Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas

OBJECTIVESulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA_1c reduction.RESEARCH DESIGN AND METHODSAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA_1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.RESULTSAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA_1c reduction at a genome-wide scale (P < 5 × 10⁻⁸). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10⁻⁸), lower reduction in HbA_1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10⁻⁵⁸). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA_1c (P = 4.80 × 10⁻⁸). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10⁻⁷), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA_1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.CONCLUSIONSWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.     

The Importance of Portal Venous Blood Flow in Ischemic‐Type Biliary Lesions after Liver Transplantation

Ischemic‐type biliary lesions (ITBL) are the most frequent cause of nonanastomotic biliary strictures after liver transplantation. This complication develops in up to 25% of patients, with a 50% retransplantation rate in affected patients. Traditionally, ischemia‐reperfusion injury to the biliary system is considered to be the major risk factor for ITBL. Several other risk factors for ITBL have been identified, including the use of liver grafts donated after cardiac death, prolonged cold and warm ischemic times and use of University of Wisconsin preservation solution. In recent years however, impaired microcirculation of the peribiliary plexus (PBP) has been implicated as a possible risk factor. It is widely accepted that the PBP is exclusively provided by blood from the hepatic artery, and therefore, the role of the portal venous blood supply has not been considered as a possible cause for the development of ITBL. In this short report, we present three patients with segmental portal vein thrombosis and subsequent development of ITBL in the affected segments in the presence of normal arterial blood flow. This suggests that portal blood flow may have an important contribution to the biliary microcirculation and that a compromised portal venous blood supply can predispose to the development of ITBL.     

High-level expression of the ER-MP58 antigen on mouse bone marrow hematopoietic progenitor cells marks commitment to the myeloid lineage

Studies on the early events in the differentiation of the nonspecific immune system require the identification and isolation of myeloid-committed progenitor cells. Using the monoclonal antibodies (mAb) ER-MP12 and ER-MP20, generated against immortalized macrophage precursors, we have shown previously that the earliest macrophage colony-stimulating factor (M-CSF)-responsive cells in the bone marrow have the ER-MP12^hi20⁻ phenotype. In addition, we found that the ER-MP12^hi20⁻ subset (comprising about 2 % of total nucleated marrow) contains progenitor cells of all hematopoietic lineages. Aiming at the identification and purification of the myeloid progenitor cells within the ER-MP12^hi20⁻ subset, we used ER-MP58, a marker expressed at high level by all M-CSF-responsive bone marrow progenitors. With this marker the ER-MP12^hi20⁻ cell population could be divided into three subfractions: one with absent or low level ER-MP58 expression, one with intermediate, and one with high ER-MP58 expression. These subfractions were isolated by fluorescence-activated cell sorting and tested in vitro and in vivo for their differentiation capacities. In addition, the expression of ER-MP58 on stem cell subsets was examined in the cobblestone area-forming cell (CAFC) assay. Our data indicate that in the ER-MP12^hi20⁻ subpopulation myeloid-committed progenitors are characterized by high-level expression of the ER-MP58 antigen, whereas cells with other or broader differentiation capacities have an ER-MP58 negative/low or intermediate phenotype. These myeloid-committed progenitors have no significant repopulating ability in vivo, in contrast to the ER-MP58 intermediate cells. Primitive CAFC-28/35, corresponding to cells providing long-term hematopoietic engraftment in vivo, also did not express the ER-MP58 Ag at a high level. Thus, cells committed to the myeloid lineage can be separated from progenitor cells with other differentiation capacities by means of multiparameter cell sorting using ER-MP58 in combination with ER-MP12 and ER-MP20.     

Zebrafish as potential model for developmental neurotoxicity testing: A mini review

The zebrafish is a powerful toxicity model; biochemical assays can be combined with observations at a structural and functional level within one individual. This mini review summarises the potency of zebrafish as a model for developmental neurotoxicity screening, and its possibilities to investigate working mechanisms of toxicants. The use of zebrafish in toxicity research can ultimately lead to the refinement or reduction of animal use.     

Bilateral traumatic carotid artery dissection in a child

Traumatic dissection of the carotid artery is an infrequent but serious complication of blunt craniocervical injury. There is controversy regarding the need for diagnostic screening and management. This report presents a child with delayed neurologic symptoms and multiple cerebral infarcts secondary to bilateral extracranial traumatic carotid artery dissection. The pathophysiology, clinical presentation, and treatment options of blunt carotid artery trauma are discussed.     

Calcium score: a new risk factor for colorectal anastomotic leakage

Background

Anastomotic leakage (AL) is the most feared complication of colorectal surgery. Atherosclerosis is suggested to have a detrimental effect on anastomotic healing. This study aimed to analyze the calcium score, a measure for atherosclerosis, as a risk factor for AL.

Study design

The calcium scores of colorectal patients operated on in 2 Dutch university medical centers were determined using a computed tomography scan and calcium scoring software. The aorta, common iliac arteries, internal and external iliac arteries were studied. Additionally, patient- and operation-related factors were scored.

Results

A total of 122 patients were included. In patients with AL, calcium scores were significantly higher in the left common iliac artery (561.4 vs 156.0, P = .028), right common iliac artery (542.0 vs 144.4, P = .041), both common iliac arteries together (1,103.3 vs 301.9, P = .046), and the left internal iliac artery (716.3 vs 35.3, P = .044).

Conclusions

Patients with higher calcium scores in the iliacal arteries have an increased leakage risk.     

ER-MP12 antigen, a new cell surface marker on mouse bone marrow cells with thymus-repopulating ability: I. Intrathymic repopulating ability of ER-MP12-positive bone marrow cells

We searched for new cell surface markers that allow a positiveidentification of thymusrepopulating cells in the bone marrow(BM) of the mouse. Recently we raised two rat monocional antibodies(ER-MP12 and ER-MP20) that recognize cell surface antigens expressedby mouse haematopoietic progenitor cells, among which are progenitorcells of the macrophage lineage. Here we show that the ER-MP12antigen, but not the ER-MP20 antigen, is also expressed by BMcells with thymus-repopulating ability. Using ER-MP12 and ER-MP20in two-colour immunofluorescence analysis six subpopulatlonsof BM cells can be identified. The thymusrepopulating abilityof each BM subpopulation was assessed after fluorescence-activatedcell sorting and subsequent intrathymic injection into sublethallyirradiated Thy-1 congenic recipient mice. Thymus-repopulatingactivity appeared to be exclusively confined to two subsetsof BM cells expressing either high or intermediate levels ofthe ER-MP12 antigen, but lacking ER-MP20 antigen expression.These BM subsets comprised 1–2% and 30% of total nucleatedBM cells respectively. The frequency of thymus-repopulatingcells was maximal in the minor BM subpopulation with the highestlevel of ER-MP12 antigen expression. We conclude that ER-MP12detects a hitherto unknown cell surface marker expressed byBM cells with thymus-repopulating ability.