Anomalous sulphur isotopes in plume lavas reveal deep mantle storage of Archaean crust.

Basaltic lavas erupted at some oceanic intraplate hotspot volcanoes are thought to sample ancient subducted crustal materials. However, the residence time of these subducted materials in the mantle is uncertain and model-dependent, and compelling evidence for their return to the surface in regions of mantle upwelling beneath hotspots is lacking. Here we report anomalous sulphur isotope signatures indicating mass-independent fractionation (MIF) in olivine-hosted sulphides from 20-million-year-old ocean island basalts from Mangaia, Cook Islands (Polynesia), which have been suggested to sample recycled oceanic crust. Terrestrial MIF sulphur isotope signatures (in which the amount of fractionation does not scale in proportion with the difference in the masses of the isotopes) were generated exclusively through atmospheric photochemical reactions until about 2.45 billion years ago. Therefore, the discovery of MIF sulphur in these young plume lavas suggests that sulphur--probably derived from hydrothermally altered oceanic crust--was subducted into the mantle before 2.45 billion years ago and recycled into the mantle source of Mangaia lavas. These new data provide evidence for ancient materials, with negative Δ(33)S values, in the mantle source for Mangaia lavas. Our data also complement evidence for recycling of the sulphur content of ancient sedimentary materials to the subcontinental lithospheric mantle that has been identified in diamond-hosted sulphide inclusions. This Archaean age for recycled oceanic crust also provides key constraints on the length of time that subducted crustal material can survive in the mantle, and on the timescales of mantle convection from subduction to upwelling beneath hotspots.

Tumor Microenvironment Modulation via Gold Nanoparticles Targeting Malicious Exosomes: Implications for Cancer Diagnostics and Therapy.

Exosomes are nanovesicles formed in the endosomal pathway with an important role in paracrine and autocrine cell communication. Exosomes secreted by cancer cells, malicious exosomes, have important roles in tumor microenvironment maturation and cancer progression. The knowledge of the role of exosomes in tumorigenesis prompted a new era in cancer diagnostics and therapy, taking advantage of the use of circulating exosomes as tumor biomarkers due to their stability in body fluids and targeting malignant exosomes' release and/or uptake to inhibit or delay tumor development. In recent years, nanotechnology has paved the way for the development of a plethora of new diagnostic and therapeutic platforms, fostering theranostics. The unique physical and chemical properties of gold nanoparticles (AuNPs) make them suitable vehicles to pursuit this goal. AuNPs' properties such as ease of synthesis with the desired shape and size, high surface:volume ratio, and the possibility of engineering their surface as desired, potentiate AuNPs' role in nanotheranostics, allowing the use of the same formulation for exosome detection and restraining the effect of malicious exosomes in cancer progression.

Superficial Epidermolytic Ichthyosis-Hypertrichosis as a Clue to Diagnosis.

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant disorder caused by a mutation in the keratin 2 gene and clinically characterized by mild hyperkeratosis, superficial blisters and shedding, referred to as the moulting phenomenon. We report a case of SEI in an 18-month-old girl presenting with marked hypertrichosis. Although not invariably present, we believe that hypertrichosis can be an important clue for diagnosis.

Genealogical and molecular analysis of a family-based cohort of congenital heart disease patients from the São Miguel Island (Azores, Portugal).

BACKGROUND: Congenital heart disease (CHD) is one common birth malformation, accounting for ∼30% of total congenital abnormalities. AIM: Considering the unknown role of consanguinity in causing CHD, this study hypothesised that consanguineous unions and/or familial aggregation may be frequent in the Azorean Island of São Miguel (Portugal). To that end, a retrospective observational study was performed based on genealogical and molecular analyses. SUBJECTS AND METHODS: The study enrolled 112 CHD patients from São Miguel Island, which allowed the assessment of type of family (simplex or multiplex), parental consanguinity and grandparental endogamy. Based on 15 STR markers, inbreeding coefficients (FIS) in the CHD cohort and healthy control group (n = 114) were estimated. RESULTS: Multiplex families were 37.6% (n = 41/109), a rate considerably higher than previously described in the literature (< 15%). Moreover, 9.2% (n = 10/109) of the CHD families were consanguineous, mostly derived from third cousin unions, and 20.2% (n = 22/109) presented full grandparental endogamy. Higher FIS values were found in patients with parental consanguinity (0.0371) and patent ductus arteriosus (0.0277). CONCLUSION: This study analysed several genealogical and genetic features related with CHD, revealing the presence of parental consanguinity and extensive familial aggregation in the CHD patients from São Miguel Island.

Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion.

Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis.

The DSPII splice variant is crucial for desmosome-mediated adhesion in HaCaT keratinocytes.

Desmosomes are intercellular junctions specialised for strong adhesion that are prominent in the epidermis and heart muscle. Defective desmosomal function due to inherited mutations in the constitutive desmosomal gene desmoplakin (DSP) causes skin or heart disorders and in some instances both. Different mutations have different disease-causing molecular mechanisms as evidenced by the varying phenotypes resulting from mutations affecting different domains of the same protein, but the majority of these mechanisms remain to be determined. Here, we studied two mutations in DSP that lead to different dosages of the two major DSP splice variants, DSPI and DSPII, and compared their molecular mechanisms. One of the mutations results in total DSP haploinsufficiency and is associated with autosomal dominant striate palmoplantar keratoderma (PPK). The other leads to complete absence of DSPI and the minor isoform DSPIa but normal levels of DSPII, and is associated with autosomal recessive epidermolytic PPK, woolly hair and severe arrhythmogenic dilated cardiomyopathy. Using siRNA treatments to mimic these two mutations and additionally a DSPII-specific siRNA, we found striking differences between DSP isoforms with respect to keratinocyte adhesion upon cellular stress with DSPII being the key component in intermediate filament (IF) stability and desmosome-mediated adhesion. In addition, reduction in DSP expression reduced the amount of plakophilin 1, desmocollin (DSC) 2 and DSC3 with DSPI having a greater influence than DSPII on the expression levels of DSC3. These results suggest that the two major DSP splice variants are not completely redundant in function and that DSPII dosage is particularly important for desmosomal adhesion in the skin.

Inflammatory skin and bowel disease linked to ADAM17 deletion.

We performed genetic and immunohistochemical studies in a sister and brother with autosomal recessive neonatal inflammatory skin and bowel lesions. The girl died suddenly at 12 years of age from parvovirus B19-associated myocarditis; her brother had mild cardiomyopathy. We identified a loss-of-function mutation in ADAM17, which encodes a disintegrin and metalloproteinase 17 (also called tumor necrosis factor α [TNF-α]-converting enzyme, or TACE), as the probable cause of this syndrome. Peripheral-blood mononuclear cells (PBMCs) obtained from the brother at 17 years of age showed high levels of lipopolysaccharide-induced production of interleukin-1ß and interleukin-6 but impaired release of TNF-α. Despite repeated skin infections, this young man has led a relatively normal life. (Funded by Barts and the London Charity and the European Commission Seventh Framework Programme.).

Screening of copy number variants in the 22q11.2 region of congenital heart disease patients from the São Miguel Island, Azores, revealed the second patient with a triplication.

