Family-Based Association Analysis Confirms the Role of the Chromosome 9q21.32 Locus in the Susceptibility of Diabetic Nephropathy

A genome-wide association scan of type 1 diabetic patients from the GoKinD collections previously identified four novel diabetic nephropathy susceptibility loci that have subsequently been shown to be associated with diabetic nephropathy in unrelated patients with type 2 diabetes. To expand these findings, we examined whether single nucleotide polymorphisms (SNPs) at these susceptibility loci were associated with diabetic nephropathy in patients from the Joslin Study of Genetics of Nephropathy in Type 2 Diabetes Family Collection. Six SNPs across the four loci identified in the GoKinD collections and 7 haplotype tagging SNPs, were genotyped in 66 extended families of European ancestry. Pedigrees from this collection contained an average of 18.5 members, including 2 to 14 members with type 2 diabetes. Among diabetic family members, the 9q21.32 locus approached statistical significance with advanced diabetic nephropathy (P = 0.037 [adjusted P = 0.222]). When we expanded our definition of diabetic nephropathy to include individuals with high microalbuminuria, the strength of this association improved significantly (P = 1.42×10−3 [adjusted P = 0.009]). This same locus also trended toward statistical significance with variation in urinary albumin excretion in family members with type 2 diabetes (P = 0.032 [adjusted P = 0.192]) and in analyses expanded to include all relatives (P = 0.019 [adjusted P = 0.114]). These data increase support that SNPs identified in the GoKinD collections on chromosome 9q21.32 are true diabetic nephropathy susceptibility loci

Palaeoenvironments and palaeoceanography changes across the Jurassic/Cretaceous boundary in the Arctic realm: case study of the Nordvik section (north Siberia, Russia)

The Jurassic/Cretaceous transition was accompanied by significant changes in palaeoceanography and palaeoenvironments in the Tethyan Realm, but outside the Tethys such data are very scarce. Here we present results of a study of the most complete section in the Panboreal Superrealm, the Nordvik section. Belemnite d18O data show an irregular decrease from values reaching up to 1.6 in the Middle Oxfordian and from 0.8 to 1.7 in the basal Ryazanian, indicating a prolonged warming. The biodiversity changes were strongly related to sea-level oscillations, showing a relatively low belemnite and high ammonite diversity during sea-level rise, accompanied by a decrease of the macrobenthos taxonomical richness. The most prominent sea-level rise is marked by the occurrence of open sea ammonites with Pacific affinities. Peak abundances of spores and prasinophytes correlate with a negative excursion in organic carbon d13C near the J/K boundary and could reflect blooms of green algae caused by disturbance of the marine ecosystem.Web of Science33art. no. 1971

Science diplomacy from the Global South: the case of intergovernmental science organizations

Intergovernmental science organizations (IGSOs) address many challenges of the 21st century. Several countries of the Global South have joined established IGSOs or have created new ones. Yet we know little about their interests in IGSOs. Our study addresses this blind spot by investigating which objectives Southern actors pursue in IGSOs and under which conditions they are likely to achieve their objectives. Using insights from three strands of literature, we compare four IGSOs with Southern participation: the European Organization for Nuclear Research, the International Thermonuclear Experimental Reactor, the Square Kilometer Array, and the African Lightsource. We show that countries of the Global South pursue a multitude of political and scientific objectives in IGSOs, ranging from capacity-building to casting off political isolation. Moreover, we demonstrate that Southern countries have varying chances of attaining these objectives, depending on their scientific community, domestic politics, industrial capacities and in some cases geographic location as well as an IGSO’s maturity.Horizon 2020(H2020)819533LIACS-Managemen

Palaeoenvironments and palaeoceanography changes across the Jurassic/Cretaceous boundary in the Arctic realm: case study of the Nordvik section (north Siberia, Russia)

The Jurassic/Cretaceous transition was accompanied by significant changes in palaeoceanography and palaeoenvironments in the Tethyan Realm, but outside the Tethys such data are very scarce. Here we present results of a study of the most complete section in the Panboreal Superrealm, the Nordvik section. Belemnite d18O data show an irregular decrease from values reaching up to 1.6 in the Middle Oxfordian and from 0.8 to 1.7 in the basal Ryazanian, indicating a prolonged warming. The biodiversity changes were strongly related to sea-level oscillations, showing a relatively low belemnite and high ammonite diversity during sea-level rise, accompanied by a decrease of the macrobenthos taxonomical richness. The most prominent sea-level rise is marked by the occurrence of open sea ammonites with Pacific affinities. Peak abundances of spores and prasinophytes correlate with a negative excursion in organic carbon d13C near the J/K boundary and could reflect blooms of green algae caused by disturbance of the marine ecosystem.Web of Science33art. no. 1971

Palaeoenvironments and palaeoceanography changes across the Jurassic/Cretaceous boundary in the Arctic realm: case study of the Nordvik section (north Siberia, Russia)

