Wnt receptors, bone mass, and fractures: gene-wide association analysis of LRP5 and LRP6 polymorphisms with replication

Objectives. Genes explaining the susceptibility to osteoporosis have not been fully elucidated. Our objective was to explore the association of polymorphisms capturing common variations of the lipoprotein receptor related protein (LRP) 5 and 6 genes, encoding two Wnt receptors, with femoral neck bone mineral density (BMD) and osteoporotic fractures of the spine and the hip. Design. Cross-sectional, case-control and replication genetic association study. Methods. Thirty nine tagging and functional single nucleotide polymorphisms (SNP) were analyzed in a group of 1043 postmenopausal women and 394 women with hip fractures. The results were replicated in a different group of 342 women. Results. Three SNPs of the LRP6 gene were associated with BMD (nominal uncorrected pvalues< 0.05) in the discovery cohort. One showed a significant association after multiple test correction; two of them were also associated in the replication cohort, with a combined standardized mean difference of 0.51 (p=0.009) and 0.65 (p<0.0001) across rs11054704 and rs2302685 genotypes. In the discovery cohort, several LRP5 SNPs were associated with vertebral fractures (odds ratio 0.67; p=0.01), with hip fractures (unadjusted odds ratios between 0.59 and 1.21, p=0.005-0.033, but not significant after multiple test- or age-adjustment), and with height and the projected femoral neck area, but not with BMD. Transcripts of LRP5 and LRP6 were similarly abundant in bone samples. Conclusions. In this study we found common polymorphisms of LRP5 associated with osteoporotic fractures, and polymorphisms of the LRP6 gene associated with BMD, thus suggesting them as likely candidates to contribute explaining the hereditary influence on osteoporosis

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism

Assessment of gene-by-sex interaction effect on bone mineral density

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.Medtronic NIH R01 AG18728 R01HL088119 R01AR046838 U01 HL084756 R01 AR43351 P01-HL45522 R01-MH-078111 R01-MH-083824 Nutrition and Obesity Research Center of Maryland P30DK072488 NIAMS/NIH F32AR059469 Instituto de Salud Carlos III-FIS (Spanish Health Ministry) PI 06/0034 PI08/0183 Canadian Institutes of Health Research (CIHR) NHLBI HHSN268201200036C N01-HC-85239 N01-HC-85079 N01-HC-85086 N01-HC-35129 N01 HC15103 N01 HC-55222 N01-HC-75150 N01-HC-45133 HL080295 HL087652 HL105756 NIA AG-023629 AG-15928 AG-20098 AG-027058 N01AG62101 N01AG62103 N01AG62106 1R01AG032098-01A1 National Center of Advancing Translational Technologies CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Diseases DK063491 EUROSPAN (European Special Populations Research Network) European Commission FP6 STRP grant 018947 LSHG-CT-2006-01947 Netherlands Organisation for Scientific Research Erasmus MC Centre for Medical Systems Biology (CMSB) Netherlands Brain Foundation (HersenStichting Nederland) US National Institute for Arthritis, Musculoskeletal and Skin Diseases National Institute on Aging R01 AR/AG41398 R01 AR050066 R21 AR056405 National Heart, Lung, and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc. N02-HL-6-4278 Canadian Institutes of Health Research from Institute of Aging 165446 Institute of Genetics 179433 Institute of Musculoskeletal health 221765 Intramural Research Program of the NIH, National Institute on Aging National Institutes of Health HHSN268200782096C Hong Kong Research Grant Council HKU 768610M Bone Health Fund of HKU Foundation KC Wong Education Foundation Small Project Funding 201007176237 Matching Grant CRCG Grant Osteoporosis and Endocrine Research Fund Genomics Strategic Research Theme of The University of Hong Kong Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810 Erasmus Medical Center and Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission (DG XII) Municipality of Rotterdam German Bundesministerium fur Forschung und Technology 01 AK 803 A-H 01 IG 07015

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

Systematische Übersichtsarbeit unter Verwendung des HTA Core Model® for Rapid Relative Effectiveness Assessment

