A genome-wide scan for type 1 diabetes susceptibility genes in nuclear families with multiple affected siblings in Finland

<p>Abstract</p> <p>Background</p> <p>A genome-wide search for genes that predispose to type 1 diabetes using linkage analysis was performed using 900 microsatellite markers in 70 nuclear families with affected siblings from Finland, a population expected to be more genetically homogeneous than others, and having the highest incidence of type 1 diabetes in the world and, yet, the highest proportion in Europe of cases (10%) carrying neither of the highest risk <it>HLA </it>haplotypes that include DR3 or DR4 alleles.</p> <p>Results</p> <p>In addition to the evidence of linkage to the <it>HLA </it>region on 6p21 (nominal p = 4.0 × 10^-6), significant evidence of linkage in other chromosome regions was not detected with a single-locus analysis. The two-locus analysis conditional on the <it>HLA </it>gave a maximum lod score (MLS) of 3.1 (nominal p = 2 × 10^-4) on chromosome 9p13 under an additive model; MLS of 2.1 (nominal p = 6.1 × 10^-3) on chromosome 17p12 and MLS of 2.5 (nominal p = 2.9 × 10^-3) on chromosome 18p11 under a general model.</p> <p>Conclusion</p> <p>Our genome scan data confirmed the primary contribution of the <it>HLA </it>genes also in the high-risk Finnish population, and suggest that non-<it>HLA </it>genes also contribute to the familial clustering of type 1 diabetes in Finland.</p

Happamien sulfaattimaiden aiheuttamat vesistövaikutukset ja kalakuolemat Suomessa

Tähän kirjallisuuskatsaukseen on koottu kattavasti tietoa happamien sulfaattimaiden (HS-maat) vaikutuksista vesistöjemme vedenlaatuun, eliöstöön ja kalakuolemiin. Kirjallisuuskatsaus tehtiin Suomen ympäristökeskuksen koordinoiman CATERMASS-hankkeen yhteydessä laajan tutkijaryhmän yhteistyönä. Happamia sulfaattimaita muodostui Itämeren rehevissä rannikko-vesissä 4000–8000 vuotta sitten, kun mikrobit pelkistivät meriveden sulfaattia sulfidiksi. Maankohoamisen myötä sulfidisavikoita sisältäviä maita alettiin kuivata viljelyskäyttöön. Tällöin hapetusreaktiossa vapautuva rikki alkoi muodostaa maaperän veden kanssa rikkihappoa, joka liuottaa maaperästä myrkyllisiä metalleja, kuten alumiinia, kadmiumia ja kuparia. Runsaiden sateiden ja kevään sulamisvesien mukana happamuus ja metallit huuhtoutuvat vesistöön. Viime vuosikymmeninä lisääntyneen salaojituksen myötä peltojen kuivatus-syvyys on kasvanut lisäten samalla HS-maiden haitallisia vesistövaikutuksia. Happamuus ja siihen liittyvä metallien myrkyllisten olomuotojen runsastuminen aiheuttavat muutoksia vesistöjen kaikissa eliöryhmissä mukaan lukien kalat, pohjaeläimet, vesikasvit ja pohjalevät. Yksilötasolla on havaittu epämuodostumia, kuten vesihyönteistoukkien rakenne-vaurioita. Kalat yrittävät suojautua hengitysveden haitallisilta aineilta lisäämällä kidusten limaneritystä, jolloin hengitys vaikeutuu. Altistuminen happamuudelle ja metalleille haittaa kalojen lisääntymistä mm. viivästyttämällä munasolujen kypsymistä sekä vaikeuttamalla mätimunien hedelmöittymistä ja alkionkehitystä. Eliöyhteisötasolla HS-maiden vaikutus näkyy usein happamuudelle herkkien lajien tai lajiryhmien puuttumisena. Virtavesien kalalajeista happamuudelle herkkiä ovat esimerkiksi kivisimppu, made ja taimen, ja jokisuistojen pohjaeläinryhmistä esimerkiksi simpukat. HS-maiden aiheuttamista kalakuolemista joissa, järvissä, jokisuistoissa ja rannikkovesissä koottiin mahdollisimman kattava listaus, joka todentaa ongelmien keskittymistä Pohjanmaan alueelle. Pahiten happamuuden ja myrkyllisten metallien vaivaamat pikkujoet ovat olleet käytännössä kalattomia viimeisten vuosikymmenten ajan

Association Testing of Previously Reported Variants in a Large Case-Control Meta-analysis of Diabetic Nephropathy

We formed the GEnetics of Nephropathy–an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10−9). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated

Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness

Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no association was observed between sCD93 and IMT, sCD93 levels were significantly lower in subjects with type 2 diabetes (n = 901, mean ± SD 156.6 ± 40.0 ng/mL) compared with subjects without diabetes (n = 2,470, 164.1 ± 44.8 ng/mL, P < 0.0001). Genetic variants associated with diabetes risk (DIAGRAM Consortium) did not influence sCD93 levels (individually or combined in a single nucleotide polymorphism score). In a prospective cohort, lower sCD93 levels preceded the development of diabetes. Consistent with this, a cd93-deficient mouse model (in addition to apoe deficiency) demonstrated no difference in atherosclerotic lesion development compared with apoe(-/-) cd93-sufficient littermates. However, cd93-deficient mice showed impaired glucose clearance and insulin sensitivity (compared with littermate controls) after eating a high-fat diet. The expression of cd93 was observed in pancreatic islets, and leaky vessels were apparent in cd93-deficient pancreases. We further demonstrated that stress-induced release of sCD93 is impaired by hyperglycemia. Therefore, we propose CD93 as an important component in glucometabolic regulation

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe