Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea.
Endocrinol Metab (Seoul). 2020 Dec;35(4):801-810. doi: 10.3803/EnM.2020.735. Epub 2020 Nov 24.
As the genetic variants of trabecular bone microarchitecture are not well-understood, we performed a genome-wide association study to identify genetic determinants of bone microarchitecture analyzed by trabecular bone score (TBS).
TBS-associated genes were discovered in the Ansung cohort (discovery cohort), a community-based rural cohort in Korea, and then validated in the Gene-Environment Interaction and Phenotype (GENIE) cohort (validation cohort), consisting of subjects who underwent health check-up programs. In the discovery cohort, 2,451 participants were investigated for 1.42 million genotyped and imputed markers.
In the validation cohort, identified as significant variants were evaluated in 2,733 participants. An intronic variant in iroquois homeobox 3 (IRX3), rs1815994, was significantly associated with TBS in men (P=3.74E-05 in the discovery cohort, P=0.027 in the validation cohort). Another intronic variant in mitogen-activated protein kinase kinase 5 (MAP2K5), rs11630730, was significantly associated with TBS in women (P=3.05E-09 in the discovery cohort, P=0.041 in the validation cohort). Men with the rs1815994 variant and women with the rs11630730 variant had lower TBS and lumbar spine bone mineral density. The detrimental effects of the rs1815994 variant in men and rs11630730 variant in women were also identified in association analysis (β=-0.0281, β=-0.0465, respectively).
In this study, the rs1815994 near IRX3 in men and rs11630730 near MAP2K5 in women were associated with deterioration of the bone microarchitecture. It is the first study to determine the association of genetic variants with TBS. Further studies are needed to confirm our findings and identify additional variants contributing to the trabecular bone microarchitecture.
由于小梁骨微观结构的遗传变异尚不清楚，我们进行了全基因组关联研究，以确定通过小梁骨评分（TBS）分析的骨微观结构的遗传决定因素。
在韩国一个以社区为基础的农村队列——安城队列（发现队列）中发现与 TBS 相关的基因，然后在基因-环境相互作用和表型（GENIE）队列（验证队列）中进行验证，该队列由接受健康检查计划的受试者组成。在发现队列中，对 2451 名参与者进行了 142 万个基因分型和推断标记物的研究。
在验证队列中，评估了确定为显著变异的 2733 名参与者。IRX3 基因内含子中的一个变异 rs1815994 与男性的 TBS 显著相关（在发现队列中 P=3.74E-05，在验证队列中 P=0.027）。MAP2K5 基因内含子中的另一个变异 rs11630730 与女性的 TBS 显著相关（在发现队列中 P=3.05E-09，在验证队列中 P=0.041）。携带 rs1815994 变异的男性和携带 rs11630730 变异的女性的 TBS 和腰椎骨密度较低。在关联分析中还发现了男性 rs1815994 变异和女性 rs11630730 变异的不利影响（β=-0.0281，β=-0.0465）。
在这项研究中，男性中靠近 IRX3 的 rs1815994 变异和女性中靠近 MAP2K5 的 rs11630730 变异与骨微观结构的恶化有关。这是第一项确定遗传变异与 TBS 相关的研究。需要进一步的研究来证实我们的发现，并确定其他导致小梁骨微观结构的变异。
