Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies

Genome-wide association and functional studies identify a role for IGFBP3 in hip osteoarthritis

International audienc

Colombia diversidad biótica IX : Ciénagas de Córdoba: Biodiversidad ecología y manejo ambiental

ilustraciones, fotografías, gráficas, mapas, tablasLa variabilidad de las ciénagas en el departamento de Córdoba se relaciona con los montos de precipitación en un régimen de distribución unimodal bi-estacional, con valores entre 1000-1500 mm de precipitación anual (ciénagas del complejo grande de Lorica) bajo la influencia del Río Sinú, hasta valores entre > 2500-3000 mm como las de Ayapel y de Arcial bajo la influencia del Río San Jorge. Las ciénagas del río Sinú (charco Pescao, Bañó, Pantano Bonito) presentan una mayor eutrofización (nutrientes, materia orgánica) que las del San Jorge (El Porro, Cintura, Arcial) y en general hubo mayores recuentos de bacterias indicadoras de contaminación, que se incrementaron durante la época lluviosa. En el zooplancton predominan los rotíferos, seguidos por las fases juveniles de los copépodos, cladóceros y copépodos adultos. El establecimiento de la vegetación acuática esta relacionado con la cantidad de sólidos suspendidos en el agua, en aguas transparentes como Arcial, Cintura, Charco pescao hay elementos acuáticos sumergidos, enraizados emergentes y flotantes con los tapetes de Eichhornia crassipes. La vegetación de pantano está conformada por diferentes ensambles dominados por especies de Cyperaceae y Polygonaceae. En la vegetación de ribera son importantes los matorrales de mangle (Symmeria paniculata). La vegetación acuática y la de la llanura aluvial son las responsables del aporte de materia orgánica a la cubeta en el proceso anual de aguas altas y bajas. En el sedimento se encontraron representantes de Nematodos, Anélidos, Moluscos y Artrópodos y una concentración de materia orgánica relativamente baja, respecto al valor (%) de materia mineral. La vegetación de los bosques alrededor de los ciénagas se reúne en la gran formación dominada por Crateva tapia y Astronium graveolens, incluye diferentes bosques que cuentan entre sus elementos característicos y dominantes a Cavanillesia platanifolia, Bursera simarouba, Cochlospermum vitifolium, Apiba aspera, Cariniana pyriformis, Guazuma ulmifolia, Tapirira guianensis, Samanea saman, y Tabebuia rosea. En el paisaje son muy vistosos los palmares de Sabal mauritiformis, Bactris guianensis, Oenocarpus mapora y O. bataua. La riqueza de la flora se cifra en 1000 especies de plantas vasculares con mayor diversidad en las familias Fabaceae, Rubiaceae, Mimosaceae y Poaceae, patrón distintivo de la riqueza de las tierras bajas de Colombia. La fauna asociada a las ciénagas incluye 47 especies de reptiles, 39 del orden Squamata (Lagartos 46% y Serpientes 54%), una perteneciente al orden Crocodylia y siete al orden Testudinata (tortugas). Se registraron 49 especies de mamíferos, algunos grandes pertenecientes a los órdenes Carnívora, Primates, Phyllophaga (osos perezosos) y Vermilingua (osos hormigueros). Se registraron 180 especies de aves de 51 familias, con la mayor representatividad en Tyrannidae. Las ciénagas de Lorica y El Porro albergan grandes grupos de especies acuáticas, especialmente de las familias Ardeidae, Anatidae y Rallidae. No obstante la fuente importante de riqueza natural de las ciénagas y su entorno, la situación socioeconómica de la mayor parte del campesinado es crítica. Esta población necesita ayuda urgente del gobierno a nivel de inversiones y planes de desarrollo, en los cuales es fundamental considerar el capital natural que significa la biodiversidad de las ciénagas y la necesaria utilización de los servicios ambientales que prestan local, regional y nacionalmente estos ambientes siempre y cuando se les conserve. (Texto tomado de la fuente).ISBN de la versión impresa: 9789587194067Incluye anexosPrimera edició

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10−8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies

mJSW and OA associated variants are co-localized with potential gene regulatory markers.

<p>We examined the epigenetic histone marks in Chondrogenic cells, osteoblasts, hMSC, K562, HUVEC, HeLA and NHEK cells. This heatmap of the percentage of variants in gene regulatory regions (enhancer/promoter associated regions) in high LD (r² >0.8) with lead GWAS SNP. Enrichment was calculated according [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006260#pgen.1006260.ref025" target="_blank">25</a>].</p

Association between protein coding variants identified by exome-sequencing and mJSW.

<p>Association between protein coding variants identified by exome-sequencing and mJSW.</p

Manhattan plot for association of mJSW in the discovery phase.

<p>The -log10 P values, for each of the 2.5 million tests performed as part of the genome wide association of minimal joint space width of the hip (mJSW), plotted against their position per chromosome. Full results of the discovery GWAS are accessible through <a href="http://www.glimdna.org" target="_blank">www.glimdna.org</a>. The gray solid horizontal line corresponds to the genome-wide significant threshold (P = 5x10-8). The dotted grey line corresponds to the selection for replication threshold (P = 1x10^-5).</p

Association of mJSW loci with previously reported phenotypes

<p>Association of mJSW loci with previously reported phenotypes</p