Genes outside The Hla Region affecting Susceptibility to Type 1 Diabetes - The Role of Iddm2 and Iddm9 in the Finnish Population

Tyypin 1 diabeteksen perinnöllinen alttius Suomessa - HLA-alueen ulkopuolisten alttiuslokusten IDDM2 ja IDDM9 rooli taudin periytymisessä HLA-alue, joka sijaitsee kromosomissa 6p21.3, vastaa noin puolesta perinnöllisestä alttiudesta sairastua tyypin 1 diabetekseen. Myös HLA-alueen ulkopuolisten lokusten on todettu liittyvän sairausalttiuteen. Näistä kolmen lokuksen on varmistettu olevan todellisia alttiuslokuksia ja lisäksi useiden muiden, vielä varmistamattomien lokusten, on todettu liittyvän sairausalttiuteen. Tässä tutkimuksessa 12:n HLA-alueen ulkopuolisen alttiuslokuksen kytkentä tyypin 1 diabetekseen tutkittiin käyttäen 107:aa suomalaista multiplex-perhettä. Jatkotutkimuksessa analysoitiin IDDM9-alueen kytkentä ja assosiaatio sairauteen laajennetuissa perhemateriaaleissa sekä IDDM2-alueen mahdollinen interaktio HLA-alueen kanssa sairauden muodostumisessa. Lisäksi suoritettiin IDDM2-alueen suojaavien haplotyyppien alatyypitys tarkoituksena tutkia eri haplotyyppien käyttökelpoisuutta sairastumisriskin tarkempaa ennustamista varten. Ensimmäisessä kytkentätutkimuksessa ei löytynyt koko genomin tasolla merkitsevää tai viitteellistä kytkentää tutkituista HLA-alueen ulkopuolisista lokuksista. Voimakkain havaittu nimellisen merkitsevyyden tavoittava kytkentä nähtiin IDDM9-alueen markkerilla D3S3576 (MLS=1.05). Tutkimuksessa ei kyetty varmistamaan tai sulkemaan pois aiempia kytkentähavaintoja tutkituilla lokuksilla, mutta IDDM9-alueen jatkotutkimuksessa havaittu voimakas kytkentä (MLS=3.4) ja merkitsevä assosiaatio (TDT p=0.0002) viittaa vahvasti siihen, että 3q21-alueella sijaitsee todellinen tyypin 1 diabeteksen alttiusgeeni, jolloin alueen kattava assosiaatiotutkimus olisi perusteltu jatkotoimenpide. Sairauteen altistava IDDM2-alueen MspI-2221 genotyyppi CC oli nimellisesti yleisempi matalan tai kohtalaisen HLA-sairastumisriskin diabeetikoilla, verrattuna korkean HLA-riskin potilaisiin (p=0.05). Myös genotyyppijakauman vertailu osoitti merkitsevää eroa ryhmien välillä (p=0.01). VNTR-haplotyyppitutkimus osoitti, että IIIA/IIIA-homotsygootin sairaudelta suojaava vaikutus on merkitsevästi voimakkaampi kuin muiden luokka III:n genotyypeillä. Nämä tulokset viittaavat IDDM2-HLA -vuorovaikutukseen sekä siihen että IDDM2-alueen haplotyyppien välillä esiintyy etiologista heterogeniaa. Tämän johdosta IDDM2-alueen haplotyyppien tarkempi määrittäminen voisi tehostaa tyypin 1 diabeteksen riskiarviointia.HLA region defines half of the genetic susceptibility to type 1 diabetes. Several susceptibility loci residing outside the HLA region have been reported and three loci have been confirmed to convey type 1 diabetes susceptibility. In the present study twelve of these loci were tested for linkage in 107 Finnish type 1 diabetes multiplex families. In the follow-up study, 121 Finnish type 1 diabetes multiplex families were analyzed for linkage across the IDDM9 region at 3q21, and 384 Finnish type 1 diabetes simplex families were analyzed for association with two markers in the same region. Additionally, the IDDM2 region was analyzed for interaction with HLA haplotypes of varying disease risk in order to assess its potential regarding refinement of disease risk prediction. In an additional attempt to refine the IDDM2 region disease risk prediction, subtyping of the protective VNTR class III haplotypes and an association study was performed in the Finnish and Swedish populations. No significant or suggestive linkage was found in the complete dataset outside the HLA region. The highest non-HLA LOD score was seen with the IDDM9 region marker D3S3576 (MLS=1.05). The follow-up study at the IDDM9 region revealed a stronger LOD score at the marker D3S1589 (MLS=3.4). Association with the disease was found close to D3S1589 with marker AFM203wd10 (TDT p=0.0002). Our linkage results did not confirm previous findings in other studies. The follow-up study revealed a LOD score close to genome-wide significance and a significant association at the 3q21 region which warrant a more comprehensive association study at this region. The predisposing MspI-2221 genotype CC was more common in diabetics with moderate or low HLA risk compared with the high risk group, and the genotype distribution between said groups also showed significant difference (p=0.05 and p=0.01 respectively). The VNTR analysis revealed a significantly stronger protective effect for the VNTR IIIA/IIIA genotype when compared to other class III genotypes. These findings suggest that etiological heterogeneity between protective lineages of the IDDM2 region possibly exist and that the HLA region could modify the IDDM2 risk and further that deconstructing the IDDM2 heterogeneity has potential in enhancing the sensitivity and specificity of type 1 diabetes risk estimation.Siirretty Doriast

