In developed countries, the majority of all violent crime is committed by a small group of antisocial recidivistic offenders, but no genes have been shown to contribute to recidivistic violent ...offending or severe violent behavior, such as homicide. Our results, from two independent cohorts of Finnish prisoners, revealed that a monoamine oxidase A (MAOA) low-activity genotype (contributing to low dopamine turnover rate) as well as the CDH13 gene (coding for neuronal membrane adhesion protein) are associated with extremely violent behavior (at least 10 committed homicides, attempted homicides or batteries). No substantial signal was observed for either MAOA or CDH13 among non-violent offenders, indicating that findings were specific for violent offending, and not largely attributable to substance abuse or antisocial personality disorder. These results indicate both low monoamine metabolism and neuronal membrane dysfunction as plausible factors in the etiology of extreme criminal violent behavior, and imply that at least about 5-10% of all severe violent crime in Finland is attributable to the aforementioned MAOA and CDH13 genotypes.
Somatic mutations contribute to tumorigenesis. Although these mutations occur in all proliferating cells, their accumulation under non-malignant conditions, such as in autoimmune disorders, has not ...been investigated. Here, we show that patients with newly diagnosed rheumatoid arthritis have expanded CD8+ T-cell clones; in 20% (5/25) of patients CD8+ T cells, but not CD4+ T cells, harbour somatic mutations. In healthy controls (n=20), only one mutation is identified in the CD8+ T-cell pool. Mutations exist exclusively in the expanded CD8+ effector-memory subset, persist during follow-up, and are predicted to change protein functions. Some of the mutated genes (SLAMF6, IRF1) have previously been associated with autoimmunity. RNA sequencing of mutation-harbouring cells shows signatures corresponding to cell proliferation. Our data provide evidence of accumulation of somatic mutations in expanded CD8+ T cells, which may have pathogenic significance for RA and other autoimmune diseases.
Each year, almost 1 million people die from suicide, which is among the leading causes of death in young people. We studied how birth order was associated with suicide and other main causes of death. ...A follow-up study based on the Swedish population register was conducted for sibling groups born from 1932 to 1980 who were observed during the period 1981-2002. Focus was on the within-family variation in suicide risk, meaning that we studied sibling groups that consisted of 2 or more children in which at least 1 died from suicide. These family-fixed effects analyses revealed that each increase in birth order was related to an 18% higher suicide risk (95% confidence interval (CI): 1.14, 1.23, P = 0.000). The association was slightly lower among sibling groups born in 1932-1955 (hazard ratio = 1.13, 95% CI: 1.06, 1.21, P = 0.000) than among those born in 1967-1980 (hazard ratio = 1.24, 95% CI: 0.97, 1.57, P = 0.080). Further analyses suggested that the association between birth order and suicide was only modestly influenced by sex, birth spacing, size of the sibling group, own socioeconomic position, own marital status, and socioeconomic rank within the sibling group. Causes of death other than suicide and other external causes were not associated with birth order.
The objective of the article was to analyse how Finnish and Swedish speakers in Finland differ in health and labour market outcomes after sickness absence. Apart from many similarities, these two ...population groups differ in life expectancy and union stability and are supposed to be culturally distinct. Our analyses, therefore, help to shed light on the interrelation between culture and health.
We monitored health and labour market-related status 3 years after the first sickness absence.
The register-based longitudinal data covered the years 1988–2010. Multinomial logistic regressions were used to quantify the odds of being unemployed, retired due to disability, otherwise outside the labour force or dead, as compared with being employed. The analyses were controlled for age, educational level, region of residence, population density, birth region, family status, job industry, income, homeownership, time period and time on sick leave.
Unemployment after sickness absence was notably more common for Finnish speakers than for Swedish speakers. In the fully adjusted models, the odds ratios were 1.48 (95% confidence interval CI 1.23–1.67) in men and 1.29 (95% CI 1.07–1.48) in women. Disability pension, being outside the labour force and having died were also more frequent outcomes for Finnish speakers than for Swedish speakers, although most of this variation could be attributed to socio-economic and demographic characteristics.
The article illustrates that register-based analyses can be effective tools for assessing and identifying persons with latent problems that impede their functioning in the labour market. These findings also suggest that culturally related factors presumably play an important role in this concern.
•Registered sickness absences describe well the health of the working population.•In contrast to most previous research, indigenous population groups are compared.•Return to work after sickness absence is more difficult for Finnish speakers.
Background
Hereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss‐of‐function variants in a serine ...peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima‐type PPK (NPPK) caused by biallelic variants in SERPINB7.
Objectives
The aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease‐related hPPKs caused by variants in SERPINA12 and SERPINB7.
Methods
Whole‐exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12‐ and SERPINB7‐related hPPKs was summarized.
Results
The phenotype of SERPINA12‐related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non‐palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis.
Conclusions
Recessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non‐Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis.
Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively ...induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials.
Background
PPKs represent a heterogeneous group of disorders with hyperkeratosis of palmar and/or plantar skin. PPK, hair shaft abnormalities, cardiomyopathy and arrhythmias can be caused by ...mutations in desmosomal genes, e.g. desmoplakin (DSP). PPK should trigger genetic testing to reveal mutations with possible related cardiac disease.
