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Germline genetic testing has implications that extend beyond the individual patient to relatives, particularly for high-penetrance variants implicated in hereditary cancer or neurodegenerative syndromes. Many countries encourage patient-led communication to inform at-risk relatives, although the efficacy and uptake of this approach varies. Alternative scenarios envisage direct contact mediated by clinicians. The familial disclosure of sensitive genetic information is also determined by complex socio-ethnic factors. To date, no study has explored whether relatives would want to be informed of familial genetic risk and their preferences on different methods of communication in Malta. We thus used a published instrument that utilizes hypothetical scenario methodology to survey the attitudes of the Maltese population (n = 334) to receiving genetic information from family members. Two vignettes on Huntington's disease and colorectal cancer were presented. We also explored preferences towards the communication of genetic risk, confidentiality, and disclosure policies. Our preliminary results show that most respondents want to be informed of their increased risk by a family member or a clinician and would opt to receive confirmatory genetic testing. Most respondents preferred being informed of genetic risk by a close relative, but in the case of non-disclosure would want to be informed by a clinician. Most respondents expressed preference in favour of the introduction of registries, legislative change and sharing of contact details to address cases of nondisclosure. Our findings contribute further to evidence that supports, in selected hypothetical scenarios, an envisioned change in disclosure of genetic data policy by the public that is different from current practice to date.

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Background: Insulin resistance (IR) is associated with increased cardiovascular disease risk, and with increased all-cause, cardiovascular, and cancer mortality. A number of surrogate markers are used in clinical practice to diagnose IR. The aim of this study was to investigate the discriminatory power of a number of routinely available anthropometric and biochemical variables in predicting IR and to determine their optimal cutoffs. Methods: We performed a cross-sectional study in a cohort of middle-aged individuals. We used receiver operator characteristics (ROC) analyses in order to determine the discriminatory power of parameters of interest in detecting IR, which was defined as homeostatic model assessment-insulin resistance ≥2.5. Results: Both the lipid accumulation product (LAP) and visceral adiposity index (VAI) exhibited good discriminatory power to detect IR in both males and females. The optimal cutoffs were 42.5 and 1.44, respectively, in males and 36.2 and 1.41, respectively, in females. Serum triglycerides (TG) and waist circumference (WC) similarly demonstrated good discriminatory power in detecting IR in both sexes. The optimal cutoffs for serum TG and WC were 1.35 mmol/L and 96.5 cm, respectively, in men and 1.33 mmol/L and 82 cm, respectively, in women. On the other hand, systolic and diastolic blood pressure, liver transaminases, high-density lipoprotein cholesterol, serum uric acid, ferritin, waist-hip ratio, "A" body shape, thigh circumference, and weight-adjusted thigh circumference all had poor discriminatory power. Conclusions: Our data show that LAP, VAI, TG, and WC all have good discriminatory power in detecting IR in both men and women. The optimal cutoffs for TG and WC were lower than those currently recommended in both sexes. Replication studies are required in different subpopulations and different ethnicities in order to be able to update the current cut points to ones which reflect the contemporary population as well as to evaluate their longitudinal relationship with longer-term cardiometabolic outcomes.

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Hidradenitis suppurativa is a chronic, inflammatory condition of the pilosebaceous unit in which patients manifest multiple, painful cutaneous nodules, abscesses and tunnels. These lesions are described to affect the intertriginous zones, however, the condition exhibits significant phenotypic variability. Such variability is influenced by the patients lifestyle, genetic predisposition and sex. In this cross-sectional study, we investigate sex differences in patterns of hidradenitis suppurativa skin involvement, specifically at site of first involvement and most bothersome cutaneous site of involvement.

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BACKGROUND: Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI. OBJECTIVES: In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes. METHODS: 814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored. RESULTS: A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution. CONCLUSION: This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.