Background: Stool DNA testing for early detection of colorectal cancer (CRC) is a non-invasive technology with the potential to supplement established CRC screening tests. The aim of this health technology assessment was to evaluate effectiveness and safety of currently CE-marked stool DNA tests, compared to other CRC tests in CRC screening strategies in an asymptomatic screening population.Methods: The assessment was carried out following the guidelines of the European Network for Health Technology Assessment (EUnetHTA). This included a systematic literature search in MED-LINE, Cochrane and EMBASE in 2018. Manufacturers were asked to provide additional data. Five patient interviews helped assessing potential ethical or social aspects and patients' experiences and preferences. We assessed the risk of bias using QUADAS-2, and the quality of the body of evidence using GRADE.Results: We identified three test accuracy studies, two of which investigated a multitarget stool DNA test (Cologuard®, compared fecal immunochemical test (FIT)) and one a combined DNA stool assay (ColoAlert®, compared to guaiac-based fecal occult blood test (gFOBT), Pyruvate Kinase Isoenzyme Type M2 (M2-PK) and combined gFOBT/M2-PK). We found five published surveys on patient satisfaction. No primary study investigating screening effects on CRC incidence or on overall mortality was found. Both stool DNA tests showed in direct comparison higher sensitivity for the detection of CRC and (advanced) adenoma compared to FIT, or gFOBT, respectively, but had lower specificity. However, these comparative results may depend on the exact type of FIT used. The reported test failure rates were higher for stool DNA testing than for FIT. The certainty of evidence was moderate to high for Cologuard® studies, and low to very low for the ColoAlert® study which refers to a former version of the product and yielded no direct evidence on the test accuracy for ad-vanced versus non-advanced adenoma.Conclusions: ColoAlert® is the only stool DNA test currently sold in Europe and is available at a lower price than Cologuard®, but reliable evidence is lacking. A screening study including the current product version of ColoAlert® and suitable comparators would, therefore, help evaluate the effectiveness of this screening option in a European context.Hintergrund: Stuhl-DNA-Tests zur Früherkennung des kolorektalen Karzinoms (KRK) sind nicht-invasiv und können etablierte KRK-Screening-Verfahren ergänzen. Ziel dieses Health Technology Assessment war die Untersuchung der Wirksamkeit und Sicherheit von CE-zertifizierten Stuhl-DNA-Tests im Vergleich zu anderen Tests für ein Screening einer asymptomatischen KRK-Screening-Population.Methodik: Das Assessment wurde nach den Richtlinien des Europäischen Netzwerks für Health Technology Assessment (EUnetHTA) durchgeführt und schloss eine systematische Literaturrecherche in MEDLINE, Cochrane und EMBASE ein, durchgeführt 2018. Die Hersteller wurden bezüglich der Übermittlung von weiteren Daten kontaktiert. Fünf Patienteninterviews halfen in der Einschätzung möglicher ethischer oder sozialer Aspekte sowie von Patientenerfahrungen und -präferenzen. Wir bewerteten das Verzerrungsrisiko mit QUADAS-2 und verwendeten GRADE, um die Qualität der Evidenz zu bewerten.Ergebnisse: Wir identifizierten drei Studien zur Testgenauigkeit; zwei untersuchten einen Multitarget-Stuhl-DNA-Test (Cologuard®, im Vergleich zu einem fäkalen immunchemischen Test (FIT)) und eine Studie einen kombinierten DNA-Stuhltest (ColoAlert®, im Vergleich zu einem guajakbasierten Stuhlbluttest (gFOBT), Pyruvate Kinase Isoenzyme Typ M2 (M2-PK) und kombiniertem gFOBT/M2-PK). Wir fanden fünf publizierte Erhebungen zur Patientenzufriedenheit, jedoch keine Primärstudien zu den Auswirkungen eines Screenings mit den beiden Tests auf KRK oder die Gesamtmortalität. Beide Stuhl-DNA-Tests zeigten im direkten Vergleich eine höhere Sensitivität für den Nachweis von KRK und (fortgeschrittenen) Adenomen als FIT beziehungsweise gFOBT, wiesen aber eine geringere Spezifität auf. Diese Ergebnisse könnten jedoch vom genauen Typ des jeweils verwendeten FIT abhängen. Die berichteten Testausfallraten waren beim Stuhl-DNA-Test höher als beim FIT. Die Stärke der Evidenz war moderat bis hoch für die Cologuard®-Studien und niedrig bis sehr niedrig für die ColoAlert®-Studie, die sich auf eine frühere, nicht mehr am Markt befindliche Version des Produkts bezieht und die in den Ergebnissen zur Testgenauigkeit nicht zwischen fortgeschrittenen und nicht-fortgeschrittenen Adenomen differenzierte.Schlussfolgerungen: ColoAlert® ist der einzige derzeit in Europa am Markt befindliche Stuhl-DNA-Test und ist zu einem niedrigeren Preis als Cologuard® erhältlich, jedoch fehlt zuverlässige Evidenz. Eine Screening-Studie mit Implementierung der aktuellen Produktversion von ColoAlert® und geeigneten Komparatoren würde daher helfen, diese Screening-Option im europäischen Kontext zu evaluieren