Naisten ja miesten työuraerot Suomen teollisuuden kuukausipalkkaisella henkilöstöllä 2002–2020

Tutkimuksessa selvitetään sukupuolten työuraeroja ja niiden yhteyttä miesten ja naisten palkkaeroon Suomen teollisuuden vuosina 2002–2020 työuransa aloittaneilla kuukausipalkkaisilla palkansaajilla. Raportin avaa taloustieteellinen tutkimuskirjallisuuskatsaus sukupuolten työura- ja palkkaeroista. Tilastollisen tarkastelun perusteella naiset sijoittuvat aloitusvuotenaan selvästi miehiä suuremmalla todennäköisyydellä alimmille ammattihierarkian tasoille. Ylemmillä tasoilla sijoittumistodennäköisyydet suosivat miehiä. Sijoittumiseroja dominoivat sukupuolten koulutusalaerot. Myös palkat eriytyvät jo aloitusvuotena: puhdas keskipalkkaero on 22.6 prosenttiyksikköä miesten eduksi. Sukupuolten koulutusalasegregaatio selittää siitä yli puolet. Laajan taustatekijäjoukon kontrolloimisen jälkeen selittämätön palkkaero on vajaa neljä prosenttiyksikköä. Myös myöhemmässä urakehityksessä on sukupuolieroja. Kun urakehitys jaetaan neljään taitotasoon, miesten ylenemistodennäköisyys on naisia suurempi erityisesti tasojen 2 ja 3 välillä. Kun sekä sukupuolten ylenemistodennäköisyyksien ero että naisten osuus ovat selvästi suurimmillaan hierarkiatasolla 2, vaikuttaa siltä kuin tasojen 2 ja 3 välissä olisi naisten etenemistä ehkäisevä "lasikatto". Kuukausipalkan suhteen miehillä ammattihierarkkista siirtymää ylöspäin seuraa keskimäärin suurempi korotus ja alaspäin pienempi palkanlasku kuin naisilla

Nuorten kannabiksen käyttö, aivojen kehitys ja psykiatriset häiriöt

Kannabis on yleisin nuorten käyttämä laiton päihde.Nuoruus on herkkää aikaa kannabiksen haitoille, sillä keskushermosto kypsyy silloin laaja-alaisesti. Käyttö voi myöhemmin altistaa mielenterveysongelmille ja päihdehäiriölle.Kannabista käyttävien nuorten ja nuorten aikuisten psyykkistä vointia on syytä arvioida rutiinisti, etenkin jos suvussa esiintyy vakavia mielenterveyden häiriöitä