BACKGROUND: The rearrangements in the 22q11.2 chromosomal region, responsible for the 22q11.2 deletion and microduplication syndromes, are frequently associated with congenital heart disease (CHD). The present work aimed to identify the genetic basis of CHD in 87 patients from the São Miguel Island, Azores, through the detection of copy number variants (CNVs) in the 22q11.2 region. These structural variants were searched using multiplex ligation-dependent probe amplification (MLPA). In patients with CNVs, we additionally performed fluorescent in situ hybridization (FISH) for the assessment of the exact number of 22q11.2 copies among each chromosome, and array comparative genomic hybridization (array-CGH) for the determination of the exact length of CNVs. RESULTS: We found that four patients (4.6%; A to D) carried CNVs. Patients A and D, both affected with a ventricular septal defect, carried a de novo 2.5 Mb deletion of the 22q11.2 region, which was probably originated by inter-chromosomal (inter-chromatid) non-allelic homologous recombination (NAHR) events in the regions containing low-copy repeats (LCRs). Patient C, with an atrial septal defect, carried a de novo 2.5 Mb duplication of 22q11.2 region, which could have been probably generated during gametogenesis by NAHR or by unequal crossing-over; additionally, this patient presented a benign 288 Kb duplication, which included the TOP3B gene inherited from her healthy mother. Finally, patient B showed a 3 Mb triplication associated with dysmorphic facial features, cognitive deficit and heart defects, a clinical feature not reported in the only case described so far in the literature. The evaluation of patient B's parents revealed a 2.5 Mb duplication in her father, suggesting a paternal inheritance with an extra copy. CONCLUSIONS: This report allowed the identification of rare deletion and microduplication syndromes in Azorean CHD patients. Moreover, we report the second patient with a 22q11.2 triplication, and we suggest that patients with triplications of chromosome 22q11.2, although they share some characteristic features with the deletion and microduplication syndromes, present a more severe phenotype probably due to the major dosage of implicated genes.

Allergic contact dermatitis caused by acrylates and methacrylates--a 7-year study.

BACKGROUND: Allergic contact dermatitis (ACD) caused by (meth)acrylates is traditionally an occupational disease among dentists, printers, and fibreglass workers. With the use of artificial nails, cases have been reported both in nail technicians and in users. OBJECTIVES: The aims of this study were to characterize ACD caused by (meth)acrylates, identify the responsible allergens, and assess the sensitivity of the patch test with 2-hydroxyethyl methacrylate (HEMA) for diagnosis. METHODS: An observational and retrospective study (January 2006-April 2013) was performed, evaluating and correlating epidemiological and clinical parameters and positive patch test results with (meth)acrylates. RESULTS: Among 2263 patch tested patients, 122 underwent aimed testing with an extended (meth)acrylate series, and 37 showed positive and relevant reactions. Twenty-five cases (67.6%) were occupational. Hand eczema with pulpitis was observed in 32 patients. Twenty-eight cases were related to artificial nails, 3 were related to dental materials, and 2 were industrial workers. Oral lesions associated with dental prostheses were observed in 4 patients. Thirty-one patients reacted to more than one (meth)acrylate. In our sample, beauty technicians working with artificial nails were the most affected group (80% of occupational cases). CONCLUSION: HEMA detected 80.6% of our cases, and may be considered a good screening allergen. However, to perform an accurate diagnosis, it is safer to use a broader series of allergens.

Exuberant connubial allergic contact dermatitis from diphenhydramine.

Connubial or consort allergic contact dermatitis occurs when the agent causing the dermatitis has not been used by the patient but by his partner or other cohabitants or proxy. Most cases are due to fragrances, cosmetics or topical nonsteroidal anti-inflammatory agents. We report a case of a connubial dermatitis caused by topical diphenhydramine in a woman who applied the cream on her husband's back.

Gamification and Oral Health in Children and Adolescents: Scoping Review.

