all of the known haplotypes and some differences were observed in the accuracy of the two methods in terms of both haplotype determination and haplotype frequencies estimation. Working with haplotypes composed by low polymorphic sites, present in more than one individual, increased the confidence in the assignment of haplotypes and in the estimation of the haplotype frequencies generated by both programs.

Conclusion: The PHASE v2.1.1 implemented method had the best overall performance both in haplotype construction and frequency calculation, although the differences between the two methods were insubstantial. To our knowledge this was the first work aiming to test statistical methods using real haplotypic data from the HLA region.
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http://dx.doi.org/10.1186/1471-2105-9-68DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2268655PMC
January 2008

Relationships of Afroablepharus Greer, 1974 skinks from the Gulf of Guinea islands based on mitochondrial and nuclear DNA: patterns of colonization and comments on taxonomy.

Mol Phylogenet Evol 2007 Dec 31;45(3):904-14. Epub 2007 Aug 31.

University of Madeira, Department of Biology, Campus da Penteada, 9000-390 Funchal, Portugal.

Partial sequences of three mitochondrial DNA genes, 12S rDNA, 16S rDNA and cytochrome b, and one nuclear gene, c-mos, were used to assess the phylogenetic relationships of species belonging to the genus Afroablepharus from the volcanic islands of the Gulf of Guinea (West Africa) and neighboring continental Africa. Additionally, partial sequences of cytochrome b were used to compare levels of sequence divergence within populations. The three forms from São Tomé, Príncipe and Annobon (one per island) are genetically distinct, with high levels of divergence, supporting the recognition of a distinct species in each island. Populations within each island contain very low levels of genetic diversity. These three forms form a monophyletic group suggesting a single initial colonization followed by radiation to the other islands, possibly from São Tomé to Príncipe and Annobon. This is contrary to what was found in other reptiles from these islands such as Mabuya (sensu lato) and Hemidactylus, which colonized the islands multiple times. Assuming a molecular clock for cytochrome b of about 2% divergence per million years (usually applied to Sauria), the lineage on Annobon island exceeds the age of the island, thus casting further doubt on this widely used divergence estimate. Partial sequences of c-mos showed no variation within islands. Five to seven sites were variable among islands, which is a high value further supporting the treatment of each island form as a distinct species.
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http://dx.doi.org/10.1016/j.ympev.2007.08.011DOI Listing
December 2007

Y-chromosomal diversity in the population of Guinea-Bissau: a multiethnic perspective.

BMC Evol Biol 2007 Jul 27;7:124. Epub 2007 Jul 27.

Department of Evolutionary Biology, Estonian Biocentre, Riia 23, Tartu, Estonia.

Background: The geographic and ethnolinguistic differentiation of many African Y-chromosomal lineages provides an opportunity to evaluate human migration episodes and admixture processes, in a pan-continental context. The analysis of the paternal genetic structure of Equatorial West Africans carried out to date leaves their origins and relationships unclear, and raises questions about the existence of major demographic phenomena analogous to the large-scale Bantu expansions. To address this, we have analysed the variation of 31 binary and 11 microsatellite markers on the non-recombining portion of the Y chromosome in Guinea-Bissau samples of diverse ethnic affiliations, some not studied before.

Results: The Guinea-Bissau Y chromosome pool is characterized by low haplogroup diversity (D = 0.470, sd 0.033), with the predominant haplogroup E3a*-M2 shared among the ethnic clusters and reaching a maximum of 82.2% in the Mandenka people. The Felupe-Djola and Papel groups exhibit the highest diversity of lineages and harbor the deep-rooting haplogroups A-M91, E2-M75 and E3*-PN2, typical of Sahel's more central and eastern areas. Their genetic distinction from other groups is statistically significant (P = 0.01) though not attributable to linguistic, geographic or religious criteria. Non sub-Saharan influences were associated with the presence of haplogroup R1b-P25 and particular lineages of E3b1-M78.

Conclusion: The predominance and high diversity of haplogroup E3a*-M2 suggests a demographic expansion in the equatorial western fringe, possibly supported by a local agricultural center. The paternal pool of the Mandenka and Balanta displays evidence of a particularly marked population growth among the Guineans, possibly reflecting the demographic effects of the agriculturalist lifestyle and their putative relationship to the people that introduced early cultivation practices into West Africa. The paternal background of the Felupe-Djola and Papel ethnic groups suggests a better conserved ancestral pool deriving from East Africa, from where they have supposedly migrated in recent times. Despite the overall homogeneity in a multiethnic sample, which contrasts with their social structure, minor clusters suggest the imprints of multiple peoples at different timescales: traces of ancestral inhabitants in haplogroups A-M91 and B-M60, today typical of hunter-gatherers; North African influence in E3b1-M78 Y chromosomes, probably due to trans-Saharan contacts; and R1b-P25 lineages reflecting European admixture via the North Atlantic slave trade.
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http://dx.doi.org/10.1186/1471-2148-7-124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1976131PMC
July 2007

Frequency of the CCR5-delta32 mutation in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and São Tomé e Príncipe.

Hum Biol 2006 Dec;78(6):697-703

Human Genetics Laboratory, University of Madeira, 9000-390 Funchal, Portugal.

There is evidence that the CCR5-delta32 mutation confers protection against HIV-1 infection to homozygous individuals. It is believed that this mutation spread through Europe with the Vikings and that it has been subjected to positive selection, leading to a high frequency in Europe (approximately 10%). We carried out the present study to determine the 32-bp deletion allele and genotype frequencies of the CCR5 gene (CCR5-delta32) in the Atlantic island populations of Madeira, the Azores, Cabo Verde, and São Tomé e Principe. These Atlantic archipelagos were all colonized by the Portuguese in the 15th and 16th centuries, but the latter two received most of their settlers from the West African coast. The frequency of the CCR5-delta32 mutation varies between 0% in São Tomé e Príncipe and 16.5% in the Azores. The Azores Islands have one of the highest frequencies of homozygotes found in Europe (4.8%). There are significant differences (P < 0.05) between some of these populations, for example, between São Tomé e Príncipe and Cabo Verde, and even within populations (e.g., Portugal, Madeira, and the Azores).
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http://dx.doi.org/10.1353/hub.2007.0011DOI Listing
December 2006