The Jurassic/Cretaceous transition was accompanied by significant changes in palaeoceanography and palaeoenvironments in the Tethyan Realm, but outside the Tethys such data are very scarce. Here we present results of a study of the most complete section in the Panboreal Superrealm, the Nordvik section. Belemnite d18O data show an irregular decrease from values reaching up to 1.6 in the Middle Oxfordian and from 0.8 to 1.7 in the basal Ryazanian, indicating a prolonged warming. The biodiversity changes were strongly related to sea-level oscillations, showing a relatively low belemnite and high ammonite diversity during sea-level rise, accompanied by a decrease of the macrobenthos taxonomical richness. The most prominent sea-level rise is marked by the occurrence of open sea ammonites with Pacific affinities. Peak abundances of spores and prasinophytes correlate with a negative excursion in organic carbon d13C near the J/K boundary and could reflect blooms of green algae caused by disturbance of the marine ecosystem.Web of Science33art. no. 1971

Confirmation of Genetic Associations at ELMO1 in the GoKinD Collection Supports Its Role as a Susceptibility Gene in Diabetic Nephropathy

Objective: To examine the association between single nucleotide polymorphisms (SNPs) in the engulfment and cell motility 1 (ELMO1) gene, a locus previously shown to be associated with diabetic nephropathy in two ethnically distinct type 2 diabetic populations, and the risk of nephropathy in type 1 diabetes. Research Design and Methods: Genotypic data from a genome-wide association scan (GWAS) of the Genetics of Kidneys in Diabetes (GoKinD) study collection were analyzed for associations across the ELMO1 locus. In total, genetic associations were assessed using 118 SNPs and 1,705 individuals of European ancestry with type 1 diabetes (885 normoalbuminuric control subjects and 820 advanced diabetic nephropathy case subjects). Results: The strongest associations in ELMO1 occurred at rs11769038 (odds ratio [OR] 1.24; P = 1.7 × 10−3) and rs1882080 (OR 1.23; P = 3.2 × 10−3) located in intron 16. Two additional SNPs, located in introns 18 and 20, respectively, were also associated with diabetic nephropathy. No evidence of association for variants previously reported in type 2 diabetes was observed in our collection. Conclusions: Using GWAS data from the GoKinD collection, we comprehensively examined evidence of association across the ELMO1 locus. Our investigation marks the third report of associations in ELMO1 with diabetic nephropathy, further establishing its role in the susceptibility of this disease. There is evidence of allelic heterogeneity, contributed by the diverse genetic backgrounds of the different ethnic groups examined. Further investigation of SNPs at this locus is necessary to fully understand the commonality of these associations and the mechanism(s) underlying their role in diabetic nephropathy

Uremic solutes and risk of end stage renal disease in type 2 diabetes

Here we studied plasma metabolomic profiles as determinants of progression to ESRD in patients with Type 2 diabetes (T2D). This nested case-control study evaluated 40 cases who progressed to ESRD during 8-12 years of follow-up and 40 controls who remained alive without ESRD from the Joslin Kidney Study cohort. Controls were matched with cases for baseline clinical characteristics; although controls had slightly higher eGFR and lower levels of urinary albumin excretion than T2D cases. Plasma metabolites at baseline were measured by mass spectrometry-based global metabolomic profiling. Of the named metabolites in the library, 262 were detected in at least 80% of the study patients. The metabolomic platform recognized 78 metabolites previously reported to be elevated in ESRD (uremic solutes). Sixteen were already elevated in the baseline plasma of our cases years before ESRD developed. Other uremic solutes were either not different or not commonly detectable. Essential amino acids and their derivatives were significantly depleted in the cases, whereas certain amino acid-derived acylcarnitines were increased. All findings remained statistically significant after adjustment for differences between study groups in albumin excretion rate, eGFR or HbA1c. Uremic solute differences were confirmed by quantitative measurements. Thus, abnormal plasma concentrations of putative uremic solutes and essential amino acids either contribute to progression to ESRD or are a manifestation of an early stage(s) of the disease process that leads to ESRD in T2D

Apolipoprotein M Gene (APOM) Polymorphism Modifies Metabolic and Disease Traits in Type 2 Diabetes

This study aimed at substantiating the associations of the apolipoproein M gene (APOM) with type 2 diabetes (T2D) as well as with metabolic traits in Hong Kong Chinese. In addition, APOM gene function was further characterized to elucidate its activity in cholesterol metabolism. Seventeen APOM SNPs documented in the NCBI database were genotyped. Five SNPs were confirmed in our study cohort of 1234 T2D and 606 control participants. Three of the five SNPs rs707921(C+1871A), rs707922(G+1837T) and rs805264(G+203A) were in linkage disequilibrium (LD). We chose rs707922 to tag this LD region for down stream association analyses and characterized the function of this SNP at molecular level. No association between APOM and T2D susceptibility was detected in our Hong Kong Chinese cohort. Interestingly, the C allele of rs805297 was significantly associated with T2D duration of longer than 10 years (OR = 1.245, p = 0.015). The rs707922 TT genotype was significantly associated with elevated plasma total- and LDL- cholesterol levels (p = 0.006 and p = 0.009, respectively) in T2D patients. Molecular analyses of rs707922 lead to the discoveries of a novel transcript APOM5 as well as the cryptic nature of exon 5 of the gene. Ectopic expression of APOM5 transcript confirmed rs707922 allele-dependent activity of the transcript in modifying cholesterol homeostasis in vitro. In conclusion, the results here did not support APOM as a T2D susceptibility gene in Hong Kong Chinese. However, in T2D patients, a subset of APOM SNPs was associated with disease duration and metabolic traits. Further molecular analysis proved the functional activity of rs707922 in APOM expression and in regulation of cellular cholesterol content

Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥ 0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction