Parviainen Roope, Skarp Sini, Korhonen Linda, Serlo Willy, Männikkö Minna, Sinikumpu Juha-Jaakko
Department of Children and Adolescents, Oulu Childhood Fracture and Sports Injury Study, Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO), Oulu Medical Research Center (MRC), University of Oulu and Oulu University Hospital, FI-90029 Oulu, Finland.
Northern Finland Birth Cohort, Faculty of Medicine, University of Oulu, FI-90014 Oulu, Finland.
Exp Ther Med. 2020 Aug;20(2):1716-1724. doi: 10.3892/etm.2020.8885. Epub 2020 Jun 12.
The understanding of the biological and environmental risk factors of fractures in pediatrics is limited. Previous studies have reported that fractures involve heritable traits, but the genetic factors contributing to the risk of fractures remain elusive. Furthermore, genetic influences specific to immature bone have not been thoroughly studied. Therefore, the aim of the present study was to identify genetic variations that are associated with fractures in early childhood. The present study used a prospective Northern Finland Birth Cohort (year 1986; n=9,432). The study population was comprised of 3,230 cohort members with available genotype data. A total of 48 members of the cohort (1.5%) had in-hospital treated bone fractures during their first 6 years of life. Furthermore, individuals without fracture (n=3,182) were used as controls. A genome-wide association study (GWAS) was performed using a frequentist association test. In the GWAS analysis, a linear regression model was fitted to test for additive effects of single-nucleotide polymorphisms (SNPs; genotype dosage) adjusting for sex and performing population stratification using genotypic principal components. Using the GWAS analysis, the present study identified one locus with a significant association with fractures during childhood on chromosome 10 (rs112635931) and six loci with a suggested implication. The lead SNP rs112635931 was located near proline- and serine-rich 2 (PROSER2) antisense RNA 1 (PROSER2-AS1) and PROSER2, thus suggesting that these may be novel candidate genes associated with the risk of pediatric fractures.
对儿科骨折的生物学和环境风险因素的了解有限。先前的研究报告称骨折涉及遗传特征，但导致骨折风险的遗传因素仍不明确。此外，针对未成熟骨骼的遗传影响尚未得到充分研究。因此，本研究的目的是确定与幼儿骨折相关的基因变异。本研究使用了前瞻性的芬兰北部出生队列（1986年；n = 9432）。研究人群包括3230名有可用基因型数据的队列成员。该队列中共有48名成员（1.5%）在其生命的前6年中因骨折住院治疗。此外，无骨折的个体（n = 3182）用作对照。使用频率关联检验进行全基因组关联研究（GWAS）。在GWAS分析中，拟合线性回归模型以检验单核苷酸多态性（SNP；基因型剂量）的加性效应，同时调整性别并使用基因型主成分进行群体分层。通过GWAS分析，本研究在10号染色体上确定了一个与儿童期骨折显著相关的位点（rs112635931）和六个有潜在关联的位点。主要SNP rs112635931位于富含脯氨酸和丝氨酸的2（PROSER2）反义RNA 1（PROSER2-AS1）和PROSER2附近，因此表明这些可能是与小儿骨折风险相关的新候选基因。