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Over the past 4 decades, research has shown that having a normal body weight does not automatically imply preserved metabolic health and a considerable number of lean individuals harbour metabolic abnormalities typically associated with obesity. Conversely, excess adiposity does not always equate with an abnormal metabolic profile. In fact, evidence exists for the presence of a metabolically unhealthy normal weight (MUHNW) and a metabolically healthy obese (MHO) phenotype. It has become increasingly recognised that different fat depots exert different effects on the metabolic profile of each individual by virtue of their location, structure and function, giving rise to these different body composition phenotypes. Furthermore, other factors have been implicated in the aetiopathogenesis of the body composition phenotypes, including genetics, ethnicity, age and lifestyle/behavioural factors. Even though to date both MHO and MUHNW have been widely investigated and documented in the literature, studies report different outcomes on long-term cardiometabolic morbidity and mortality. Future large-scale, observational and population-based studies are required for better profiling of these phenotypes as well as to further elucidate the pathophysiological role of the adipocyte in the onset of metabolic disorders to allow for better risk stratification and a personalised treatment paradigm.

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Importance: Hidradenitis suppurativa (HS) is a complex trait that has a monogenic etiology in a subset of patients. Variation in genes that encode proteins of the γ secretase complex, particularly NCSTN, account for few patients who exhibit familial forms of HS. Thus far, extensive genotype-phenotype correlations have been lacking. Objective: To establish the prevalence of the NCSTN:c.671_682del variant and explore potential genotype-phenotype associations in an ethnically Maltese HS cohort. Design, Setting, and Participants: This cross-sectional study conducted from December 2021 to September 2022 included patients 18 years or older with a diagnosis of HS as defined by recurrent nodules, abscesses, and/or draining tunnels in typical (axilla, breast, groin, buttock, thighs, and inframammary folds) and less typical (scalp, ear pinnae, neck, arms, antecubital fossae) sites who were recruited from the sole national dermatology reference center servicing the Maltese archipelago. Clinical examination and targeted genetic analysis for an NCSTN deletion that was originally identified through whole-exome sequencing in a family with multigenerational disease were performed. Exposure: Recruited patients were phenotyped and genotyped for the NCSTN:c.671_682del variant. Main Outcome and Measures: To determine the prevalence of the NCSTN:c.671_682del variant and establish possible genotype-phenotype associations in the ethnically Maltese HS cohort. Results: A total of 113 patients with HS (56 women [49.6%]) met the inclusion criteria and were enrolled in this study. The median age of disease onset was 18 years (range, 7-62 years), and the median International Hidradenitis Suppurativa Severity Score System score was 4.39 (range, 1.0-64.0). The NCSTN variant was identified in the heterozygous state in 14 patients (12.4%) from 5 unrelated, nonconsanguineous families of Maltese ethnicity. The variant was not identified in an ethnically matched reference genomic data set of disease-free individuals. Variant carriers manifested HS symptoms earlier and were more likely to exhibit a distinctive HS phenotype, which was characterized by involvement of the scalp, neck, torso, and antecubital fossae. Despite manifesting similar clinical disease severity, variant carriers were more likely to require treatment with adalimumab. Conclusions and Relevance: The results of this cross-sectional study suggest that monogenic variation in NCSTN is associated with HS in a subset of patients who have a distinct, atypical phenotype.

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Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.

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BACKGROUND: Obesity and hidradenitis suppurativa (HS) are related through meta-inflammation and are both associated with increased cardiometabolic risk. Notwithstanding, cardiometabolic pathology is not uniform in obesity and a subset of individuals with excess adiposity exhibit a healthy metabolic profile. Whilst the incidence of cardiometabolic endpoints and transitions across different adiposity-related body composition phenotypes within several populations and across different ethnicities have been investigated, data regarding metabolic health (MetH) and body composition phenotypes in individuals with HS are lacking. The objective of this study was to evaluate the relationship between different body composition phenotypes in individuals with HS. METHODS: This was a cross-sectional study of 632 individuals with and without HS from a population with a high prevalence of both obesity and HS. A total of four body composition phenotypes were generated based on BMI and metabolic status (defined using either the metabolic syndrome definition or the homeostasis model of insulin resistance (HOMA-IR)): metabolically healthy overweight/obese (MHOWOB), metabolically unhealthy overweight/obese (MUOWOB), metabolically healthy normal weight (MHNW), and metabolically unhealthy normal weight (MUNW). RESULTS: Generally, subjects with HS exhibited a worse metabolic profile with higher levels of indices of central adiposity measures (including Visceral Adiposity Index and waist circumference), systolic blood pressure and markers of insulin resistance, as well as a higher prevalence of the metabolic syndrome. Moreover, when sub-stratified into the different body composition phenotypes, individuals with HS typically also demonstrated adverse metabolic characteristics relative to controls matched for both adiposity and metabolic health, particularly in the normal weight category and despite being classified as metabolically healthy. Being metabolically unhealthy in addition to being overweight/obese increases an individual's risk of HS. CONCLUSIONS: Metabolic risk-assessment should be prioritized in the clinical management of individuals with HS even in those who are lean. Patients attending HS clinics provide a valuable opportunity for targeted cardiovascular risk reduction with respect to the management of both obesity and metabolic health.

