The trans-ancestral genomic architecture of glycemic traits

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 x 10(-8)), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.Diabetes mellitus: pathophysiological changes and therap

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

A Bethe ansatz solvable model for superpositions of Cooper pairs and condensed molecular bosons

We introduce a general Hamiltonian describing coherent superpositions of Cooper pairs and condensed molecular bosons. For particular choices of the coupling parameters, the model is integrable. One integrable manifold, as well as the Bethe ansatz solution, was found by Dukelsky et al. [J. Dukelsky, G.G. Dussel, C. Esebbag, S. Pittel, Phys. Rev. Lett. 93 (2004) 050403]. Here we show that there is a second integrable manifold, established using the boundary quantum inverse scattering method. In this manner we obtain the exact solution by means of the algebraic Bethe ansatz. In the case where the Cooper pair energies are degenerate we examine the relationship between the spectrum of these integrable Hamiltonians and the quasi-exactly solvable spectrum of particular Schrodinger operators. For the solution we derive here the potential of the Schrodinger operator is given in terms of hyperbolic functions. For the solution derived by Dukelsky et al., loc. cit. the potential is sextic and the wavefunctions obey PT-symmetric boundary conditions. This latter case provides a novel example of an integrable Hermitian Hamiltonian acting on a Fock space whose states map into a Hilbert space of PE-symmetric wavefunctions defined on a contour in the complex plane

Stabilization of acromioclavicular joint using DogBone dynamic system (Arthrex): A literature review and long-term follow-up

Objectives The purpose of the study was to evaluate long-term follow-ups of stabilized acromioclavicular joint (ACJ) dislocations using button dynamic system applied via arthroscopic technique or mini-open. Material and methods The review included follow-ups of 40 patients (39 males, 1 female) who underwent 40 ACJ stabilization procedures with Arthrex DogBone button between 2014 and 2017 using arthroscopy (n = 28) or mini-open technique (n = 12). The mean age of the patients was 34 years (range, 15 to 59 years). Patient reported outcomes were evaluated with UCLA shoulder rating scale, American Shoulder and Elbow Surgeons (ASES) shoulder score and the Constant Shoulder Score (CSS). Coraco- Clavicular Distance (CCD) was measured on pre- and postoperative anteroposterior views. Postoperative AP view was used to measure Clavicular Tunnel Distance (CTD). Arthroscopy patients had available preoperative radiographs (n = 21), postoperative radiographs (n = 26) and patient reported outcomes (n = 18). Mini open group had available preoperative radiographs (n = 2), postoperative radiographs (n=8) and patient reported outcomes (n = 8). Results One hundred percent of Arthroscopy/Mini open (26/26) cases were rated as excellent and good on UCLA shoulder rating scale at a long-term follow-up. One hundred percent of Arthroscopy patients (18/18) were rated as excellent and good; 75 % (6/8) of Mini-open cases evaluated as excellent and 25 % (2/8) as good on ASES shoulder score. Sixty seven percent of Arthroscopy (12/18) patients were rated as excellent and 33 % (6/18) as good; 62 % (5/8) of Mini open cases evaluated as excellent and 38 % (3/8) as good. Neither fair nor poor results were observed in both groups. No statistically significant differences were detected in median scores between Arthroscopy and Miniopen groups (p > 0.05). Preoperative radiographs showed Tossy grade IV dislocation (n = 3) and Tossy grade III (n = 20). Distal clavicle fracture was diagnosed in 2 cases. Median preoperative CCD radiologically measured 15.5 mm in both groups (n = 23). Median postoperative CCD and CTD radiologically measured 6.12 mm and 28.9 mm in both groups (n = 35), correspondingly. Decrease in postoperative CCD was significantly different (p = 0.0003). No statistically significant differences in postoperative CCD were detected between Arthroscopy and Miniopen groups (p > 0.05). Statistically significant differences in preoperative CCD were observed in both groups (n = 15) using weight-bearing/no weight-bearing AP views (P = 0.0009). Conclusion Stabilization of dislocated ACJ with dynamic systems is the method of choice providing excellent and good outcomes rated by UCLA rating scale, ASES shoulder score and CSS at long-term follow-up. One-stage surgical treatment is an advantage of dynamic systems with no need of construct removal. Standard and weighted stress radiographs of the involved side indicate to ACJ injury in comparison with contralateral side. Further research is needed for a longer term follow-up with the bone reduction maintained with dynamic system. © Ryazantsev M.S., Il'in D.O., Rybin K.E., Magnitskaya N.E., A.P. Afanasyev, Logvinov A.N., Korolev A.V., 2018

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Genetic studies of body mass index yield new insights for obesity biology

Note: A full list of authors and affiliations appears at the end of the article. Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P 20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.</p