BACKGROUND: Oral health is a determinant of overall well-being and quality of life. Individual behaviors, such as oral hygiene and dietary habits, play a central role in oral health. Motivation is a crucial factor in promoting behavior change, and gamification offers a means to boost health-related knowledge and encourage positive health behaviors. OBJECTIVE: This study aims to evaluate the impact of gamification and its mechanisms on oral health care of children and adolescents. METHODS: A systematic search covered multiple databases: PubMed/MEDLINE, PsycINFO, the Cochrane Library, ScienceDirect, and LILACS. Gray literature, conference proceedings, and WHOQOL internet resources were considered. Studies from January 2013 to December 2022 were included, except for PubMed/MEDLINE, which was searched until January 2023. A total of 15 studies were selected following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The eligibility criteria were peer-reviewed, full-text, and empirical research related to gamification in oral health care, reports of impact, and oral health care outcomes. The exclusion criteria encompassed duplicate articles; unavailable full texts; nonoriginal articles; and non-digital game-related, non-oral health-related, and protocol studies. Selected studies were scrutinized for gamification mechanisms and outcomes. Two main questions were raised: "Does gamification in oral health care impact oral health?" and "Does oral health care gamification enhance health promotion and literacy?" The PICO (Patient, Intervention, Comparison, Outcome) framework guided the scoping review. RESULTS: Initially, 617 records were obtained from 5 databases and gray literature sources. After applying exclusion criteria, 15 records were selected. Sample size in the selected studies ranged from 34 to 190 children and adolescents. A substantial portion (11/15, 73%) of the studies discussed oral self-care apps supported by evidence-based oral health. The most clearly defined data in the apps were "brushing time" (11/11, 100%) and "daily amount brushing" (10/11, 91%). Most studies (11/15, 73%) mentioned oral health care behavior change techniques and included "prompt intention formation" (11/26, 42%), "providing instructions" (11/26, 42%), "providing information on the behavior-health link" (10/26, 38%), "providing information on consequences" (9/26, 35%), "modeling or demonstrating behavior" (9/26, 35%), "providing feedback on performance" (8/26, 31%), and "providing contingent rewards" (8/26, 31%). Furthermore, 80% (12/15) of the studies identified game design elements incorporating gamification features in oral hygiene applications. The most prevalent gamification features were "ideological incentives" (10/12, 83%) and "goals" (9/16, 56%), which were found in user-specific and challenge categories, respectively. CONCLUSIONS: Gamification in oral health care shows potential as an innovative approach to promote positive health behaviors. Most studies reported evidence-based oral health and incorporated oral health care behavior change techniques.

Seroprevalence of Protective Antibodies Against Influenza and the Reduction of the Influenza Incidence Rate: An Annual Repeated Cross-Sectional Study From 2014 to 2019.

BACKGROUND: Seroepidemiological studies provide estimates of population-level immunity, prevalence/incidence of infections, and evaluation of vaccination programs. We assessed the seroprevalence of protective antibodies against influenza and evaluated the correlation of seroprevalence with the cumulative annual influenza incidence rate. METHODS: We conducted an annual repeated cross-sectional seroepidemiological survey, during June-August, from 2014 to 2019, in Portugal. A total of 4326 sera from all age groups, sex, and regions was tested by hemagglutination inhibition assay. Seroprevalence and geometric mean titers (GMT) of protective antibodies against influenza were assessed by age group, sex, and vaccine status (65+ years old). The association between summer annual seroprevalence and the difference of influenza incidence rates between one season and the previous one was measured by Pearson correlation coefficient (r). RESULTS: Significant differences in seroprevalence of protective antibodies against influenza were observed in the population. Higher seroprevalence and GMT for A(H1N1)pdm09 and A(H3N2) were observed in children (5-14); influenza B seroprevalence in adults 65+ was 1.6-4.4 times than in children (0-4). Vaccinated participants (65+) showed significant higher seroprevalence/GMT for influenza. A strong negative and significant correlation was found between seroprevalence and ILI incidence rate for A(H1N1)pdm09 in children between 5 and 14 (r = -0.84; 95% CI, -0.98 to -0.07); a weak negative correlation was observed for A(H3N2) and B/Yamagata (r ≤ -0.1). CONCLUSIONS: The study provides new insight into the anti-influenza antibodies seroprevalence measured in summer on the ILI incidence rate in the next season and the need for adjusted preventive health care measures to prevent influenza infection and transmission.

Contact allergy to local anaesthetics-value of patch testing with a caine mix in the baseline series.

BACKGROUND: Contact allergy to local anaesthetics is relatively common. Patch testing with benzocaine in the European baseline series is recommended for diagnosis, even though a caine mix has been previously suggested to be superior. OBJECTIVES: To assess the frequency and patterns of contact allergy to local anaesthetics by using a caine mix (benzocaine, tetracaine, and cinchocaine) in the baseline series, and evaluate its efficiency as compared with benzocaine alone. METHODS: We reviewed the results of 2736 patch tests performed between 2000 and 2010, identifying patients with positive reactions to caine mix or to one of seven local anaesthetics. RESULTS: One hundred and twelve patients (4.1%) had at least one allergic reaction to local anaesthetics; 86 were tested with all seven local anaesthetics, resulting in 71 reactions in 53 patients. Cinchocaine gave the most reactions (50.7%); these occurred as a single reaction in 83.3% of patients, mostly with current or past relevance (97%). Benzocaine represented 22.5% of reactions, many of which were non-relevant (44%) or resulting from cross-reactions with para-compounds. CONCLUSIONS: Almost 70% of allergic reactions to local anaesthetics would have been missed if benzocaine had been used as a screening allergen. This study supports a recommendation to replace benzocaine with a caine mix containing cinchocaine in the baseline patch test series.

Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome.

Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A.

Sub 4 minute superfast single-photon emission computed tomography/computed tomography as an add-on for problem-solving in planar bone scintigraphy: a time-saving solution for departments without whole-body single-photon emission computed tomography/computed tomography.

Whole-body bone scintigraphy remains widely used in nuclear medicine as it is a relatively inexpensive and quick test in which the whole body can be imaged with good sensitivity. However, one downside of the technique is its lack of specificity. The difficulty comes when there is a single 'hot spot' which usually requires further anatomical imaging to identify the cause and differentiate malignant from benign lesions. In this situation, hybrid imaging with single-photon emission computed tomography/computed tomography (SPECT/CT) can be a useful problem solver. The addition of SPECT/CT can however, be time-consuming, adding up to 15-20 min for every bed position required, a process that can tax the compliance of the patient and reduce the scanning capacity of the department. We report the successful implementation of a new superfast SPECT/CT protocol comprising a 1 s per view over 24 views point and shoot approach, reducing the SPECT scan time to less than 2 min and the whole SPECT/CT to under 4 min while still producing images that allow diagnostic certainty in previously equivocal lesions. This is faster than previously reported ultrafast SPECT/CT protocols. The utility of the technique is demonstrated in a pictorial review of four disparate causes of solitary bone lesions: fracture, metastasis, degenerative arthropathy and Paget's disease. This technique may prove a cost-effective problem-solving adjunct in nuclear medicine departments unable to yet offer whole-body SPECT/CT to every patient, without adding much burden to the department's gamma camera usage and patient throughput.

The genetics of alopecia areata: What's new and how will it help our patients?

In the United States, alopecia areata (AA) is the most prevalent autoimmune disease, affecting approximately 5.3 million people, including males and females of all ages and across all ethnic groups. AA affects more individuals than most other autoimmune diseases combined, and yet despite its prevalence, there is little information on the underlying pathogenesis and there are currently no evidence-based treatments available to treat or cure this disease. Genetics has provided a valuable tool for gaining insight into disease pathology. We recently completed the first genome-wide association study (GWAS) in AA and successfully identified at least eight regions in the genome with evidence for association to AA. Importantly, this work identifies a discrete set of genes, some of which have been well studied within the context of other autoimmune diseases and already have targeted therapies available or in development. The insight that we have gained through our GWAS sets the stage for the rational development of novel effective therapeutic approaches and heralds in an exciting new era with the commencement of translational research in AA based on genetic findings.

Copy number variations on chromosome 4q26-27 are associated with Cantu syndrome.

BACKGROUND: Cantu syndrome is a rare condition which is characterized clinically by hypertrichosis, cardiomegaly and bone abnormalities. Inherited hypertrichoses are very rare human disorders whose incidence has been estimated as low as 1 in 1 billion. The genetic basis of hypertrichosis is largely unknown, and currently no single gene has been directly implicated in its pathogenesis, although position effects have been reported. METHODS: We analyzed the DNA of a patient with Cantu syndrome on the Affymetrix Cytogenetics Whole-Genome 2.7M array for copy number variations (CNVs). We then performed genomic copy number quantification using qPCR, and finally we performed gene expression analysis in the hair follicle for the genes lying within and around the region of the duplication. RESULTS: We identified a 375 kb duplication on chromosome 4q26-27. The duplication region encompassed three genes, which included MYOZ2, USP53 and FABP2. MYOZ2 and USP53 are known to be highly expressed in the cardiac muscle, and we found that USP53 is expressed in the hair follicle. CONCLUSION: We propose that CNVs involving chromosome 4q26-27 may be associated with Cantu syndrome. CNVs spanning several genes may help define the molecular basis of syndromes which have unrelated clinical features.