Objectives
To report a large multigenerational family with a novel DSP mutation associated with early‐onset PPK and adult‐onset cardiomyopathy and arrhythmias.
Methods
A custom‐designed in‐house panel of 35 PPK related genes was used to screen mutations in the index patient with focal PPK. The identified DSP mutation was verified by Sanger sequencing. DNA samples from 20 members of the large multigenerational family were sequenced for the DSP mutation. Medical records were reviewed. Clinical dermatological evaluation was performed, including light microscopy of hair samples. Cardiac evaluation included clinical examination, echocardiography, cardiac magnetic resonance imaging (CMR), electrocardiogram (ECG), Holter monitoring and laboratory tests.
Results
We identified a novel autosomal dominant truncating DSP c.2493delA p.(Glu831Aspfs*33) mutation associated with dilated cardiomyopathy (DCM) with arrhythmia susceptibility and focal PPK as an early cutaneous sign. The mutation was found in nine affected family members, but not in any unaffected members. Onset of dermatological findings preceded cardiac symptoms which were variable and occurred at adult age.
Conclusions
We report a novel truncating DSP mutation causing focal PPK with varying severity and left ventricular dilatation and ventricular extrasystoles. This finding emphasizes the importance of genetic diagnosis in patients with PPK for clinical counselling and management of cardiomyopathies and arrhythmias.
Hereditary palmoplantar keratoderma – phenotypes and mutations in 64 patients Harjama, L.; Karvonen, V.; Kettunen, K. ...
JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology,
September 2021, Letnik:
35, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Background
Hereditary palmoplantar keratodermas (PPK) represent a heterogeneous group of rare skin disorders with epidermal hyperkeratosis of the palms and soles, with occasional additional ...manifestations in other tissues. Mutations in at least 69 genes have been implicated in PPK, but further novel candidate genes and mutations are still to be found.
Objectives
To identify mutations underlying PPK in a cohort of 64 patients.
Methods
DNA of 48 patients was analysed on a custom‐designed in‐house panel for 35 PPK genes, and 16 patients were investigated by a diagnostic genetic laboratory either by whole‐exome sequencing, gene panels or targeted single‐gene sequencing.
Results
Of the 64 PPK patients, 32 had diffuse (50%), 19 focal (30%) and 13 punctate (20%) PPK. None had striate PPK. Pathogenic mutations in altogether five genes were identified in 31 of 64 (48%) patients, the majority (22/31) with diffuse PPK. Of them, 11 had a mutation in AQP5, five in SERPINB7, four in KRT9 and two in SLURP1. AAGAB mutations were found in nine punctate PPK patients. New mutations were identified in KRT9 and AAGAB. No pathogenic mutations were detected in focal PPK. Variants of uncertain significance (VUS) in PPK‐associated and other genes were observed in 21 patients that might explain their PPK. No suggestive pathogenic variants were found for 12 patients.
Conclusions
Diffuse PPK was the most common (50%) and striate PPK was not observed. We identified pathogenic mutations in 48% of our PPK patients, mainly in five genes: AQP5, AAGAB, KRT9, SERPINB7 and SLURP1.
In this issue of the Journal, Bjørngaard et al. give us new insights into the etiology of mental health by studying birth order and suicide risk (Am J Epidemiol. 2013;177(7):638-644). Although the ...authors provided empirical evidence that each increase in birth order (i.e., from first-born to second-born, second-born to third-born, etc.) is associated with a 46% higher suicide risk, they gave us very little information on the likely explanations. In our commentary, we draw attention to the possible mechanisms underlying a causal relationship between birth order and suicide. Given that Norway is one of the richest countries in the world, the findings of Bjørngaard et al. in a Norwegian cohort also call for a discussion of whether their results are representative of other societies that are similar or dissimilar with respect to economic institutions, social conditions, and political environment. We suggest that there are several plausible mechanisms to explain higher suicide rates among later-born children, but other mechanisms might also operate in the opposite direction, that is, have beneficial outcomes among later-born children. Specifically, there are reasons to expect a different relationship between birth order and psychiatric outcomes in poorer societal contexts.
BackgroundAlthough recent genome-wide association studies have identified several genetic variants contributing to the complex aetiology of multiple sclerosis (MS), expression and functional studies ...are required to further understand its molecular basis.ObjectivesTo identify genes and pathways with differential expression in MS.DesignThe authors conducted a systematic review of seven microarray studies, in which expression in immune cells was compared between MS patients and controls. These studies include a previously unpublished study, which is described here in detail.Results and conclusionAlthough in general the overlap between studies was poor, 229 genes were found to be differentially expressed in MS in at least two studies, of which 11 were in three studies and HSPA1A in four studies. After excluding the authors' unpublished experiment which may have been affected by certain confounding factors and inclusion of treated subjects, 135 genes were identified in at least two studies. The differentially expressed genes were significantly associated with several immunological pathways, including interleukin (IL)-4, IL-6, IL-17 and glucocorticoid receptor signalling pathways. 15 of the 229 loci have shown some association with MS in published genome-wide association studies (p<0.0001), including three loci with confirmed MS risk variants.
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