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Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

ABSTRACT: Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population.Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study.In a combined meta-analysis of a discovery cohort (288 cases and 1139 controls), three hospital based sets in replication stage I (462 cases and 1745 controls), and an independent ethnic group in replication stage II (369 cases and 560 for controls), we identified a new locus associated with OF (rs784288 in the MECOM gene) that showed genome-wide significance (p=3.59×10(-8); OR 1.39). RNA interference revealed that a MECOM knockdown suppresses osteoclastogenesis.Our findings provide new insights into the genetic architecture underlying OF in East Asians.

SUBMITTER: Hwang JY

PROVIDER: S-EPMC4169276 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

Hwang Joo-Yeon JY Lee Seung Hun SH Go Min Jin MJ Kim Beom-Jun BJ Kou Ikuyo I Ikegawa Shiro S Guo Yan Y Deng Hong-Wen HW Raychaudhuri Soumya S Kim Young Jin YJ Oh Ji Hee JH Kim Youngdoe Y Moon Sanghoon S Kim Dong-Joon DJ Koo Heejo H Cha My-Jung MJ Lee Min Hye MH Yun Ji Young JY Yoo Hye-Sook HS Kang Young-Ah YA Cho Eun-Hee EH Kim Sang-Wook SW Oh Ki Won KW Kang Moo Il MI Son Ho Young HY Kim Shin-Yoon SY Kim Ghi Su GS Han Bok-Ghee BG Cho Yoon Shin YS Cho Myeong-Chan MC Lee Jong-Young JY Koh Jung-Min JM

Journal of medical genetics 20130124 4

<h4>Background</h4>Osteoporotic fracture (OF) as a clinical endpoint is a major complication of osteoporosis. To screen for OF susceptibility genes, we performed a genome-wide association study and carried out de novo replication analysis of an East Asian population.<h4>Methods</h4>Association was tested using a logistic regression analysis. A meta-analysis was performed on the combined results using effect size and standard errors estimated for each study.<h4>Results</h4>In a combined meta-anal ...[more]

PMID: 23349225

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Project description:BackgroundOsteoporosis is a highly heritable trait. Many candidate genes have been proposed as being involved in regulating bone mineral density (BMD). Few of these findings have been replicated in independent studies.ObjectiveTo assess the relationship between BMD and fracture and all common single-nucleotide polymorphisms (SNPs) in previously proposed osteoporosis candidate genes.DesignLarge-scale meta-analysis of genome-wide association data.Setting5 international, multicenter, population-based studies.ParticipantsData on BMD were obtained from 19 195 participants (14 277 women) from 5 populations of European origin. Data on fracture were obtained from a prospective cohort (n = 5974) from the Netherlands.MeasurementsSystematic literature review using the Human Genome Epidemiology Navigator identified autosomal genes previously evaluated for association with osteoporosis. We explored the common SNPs arising from the haplotype map of the human genome (HapMap) across all these genes. BMD at the femoral neck and lumbar spine was measured by dual-energy x-ray absorptiometry. Fractures were defined as clinically apparent, site-specific, validated nonvertebral and vertebral low-energy fractures.Results150 candidate genes were identified and 36 016 SNPs in these loci were assessed. SNPs from 9 gene loci (ESR1, LRP4, ITGA1, LRP5, SOST, SPP1, TNFRSF11A, TNFRSF11B, and TNFSF11) were associated with BMD at either site. For most genes, no SNP was statistically significant. For statistically significant SNPs (n = 241), effect sizes ranged from 0.04 to 0.18 SD per allele. SNPs from the LRP5, SOST, SPP1, and TNFRSF11A loci were significantly associated with fracture risk; odds ratios ranged from 1.13 to 1.43 per allele. These effects on fracture were partially independent of BMD at SPP1 and SOST.LimitationOnly common polymorphisms in linkage disequilibrium with SNPs in HapMap could be assessed, and previously reported associations for SNPs in some candidate genes could not be excluded.ConclusionIn this large-scale collaborative genome-wide meta-analysis, 9 of 150 candidate genes were associated with regulation of BMD, 4 of which also significantly affected risk for fracture. However, most candidate genes had no consistent association with BMD.

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Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

Publications

Meta-analysis identifies a MECOM gene as a novel predisposing factor of osteoporotic fracture.

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