Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, Connecticut, USA.
Institute of Physical Activity and Nutrition, Deakin University, Melbourne, Victoria, Australia.
Obesity (Silver Spring). 2022 Dec;30(12):2468-2476. doi: 10.1002/oby.23559. Epub 2022 Oct 25.
The aim of this study was to understand whether the paradoxical association of missense variant rs373863828 in CREB3 regulatory factor (CREBRF) with higher BMI but lower odds of diabetes is explained by either metabolically favorable body fat distribution or greater fat-free mass.
This study explored the association of the minor allele with dual-energy x-ray absorptiometry-derived body composition in n = 421 Samoans and used path analysis to examine the mediating role of fat and fat-free mass on the relationship between rs373863828 and fasting glucose.
Among females, the rs373863828 minor A allele was associated with greater BMI. There was no association of genotype with percent body fat, visceral adiposity, or fat distribution in either sex. In both females and males, lean mass was greater with each A allele: 2.16 kg/copy (p = 0.0001) and 1.73 kg/copy (p = 0.02), respectively. Path analysis showed a direct negative effect of rs373863828 genotype on fasting glucose (p = 0.004) consistent with previous findings, but also an indirect positive effect on fasting glucose operating through fat-free mass (p = 0.027).
The protective effect of rs373863828 in CREBRF, common among Pacific Islanders, on type 2 diabetes does not operate through body composition. Rather, the variant's effects on body size/composition and fasting glucose likely operate via different, tissue-specific mechanisms.
本研究旨在探讨 CREB 调节因子 (CREBRF) 中错义变异 rs373863828 与较高 BMI 但较低糖尿病风险之间的矛盾关联是否可由代谢有利的体脂分布或更大的去脂体重来解释。
本研究通过对 n=421 名萨摩亚人进行双能 X 射线吸收法（DXA）衍生的身体成分研究，探讨了该次要等位基因与 rs373863828 之间的关联，并采用路径分析来检验 rs373863828 与空腹血糖之间关系中脂肪和去脂体重的中介作用。
在女性中，rs373863828 次要 A 等位基因与更高的 BMI 相关。基因型与身体脂肪百分比、内脏脂肪或两性的脂肪分布均无关联。在女性和男性中，每个 A 等位基因的瘦体重均更大：分别为 2.16 公斤/副本（p=0.0001）和 1.73 公斤/副本（p=0.02）。路径分析显示，rs373863828 基因型对空腹血糖有直接的负向影响（p=0.004），与之前的发现一致，但也通过去脂体重对空腹血糖产生间接的正向影响（p=0.027）。
在 2 型糖尿病中，CREBRF 中的 rs373863828 变异在太平洋岛民中很常见，但它对糖尿病的保护作用并非通过身体成分起作用。相反，该变异对身体大小/组成和空腹血糖的影响可能通过不同的、组织特异性的机制起作用。
