致病性,总功能丧失的DYRK1B变体导致与2型糖尿病相关的单一性肥胖症
Lise Folon1,2, Morgane Baron1,2, Victoria Scherrer1,2
1Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France.
Diabetes care
|January 3, 2024
概括
罕见的DYRK1B基因变异会导致单基性肥胖,并增加2型糖尿病的风险. 功能性评估对于理解这些遗传变异的影响至关重要.
科学领域:
- 遗传学 遗传学 是一个
- 代谢疾病 代谢疾病
- 分子生物学分子生物学
背景情况:
- DYRK1B基因的罕见变异与中心肥胖,2型糖尿病和早期冠状动脉疾病有关.
- 之前对DYRK1B变异的研究是有限的,需要对其更广泛的影响进行更大规模的调查.
研究的目的:
- 在更大的规模上调查DYRK1B变异的影响.
- 功能性评估DYRK1B变体并确定它们的致病性.
- 评估致病性DYRK1B变体与代谢特征之间的关联.
主要方法:
- 从肥胖和2型糖尿病的病例对照研究中对9,353名参与者进行DYRK1B的测序.
- 鉴定DYRK1B变体的体外功能评估.
- 使用美国医学遗传学和基因组学学院 (ACMG) 标准进行致病性确定.
- 用调整的混合效应得分测试评估变异对代谢特征的影响.
主要成果:
- 鉴定了65种罕见的异合体DYRK1B变体,但与肥胖或2型糖尿病无关.
- 确定了20种致病或可能致病 (P/LP) 变异,其中6种对DYRK1B活性表现出完全抑制作用 (P/LP-null).
- P/LP和P/LP-null DYRK1B变体与增加的BMI和肥胖风险有关,P/LP-null变体的影响更为明显.
- P/LP-null变体与更高的禁食葡萄糖和2型糖尿病风险有关,而P/LP变体对葡萄糖平衡没有影响.
结论:
- 在DYRK1B中,致病或可能致病 (P/LP) 变异,特别是那些导致功能完全丧失的变异,是导致与2型糖尿病相关的单一致肥胖的原因.
- 功能性评估对于准确确定P/LP DYRK1B变体的有形影响至关重要.
- 这项研究强调了DYRK1B在代谢调节和疾病发展中的关键作用.
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