SIRT1/HERC4 Locus Associated With Bisphosphonate‐Induced Osteonecrosis of the Jaw: An Exome‐Wide Association Analysis

Osteonecrosis of the jaw (ONJ) is a rare, but serious drug side effect, mainly associated with the use of intravenous (iv) bisphosphonates (BPs). The purpose of this study was to identify genetic variants associated with ONJ in patients of European ancestry treated with iv BPs using whole‐exome sequencing (WES). The WES phase 1 included 44 multiple myeloma patients (22 ONJ cases and 22 controls) and WES phase 2 included 17 ONJ patients with solid tumors. Multivariable logistic regression analysis was performed to estimate the odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and principal components for ancestry. Meta‐analysis of WES phase 1 and 2 was performed to estimate the combined ORs. In silico analyses were then performed to identify expression quantitative loci (eQTL) single‐nucleotide polymorphisms (SNPs) that are in high linkage disequilibrium (LD) with the top SNPs. The associations of the potentially functional SNPs were replicated and validated in an independent case‐control study of 48 patients of European ancestry treated with iv BPs (19 ONJ cases and 29 controls). The top SNPs in the exome‐wide association meta‐analysis were two SNPs on chromosome 10: SIRT1 SNP rs7896005 and HERC4 SNP rs3758392 with identical OR of 0.07 (0.01–0.46; p = 3.83 × 10^?5). In the in silico functional analyses, two promoter region SNPs (rs7894483 and rs3758391) were identified to be in high LD with the index SNPs and are eQTLs for SIRT1 gene in whole blood in the GTEx database. The ORs were 0.30 (0.10–0.88), 0.26 (0.12–0.55), and 0.26 (0.12–0.55) for the WES top SNP rs7896005 and two promoter SNPs rs7894483 and rs3758391, respectively, in the replication sample. In summary, we identified the SIRT1/HERC4 locus on chromosome 10 to be associated with iv BP‐induced ONJ and two promoter SNPs that might be the potential genetic markers for this association. © 2017 The Authors.Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.     

Urate Transporter Gene SLC22A12 Polymorphisms Associated with Obesity and Metabolic Syndrome in Caucasians with Hypertension

Background/Aims: Hyperuricemia is associated with obesity and the metabolic syndrome. URAT1 is a urate transporter, and we tested the association of URAT1 transporter gene (SLC22A12) polymorphisms with obesity and the metabolic syndrome in hypertensive subjects. Methods: Patients with essential hypertension (n = 414) from a randomized controlled study were genotyped for SLC22A12 SNPs rs11602903, rs505802 and rs11231825. Results: In Caucasians, SLC22A12 SNPs were associated with the body mass index (BMI). rs11602903 was associated with BMI (p < 0.0001), waist circumference (p = 0.003), HDL cholesterol (p = 0.018) and the metabolic syndrome (p = 0.033), and accounted for 7% of the variation of BMI in Caucasians. In African Americans, SLC22A12 SNP rs11602903 was not associated with BMI, waist circumference, HDL cholesterol or triglycerides. Conclusion: The URAT1 gene SLC22A12 polymorphism may play a role in obesity and the metabolic syndrome in Caucasian hypertensive subjects.     

Screening for coronary artery disease in patients with type 2 diabetes mellitus: An evidence-based review

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in patients with diabetes. CAD is often asymptomatic in these patients, until the onset of myocardial infarction or sudden cardiac death. Consequently, proper screening and diagnosis of CAD is crucial for the prevention and early treatment of coronary events. This review deals with selection of the sub group of patients who have type 2 diabetes, who are at high risk for developing CAD and need to be screened for the same. The various diagnostic modalities which can be used in the screening process for enhancing risk stratification and management are also discussed.     

Aortic diameter at age 65 in men with newly diagnosed type 2 diabetes

Objectives. Type 2 diabetes mellitus has been linked to a decreased risk for abdominal aortic aneurysm (aortic diameter ≥30?mm, AAA) development in men. The aim of this study was to evaluate if such an effect is detectable already around the time of diabetes diagnosis. Design. We cross-sectionally compared aortic diameter at ultrasound screening for AAA in 691 men aged 65 years with incipient or newly diagnosed type 2 diabetes (group A) with 18,262 65-year old control men without diabetes (group B). Results. Aortic diameter did not differ between groups (18.8[17.4–20.8] vs. 19.0[17.5–28.7] mm; p?=?0.43). AAA prevalence was 2.5% in group A and 1.5% in group B (p?=?.010). In logistic regression taking group differences in body mass index (BMI), smoking, presence of atherosclerotic disease and hypertension into account, the difference in AAA prevalence was no longer significant (p?=?.15). Among men in group A, C-peptide (r?=?.093; p?=?.034), but not HbA1c (r?=?.060; p?=?.24) correlated with aortic diameter. Conclusion. Among 65 year old men aortic diameter and AAA prevalence do not differ between those with newly diagnosed type 2 diabetes and those without diabetes. Putative protective effects of type 2 diabetes mellitus against aortic dilatation and AAA development therefore probably occur later after diagnosis of diabetes.