Non-HLA Gene Polymorphisms in the Pathogenesis of Type 1 Diabetes : Phase and Endotype Specific Effects

The non-HLA loci conferring susceptibility to type 1 diabetes determine approximately half of the genetic disease risk, and several of them have been shown to affect immune-cell or pancreatic beta-cell functions. A number of these loci have shown associations with the appearance of autoantibodies or with progression from seroconversion to clinical type 1 diabetes. In the current study, we have re-analyzed 21 of our loci with prior association evidence using an expanded DIPP follow-up cohort of 976 autoantibody positive cases and 1,910 matched controls. Survival analysis using Cox regression was applied for time periods from birth to seroconversion and from seroconversion to type 1 diabetes. The appearance of autoantibodies was also analyzed in endotypes, which are defined by the first appearing autoantibody, either IAA or GADA. Analyzing the time period from birth to seroconversion, we were able to replicate our previous association findings at PTPN22, INS, and NRP1. Novel findings included associations with ERBB3, UBASH3A, PTPN2, and FUT2. In the time period from seroconversion to clinical type 1 diabetes, prior associations with PTPN2, CD226, and PTPN22 were replicated, and a novel association with STAT4 was observed. Analyzing the appearance of autoantibodies in endotypes, the PTPN22 association was specific for IAA-first. In the progression phase, STAT4 was specific for IAA-first and ERBB3 to GADA-first. In conclusion, our results further the knowledge of the function of non-HLA risk polymorphisms in detailing endotype specificity and timing of disease development.Peer reviewe

Decreased maximum clot firmness in rotational thromboelastometry (ROTEM (R)) is associated with bleeding during extracorporeal mechanical circulatory support

Background: We aimed to characterize the coagulation disturbances which may increase the risk of bleeding, thrombosis or death shortly after implantation of an extracorporeal membrane oxygenation (ECMO) or ventricular assist (VAD) device. Methods: Antithrombotic treatment was started in 23 VAD and 24 ECMO patients according to the hospital protocol. Additionally, conventional laboratory testing, rotational thromboelastometry (ROTEM (R)) and platelet function analysis (Multiplate) were performed at predetermined intervals. Results: Four out of twenty-four (16.7%) of ECMO patients and 6/23 (26.1%) of VAD patients had severe bleeding after the procedure. When all the patients were analyzed together, low maximum clot firmness (MCF) in ExTEM and FibTEM analyses was associated with severe bleeding (p Conclusion: Hypocoagulation shown by ROTEM (R) was associated with bleeding complications in patients with mechanical circulatory support. In contrast, hypercoagulation did not correlate with clinical thrombosis.Peer reviewe

Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

Objectives We aimed to further characterize demography and genetic associations of type 1 diabetes "endotypes" defined by the first appearing islet specific autoantibodies. Research Design and Methods We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity.Peer reviewe

Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes

Objectives We aimed to further characterize demography and genetic associations of type 1 diabetes "endotypes" defined by the first appearing islet specific autoantibodies. Research Design and Methods We analyzed 3277 children diagnosed before the age of 10 years from the Finnish Pediatric Diabetes Register. The most likely first autoantibody could be deduced in 1636 cases (49.9%) based on autoantibody combinations at diagnosis. Distribution of age, sex, HLA genotypes and allele frequencies of 18 single nucleotide polymorphisms (SNPs) in non-HLA risk genes were compared between the endotypes. Results Two major groups with either glutamic acid decarboxylase (GADA) or insulin autoantibodies (IAA) as the deduced first autoantibody showed significant differences in their demographic and genetic features. Boys and children diagnosed at young age had more often IAA-initiated autoimmunity whereas GADA-initiated autoimmunity was observed more frequently in girls and in subjects diagnosed at an older age. IAA as the first autoantibody was also most common in HLA genotype groups conferring high-disease risk while GADA first was seen more evenly and frequently in HLA groups associated with lower type 1 diabetes risk. The risk alleles in IKZF4 and ERBB3 genes were associated with GADA-initiated whereas those in PTPN22, INS and PTPN2 genes were associated with IAA-initiated autoimmunity. Conclusions The results support the assumption that in around half of the young children the first autoantibody can be deduced based on islet autoantibody combinations at disease diagnosis. Strong differences in sex and age distributions as well as in genetic associations could be observed between GADA- and IAA-initiated autoimmunity.Peer reviewe