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Hidradenitis suppurativa (HS) is a chronic, inflammatory condition of the pilosebaceous unit. The typical patient with HS is characterized as someone with obesity, who smokes and who has nodules, abscesses and/or draining tunnels predominantly distributed in intertriginous skin. It has been established that lifestyle and genetic factors are the main pathophysiological drivers of HS. In this critical review, we explore the interrelatedness of meta-inflammation, obesity and HS and discuss if and how this relationship may be manipulated for a therapeutic end.

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INTRODUCTION: Adipose tissue is the source of a broad array of signalling molecules (adipokines), which mediate interorgan communication and regulate metabolic homeostasis. Alterations in adipokine levels have been causally implicated in various metabolic disorders, including changes in bone mass. Osteoporosis is the commonest progressive metabolic bone disease, characterized by elevated risk of fragility fractures as a result of a reduced bone mass and microarchitectural deterioration. The effects of different adipokines on bone mass have been studied in an attempt to identify novel modulators of bone mass or diagnostic biomarkers of osteoporosis. METHODS: In this review, we sought to aggregate and assess evidence from independent studies that quantify specific adipokines and their effect on bone mineral density (BMD). RESULTS: A literature search identified 57 articles that explored associations between different adipokines and BMD. Adiponectin and leptin were the most frequently studied adipokines, with most studies demonstrating that adiponectin levels are associated with decreased BMD at the lumbar spine and femoral neck. Conversely, leptin levels are associated with increased BMD at these sites. However, extensive heterogeneity with regards to sample size, characteristics of study subjects, ethnicity, as well as direction and magnitude of effect at specific skeletal anatomical sites was identified. The broad degree of conflicting findings reported in this study can be attributed several factors. These include differences in study design and ascertainment criteria, the analytic challenges of quantifying specific adipokines and their isoforms, pre-analytical variables (in particular patient preparation) and confounding effects of co-existing disease. CONCLUSIONS: This review highlights the biological relevance of adipokines in bone metabolism and reinforces the need for longitudinal research to elucidate the causal relationship of adipokines on bone mass.

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Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the pilosebaceous unit characterized by inflammation and hyperkeratinization. A small but significant proportion of patients with HS have a strong genetic susceptibility to (or a syndromic form of) the disease. Current HS treatment guidelines prioritize patients who manifest classic HS and may therefore not be suitable for the minority of patients harbouring genetically driven forms of disease. In this manuscript, we review the extant literature with regards to therapeutic strategies used for patients with HS having disease-associated genetic variants and syndromic forms of the condition. The findings of this review suggest that patients with HS harbouring underlying genetic variants may not be adequately represented in current European and British HS treatment guidelines. Moreover, these patients may be less responsive to the recommended therapeutic options. We therefore make recommendations for future therapeutic guidelines to incorporate considerations for the management of this patient subset.

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Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the skin that is brought about by autoinflammation and hyperkeratosis at the pilosebaceous unit. The clinical severity of HS can be measured using static (Hurley Severity Scoring (HSS)) and/or dynamic (International HS Severity Scoring System (IHS4)) severity scoring instruments. However, few clinically available serological parameters have been found to correlate with disease severity. In this study, we sought to investigate the role of serum immunoglobulin (Ig) G, M and A levels as biomarkers of disease severity and to compare them with other, more conventional inflammatory indices, such as the erythrocyte sedimentation rate, C-reactive protein, the neutrophil-lymphocyte ratio, the platelet-lymphocyte ratio and the systemic immune-inflammation index. In this cross-sectional study, patients were recruited from the only dermatology referral centre in Malta, Europe, and subjected to clinical examination and the assessment of inflammatory and immunologic parameters. Serum IgG, M and A levels were assessed using the Atellica® NEPH 630 System (SIEMENS-Healthineers AF, Erlangen, Germany) nephelometric analyser. Serum IgG, M and A levels correlate with both dynamic and static HS severity scoring systems. Serum IgG behaves as a marker of severe HS disease as categorised by HSS and the IHS4. Our findings suggest that the serum IgG level can be used in the clinical setting as a biomarker of disease severity and, therefore, as an adjunct to clinical severity scoring.