Multiple glomus tumors and segmental neurofibromatosis: there are no coincidences.

Segmental neurofibromatosis is a rare subtype of neurofibromatosis type 1 (NF1). Glomus tumors are uncommon benign tumors. The authors report the association between these two rare conditions, not yet reported.

Identification and characterization of DSPIa, a novel isoform of human desmoplakin.

Desmoplakin is a ubiquitous component of desmosomes and desmosome-like structures, such as the cardiomyocyte area composita. Two major isoforms, desmoplakin I (DSPI) and desmoplakin II (DSPII) are encoded by alternative mRNA transcripts differentially spliced from the same gene. The resulting proteins are identical in amino acid sequence with the exception that DSPII contains only one third of the central alpha-helical rod domain present in DSPI. Here we describe a novel minor isoform of desmoplakin that is also produced by alternative splicing of the desmoplakin gene and that we name desmoplakin Ia (DSPIa). DSPIa is an alternatively spliced DSPI mRNA with a unique splice donor site that is 90% homologous to and downstream of the DSPII specific donor. The resulting DSPIa mRNA is in-frame and encodes a protein that has a central alpha-helical rod domain of intermediate size and that is 156 amino acids larger than DSPII and 443 amino acids smaller than DSPI. We demonstrate, through recombinant expression and short interfering RNA knockdown, that the DSPIa protein is readily detectable, albeit at substantially lower levels than the dominant isoforms, DSPI and DSPII. DSPIa mRNA has a similar tissue distribution to that of DSPI and of DSPII.

Thrombotic genetic risk factors and warfarin pharmacogenetic variants in São Miguel's healthy population (Azores).

BACKGROUND: The Azorean population presents the highest standardized mortality rate for cardiovascular diseases (CVD) when compared to mainland Portugal and other populations. Since thrombosis is a common cause of CVD, we assessed four polymorphisms in three thrombotic risk genes - F5 (G1691A), F2 (G20210A) and MTHFR (C677T, A1298C), in 469 healthy blood donors from São Miguel Island (Azores). We also analysed the CYP2C9 (C430T, A1075C) and VKORC1 (G1639A) variants in fifty-eight individuals with predisposition to thrombosis (possessing at least one variation in F5 or F2 genes and one in MTHFR) to evaluate their warfarin drug response genetic profiles. RESULTS: Among the 469 individuals, the data showed that thrombotic risk allele frequencies - 1691A (4.9%), 20210A (1.8%), 677T (41.7%) and 1298C (24.8%) - were similar to other Caucasians, but significantly different from mainland Portuguese (chi2, p < 0.001). The combined analysis of these variants identified twenty-two different genetic profiles (genotype order: F5, F2, MTHFR C677T and A1298C). Complete homozygosity for all wild-type alleles (GG GG CC AA) was present in 11.7%, being GG GG CT AA (22.4%) the most frequent profile. The results also demonstrated that 12.4% (58 out of 469) of São Miguel islanders have increased genetic predisposition to thrombosis. Subsequently, we evaluated these individuals for their warfarin response genetic profiles. The data showed that seven out of fifty-eight individuals are poor metabolizers (two with CYP2C9*2/*2 and five with CYP2C9*2/*3 genotypes). VKORC1 polymorphism analysis identified twelve individuals (20.7%) with AA genotype, who probably will require lower doses of warfarin. The joint analysis of CYP2C9 and VKORC1 revealed that 79.3% (46 out of 58) of the individuals carry at least one polymorphism in these genes. Within these, twenty-five individuals (43.1%) need intermediate and/or low doses of warfarin, if treatment is started. CONCLUSION: The present study demonstrated, for the first time, that São Miguel, and possibly the Azores population, shows significant differences on allele frequencies of thrombotic risk factors when compared to mainland Portugal. This research constitutes a primary approach for future studies on CVD, as well as for the implementation of warfarin dosing protocols using the patient's genotypic information.