Characteristics of Slow Progression to Type 1 Diabetes in Children With Increased HLA-Conferred Disease Risk

Context: Characterization of slow progression to type 1 diabetes (T1D) may reveal novel means for prevention of T1D. Slow progressors might carry natural immunomodulators that delay beta-cell destruction and mediate preservation of beta-cell function. Objective: To identify demographic, genetic, and immunological characteristics of slow progression from seroconversion to clinical T1D. Design: H LA-susceptible children (n = 7410) were observed from birth for islet cell antibody (ICA), insulin autoantibody (IAA), glutamic acid decarboxylase (GADA), and islet antigen-2 autoantibodies (IA-2A), and for clinical T1D. Disease progression that lasted >= 7.26 years (slowest) quartile from initial seroconversion to diagnosis was considered slow. Autoantibody and genetic characteristics including 45 non-HLA single nucleotide polymorphisms (SNPs) predisposing to T1D were analyzed. Results: By the end of 2015, 1528 children (21 %) had tested autoantibody positive and 247 (16%) had progressed to T1D. The median delay from seroconversion to diagnosis was 8.7 years in slow (n = 62, 25%) and 3.0 years in other progressors. Compared with other progressors, slow progressors were less often multipositive, had lower ICA and IAA titers, and lower frequency of IA-2A at seroconversion. Slow progressors were born more frequently in the fall, whereas other progressors were born more often in the spring. Compared with multipositive nonprogressors, slow progressors were younger, had higher ICA titers, and higher frequency of IAA and multiple autoantibodies at seroconversion. We found no differences in the distributions of non-HLA SNPs between progressors. Conclusions: We observed differences in autoantibody characteristics and the season of birth among progressors, but no characteristics present at seroconversion that were specifically predictive for slow progression.Peer reviewe

HLA and non-HLA genes and familial predisposition to autoimmune diseases in families with a child affected by type 1 diabetes

Genetic predisposition could be assumed to be causing clustering of autoimmunity in individuals and families. We tested whether HLA and non-HLA loci associate with such clustering of autoimmunity. We included 1,745 children with type 1 diabetes from the Finnish Pediatric Diabetes Register. Data on personal or family history of autoimmune diseases were collected with a structured questionnaire and, for a subset, with a detailed search for celiac disease and autoimmune thyroid disease. Children with multiple autoimmune diseases or with multiple affected first-or second-degree relatives were identified. We analysed type 1 diabetes related HLA class II haplotypes and genotyped 41 single nucleotide polymorphisms (SNPs) outside the HLA region. The HLA-DR4-DQ8 haplotype was associated with having type 1 diabetes only whereas the HLA-DR3-DQ2 haplotype was more common in children with multiple autoimmune diseases. Children with multiple autoimmune diseases showed nominal association with RGS1 (rs2816316), and children coming from an autoimmune family with rs11711054 (CCR3-CCR5). In multivariate analyses, the overall effect of non-HLA SNPs on both phenotypes was evident, associations with RGS1 and CCR3-CCR5 region were confirmed and additional associations were implicated: NRP1, FUT2, and CD69 for children with multiple autoimmune diseases. In conclusion, HLA-DR3-DQ2 haplotype and some non-HLA SNPs contribute to the clustering of autoimmune diseases in children with type 1 diabetes and in their families.Peer reviewe