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Hidradenitis suppurativa (HS) is a disease of the pilosebaceous unit characterized by recurrent nodules, abscesses and draining tunnels with a predilection to intertriginous skin. The pathophysiology of HS is complex. However, it is known that inflammation and hyperkeratinization at the hair follicle play crucial roles in disease manifestation. Genetic and environmental factors are considered the main drivers of these two pathophysiological processes. Despite a considerable proportion of patients having a positive family history of disease, only a minority of patients suffering from HS have been found to harbor monogenic variants which segregate to affected kindreds. Most of these variants are in the ɣ secretase complex (GSC) protein-coding genes. In this manuscript, we set out to characterize the burden of missense pathogenic variants in healthy reference population using large scale genomic dataset thereby providing a standard for comparing genomic variation in GSC protein-coding genes in the HS patient cohort.

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Objective: This study aimed to investigate the associations between peripheral blood leukocyte mitochondrial copy number, metabolic syndrome, and adiposity-related body composition phenotypes in a high prevalence population. Methods: A single center cross-sectional study was conducted, consisting of 521 middle-aged subjects of Maltese-Caucasian ethnicity. Participants were stratified according to the presence of metabolic syndrome and different metabolic health definitions based on NCEP-ATP III criteria. Relative leukocyte mitochondrial DNA copy number was determined by quantitative polymerase chain reaction and corrected for leukocyte and platelet count. The associations between mitochondrial copy number and metabolic syndrome components was evaluated and adjusted for age and gender. Results: Significant negative correlations between mtDNA copy number and BMI, waist circumference, triglyceride levels, fasting plasma glucose, HbA1c, HOMA-IR and hsCRP were observed, along with a positive correlation with HDL-C levels. Mitochondrial copy number was lower in individuals with metabolic syndrome. When compared to metabolically healthy normal weight subjects, a reduction in mtDNA copy number was observed in both the metabolically healthy and unhealthy obese categories. Conclusion: Our data supports the association between reduced leukocyte mtDNA copy number, obesity, and metabolic syndrome. This investigation expands on the spectrum of associations between mtDNA copy number and metabolic phenotypes in different populations and underpins the role of mitochondrial dysfunction in the development and progression of metabolic syndrome and its components.

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INTRODUCTION: Hyperinsulinemia and insulin resistance are known to be associated with increased cardiovascular morbidity and mortality. A metabolically unhealthy phenotype is frequently used as a surrogate marker for insulin resistance. The aims of the current study were to compare the prevalence of the body size phenotypes using different definitions of metabolic health and to investigate which one of them is most strongly associated with insulin resistance in men and women. METHODS: We conducted a cross-sectional study in a middle-aged cohort of Maltese Caucasian non-institutionalized population. Metabolic health was defined using the various currently used definitions. RESULTS: There were significant differences in the prevalence of body size phenotypes according to the different definitions. We also found significant sex differences in the predictive value of the various definitions of the metabolically unhealthy phenotype to predict insulin resistance. The strongest association was for the definition of having >2 NCEP-ATPIII criteria to characterize the metabolic unhealthy phenotype in women (odds ratio of 19.7). On the other hand, the Aguilar-Salinas et al. definition had the strongest association in men (odds ratio of 18.7). CONCLUSIONS: We found large differences in the prevalence of the various body size phenotypes when using different definitions, highlighting the need for having standard criteria. Our data also suggest the need for sex-specific definitions of metabolic health.

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Hidradenitis suppurativa is a chronic, suppurative condition of the pilosebaceous unit manifesting as painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin. Great strides have been made at elucidating the pathophysiology of hidradenitis suppurativa, which appears to be the product of hyperkeratinization and inflammation brought about by environmental factors and a genetic predisposition. The identification of familial hidradenitis suppurativa has sparked research aimed at identifying underlying pathogenic variants in patients who harbor them. The objective of this review is to provide a broad overview of the role of genetics in various aspects of hidradenitis suppurativa, specifically the pathophysiology, diagnosis, and clinical application.