骨质疏松症是一种具有强烈遗传背景的骨骼疾病。该研究旨在确定两代马耳他家族中早发性家族性骨质疏松症和低骨密度(BMD)的遗传决定因素。
招募了15名年龄在28-74岁之间的亲戚。对12个亲属进行全基因组测序,并在马耳他骨质疏松性骨折研究(MOFS)中对入围变体进行基因分型以进行复制。
遵循显性遗传模式的顺序变体过滤在SELP中识别出罕见的错义变体,TGF-β2和ADAMTS20均被预测为可能致病并参与骨免疫学。TGF-β2c.1136C>T在MOFS的5个个体中被鉴定为杂合性,其中四人腰椎和髋部骨质减少/骨质疏松,和/或患有低创伤骨折。ADAMTS20c.4090A>T的杂合性伴随着较低的总髋部BMD(p=0.018)和较低的MOFS中的总血清钙水平(p<0.01),重述家庭的发现。携带SELPc.2177T>C的替代等位基因(TC/CC)的至少一个拷贝的女性相对于具有TT基因型的女性表现出下腰椎BMD和/或腕部骨折史的趋势。
我们的研究结果表明,识别出的变异体,单独或组合,可能是家族性骨质疏松症和低骨密度的原因,需要在更大的集合中复制。
Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family.
Fifteen relatives aged between 28-74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication.
Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-β2 and
ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-β2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the
ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype.
Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.