Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The Erythropoetin rs1617640 Gene Polymorphism Associates with Hemoglobin Levels, Hematocrit and Red Blood Cell Count in Patients with Peripheral Arterial Disease

Background: Erythropoietin has a pivotal role in erythropoiesis and angiogenesis. A common polymorphism (rs1617640, A &gt; C) in the promoter of the erythropoietin gene (EPO) has been associated with erythropoietin expression and microvascular complications of diabetes. We aimed to analyze the potential role of this polymorphism in the pathogenesis of peripheral arterial disease (PAD). Methods: EPO genotypes and laboratory markers for erythropoiesis were determined in 945 patients with PAD. Results: The minor EPO rs1617640 C-allele was associated in an allele-dose-dependent manner with hemoglobin levels (p = 0.006), hematocrit (p = 0.029), and red blood cell count (p = 0.003). In a multivariate linear regression analysis including conventional risk factors diabetes, sex, and smoking, EPO genotypes were furthermore associated with age at onset of PAD symptoms (p = 0.009). Conclusions: The EPO rs1617640 gene polymorphism affects erythropoiesis, leads to an earlier onset of PAD, and is a potential biomarker for the pathogenesis of this disease

Identification of Novel Intronic SNPs in Transporter Genes Associated with Metformin Side Effects

Metformin is a widely used and effective medication in type 2 diabetes (T2DM) as well as in polycystic ovary syndrome (PCOS). Single nucleotide polymorphisms (SNPs) contribute to the occurrence of metformin side effects. The aim of the present study was to identify intronic genetic variants modifying the occurrence of metformin side effects and to replicate them in individuals with T2DM and in women with PCOS. We performed Next Generation Sequencing (Illumina Next Seq) of 115 SNPs in a discovery cohort of 120 metformin users and conducted a systematic literature review. Selected SNPs were analysed in two independent cohorts of individuals with either T2DM or PCOS, using 5′-3′exonucleaseassay. A total of 14 SNPs in the organic cation transporters (OCTs) showed associations with side effects in an unadjusted binary logistic regression model, with eight SNPs remaining significantly associated after appropriate adjustment in the discovery cohort. Five SNPs were confirmed in a combined analysis of both replication cohorts but showed different association patterns in subgroup analyses. In an unweighted polygenic risk score (PRS), the risk for metformin side effects increased with the number of risk alleles. Intronic SNPs in the OCT cluster contribute to the development of metformin side effects in individuals with T2DM and in women with PCOS and are therefore of interest for personalized therapy options

Expression Profiles of miR-22-5p and miR-142-3p Indicate Hashimoto&rsquo;s Disease and Are related to Thyroid Antibodies

Hashimoto&rsquo;s thyroiditis (HT) is the most prevalent autoimmune disorder of the thyroid (AITD) and characterized by the presence of circulating autoantibodies evoked by a, to date, not fully understood dysregulation of the immune system. Autoreactive lymphocytes and inflammatory processes in the thyroid gland can impair or enhance thyroid hormone secretion. MicroRNAs (miRNAs) are small noncoding RNAs, which can play a pivotal role in immune functions and the development of autoimmunity. The aim of the present study was to evaluate whether the expression of 9 selected miRNAs related to immunological functions differ in patients with HT compared to healthy controls. MiRNA profiles were analysed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 24 patients with HT and 17 healthy controls. Systemic expressions of miR-21-5p, miR-22-3p, miR-22-5p, miR-142-3p, miR-146a-5p, miR-301-3p and miR-451 were significantly upregulated in patients with HT (p &le; 0.01) and were suitable to discriminate between HT and healthy controls in AUC analysis. Altered expressions of miR-22-5p and miR-142-3p were associated with higher levels of thyroid antibodies, suggesting their contribution to the pathogenesis of HT

Dp-ucMGP as a Biomarker in Sarcopenia

Sarcopenia is linked with an increased risk of falls, osteoporosis and mortality and is an increasing problem for healthcare systems. No satisfying biomarkers for sarcopenia diagnosis exist, connecting bone, fat and muscle. Matrix-GLA-protein (MGP) is an adipokine that regulates bone metabolism and is associated with decreased muscle strength. Associations of dp-ucMGP were analyzed in the BioPersMed cohort (58 &plusmn; 9 years), including 1022 asymptomatic subjects at moderate cardiovascular risk. Serum measurements of dp-ucMGP in 760 persons were performed with the InaKtif MGP Kit with the IDS-iSYS Multi-Discipline Automated System. DXA data (792 persons) measured with the Lunar iDXA system and physical performance data (786 persons) were available. Dp-ucMGP plasma levels correlate with sarcopenia parameters like gait speed (&rho; = &minus;0.192, p &lt; 0.001), appendicular skeletal muscle mass (&rho; = 0.102, p = 0.005) and appendicular skeletal muscle mass index (&rho; = 0.112, p = 0.001). They are lower in persons with sarcopenia (p &lt; 0.001) and higher in persons with reduced physical performance (p = 0.019). Persons in the lowest dp-ucMGP quartile have the highest risk for reduced muscle mass, decreasing with each quartile, whereas persons in the highest quartile have the highest risk of reduced muscle strength. Dp-ucMGP might be a good biomarker candidate in sarcopenia characterization