Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesA meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.Swedish Research Council Knut and Alice Wallenberg Foundation AFA Foundation Swedish Brain Foundatio

The prognostic effect of known and newly detected type 2 diabetes in patients with acute coronary syndrome.

To access publisher's full text version of this article click on the hyperlink belowBackground: Dysglycemia is a well-established risk factor of coronary artery disease. Less is known of the prognostic effect of dysglycemia in acute coronary syndromes (ACSs). The aim of this study was to evaluate the long-term outcome of patients with ACSs according to glucometabolic categories. Methods: Patients with ACSs were consecutively included in the study. Among those with no previous history of type 2 diabetes (T2DM) glucose metabolism was evaluated with fasting glucose in plasma, glycated hemoglobin and a standard 2-h oral glucose tolerance test. Patients were classified having normal glucose metabolism, prediabetes, newly detected T2DM (nT2DM) and previously known T2DM (kT2DM). The clinical outcome parameters were death or myocardial infarction and other major adverse cardiac events (MACEs). Results: A total of 372 ACS patients (male 75.8%, 65.1 years (SD: 11.8)) constituted the study population. The proportion diagnosed with normal glucose metabolism, prediabetes, nT2DM and kT2DM was 20.7%, 46.5%, 6.2% and 26.6%, respectively. The mean follow-up period was 2.9 years. Patients with prediabetes, nT2DM and kT2DM had a hazard ratio of 5.8 (95% confidence interval (CI) 0.8-44.6), 10.9 (95% CI 1.2-98.3) and 14.9 (95% CI 2.0-113.7), respectively, for death/myocardial infarction and 1.4 (95% CI 0.6-3.1), 2.9 (95% CI 1.1-8.0) and 3.3 (95% CI 1.5-7.6), respectively, for a composite of MACEs. Conclusion: Patients with ACS and nT2DM or kT2DM were at increased risk of death/myocardial infarction and MACE compared with patients with normal glucose metabolism after approximately three years of follow-up. Keywords: Acute coronary syndrome; prognosis; survival; type 2 diabetes.University of Iceland Research Fund Landspitali University Hospital Research Fund Icelandic Society of Cardiology Research Fun

Diagnosis of type 2 diabetes and prediabetes among patients with acute coronary syndromes.

To access publisher's full text version of this article click on the hyperlink belowPreviously undetected dysglycaemia is common among patients with acute coronary syndromes (ACSs). The aim of this study was to identify the most reliable method of diagnosing type 2 diabetes mellitus (T2DM) and prediabetes in ACS patients.Patients admitted to the coronary care unit with ACSs and no previous history of T2DM were consecutively included in the study. Glucose metabolism was measured by glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG) with a standard oral glucose tolerance test during hospital admission, and this process was repeated 3 months later. In this study, the diagnosis of T2DM required at least two measurements above the diabetes cut-off point according to current American Diabetes Association and World Health Organization criteria.A total of 250 patients were included in the study. T2DM was diagnosed in 7.2%. The sensitivities for detecting T2DM were 33.3%, 61.1% and 77.8% during admission and 27.8%, 61.1% and 72.2% at follow-up for HbA1c, FPG and 2hPG, respectively. The positive predictive values (PPVs) for diagnosing T2DM were 100%, 91.7% and 51.9% during admission and 71.4%, 91.7% and 65.0% at follow-up for HbA1c, FPG and 2hPG, respectively. The specificities and negative predictive values were high for all methods. By combining all measurements, the sensitivity was 100% and the PPV was 44.2%, while the combination of all HbA1c and FPG measurements provided 88.9% sensitivity and 80.0% PPV.Diagnosis of T2DM can be reliably carried out by repeated measurements of FPG and HbA1c in ACS patients, with limited added value of an oral glucose tolerance test.University of Iceland Research Fund and Landspitali University Hospital Research Fund

Oral glucose tolerance test predicts increased carotid plaque burden in patients with acute coronary syndrome.

Type 2 diabetes and prediabetes are established risk factors for atherosclerosis. The aim of this study was to evaluate the atherosclerotic plaque burden in the carotid arteries of patients with acute coronary syndrome according to their glycemic status.Patients with acute coronary syndrome and no previous history of type 2 diabetes were consecutively included in the study. Glucose metabolism was evaluated with fasting glucose in plasma, HbA1c and a standard two-hour oral glucose tolerance test. Atherosclerotic plaque in the carotid arteries was evaluated with a standardized ultrasound examination where total plaque area was measured and patients classified as having no plaque or a significant plaque formation.A total of 245 acute coronary syndrome patients (male 78%, 64 years (SD: 10.9)) were included. The proportion diagnosed with normal glucose metabolism, prediabetes and type 2 diabetes was 28.6%, 64.1% and 7.3%, respectively. A significant atherosclerotic plaque was found in 48.5%, 66.9% and 72.2% of patients with normal glucose metabolism, prediabetes and type 2 diabetes, respectively. An incremental increase in total plaque area was found from normal glucose metabolism to prediabetes (25.5%) and from normal glucose metabolism to type 2 diabetes (35.9%) (p = 0.04). When adjusted for conventional cardiovascular risk factors the OR of having significant atherosclerotic plaque in the carotid arteries was 2.17 (95% CI 1.15-4.15) for patients with newly diagnosed dysglycemia compared to patients with normal glucose metabolism. When additionally adjusted for the 2-hour plasma glucose after glucose loading (2hPG) the OR attenuated to 1.77 (95% CI 0.83-3.84).Newly detected dysglycemia is an independent predictor of significant atherosclerotic plaque in the carotid arteries with oral glucose tolerance test as a major determinant of carotid plaque burden in this group of individuals with acute coronary syndrome

Carotid plaque burden among patients with IFG, IGT and combination of IFG and IGT.

<p>Carotid plaque burden among patients with IFG, IGT and combination of IFG and IGT.</p

Pertinent characteristics of patients divided according to their glucose metabolism.

<p>Pertinent characteristics of patients divided according to their glucose metabolism.</p

Glucose metabolic derangements and carotid plaque burden.

<p>Glucose metabolic derangements and carotid plaque burden.</p

Baseline characteristics.

<p>Baseline characteristics.</p

Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene