Muller Yunhua L, Sutherland Jeff, Nair Anup K, Koroglu Cigdem, Kobes Sayuko, Knowler William C, Van Hout Cristopher V, Shuldiner Alan R, Hanson Robert L, Bogardus Clifton, Baier Leslie J
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
Regeneron Genetics Centre, Regeneron Pharmaceuticals, Tarrytown, New York, USA.
Diabetes Metab Res Rev. 2022 Mar;38(3):e3504. doi: 10.1002/dmrr.3504. Epub 2021 Oct 28.
Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians.
Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE.
Amongst the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys-allele frequency = 0.087) significantly associated with T2D (OR [95% CI] = 1.38 [1.17-1.64], p = 0.0002, adjusted for age, sex, birth year, and the first five genetic principal components) and an earlier onset age of T2D (HR = 1.22 [1.09-1.36], p = 0.0005). This variant was further analysed for quantitative traits related to T2D. Amongst non-diabetic American Indians, those with the T2D risk Cys-allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys-allele, p = 0.04) and a mixed meal test (0.08 log µU/ml per Cys-allele, p = 0.003), and had increased lipid oxidation rates post-absorptively and during insulin infusion (0.07 mg [kg estimated metabolic body size {EMBS}] min per Cys-allele for both, p = 0.01 and 0.009, respectively), compared to individuals with the non-risk Arg-allele. In vitro functional studies showed that cells expressing the Cys-allele had a 17.2% decrease in lipolysis under isoproterenol stimulation (p = 0.03) and a 21.3% decrease in lipase enzyme activity measured by using p-nitrophenyl butyrate as a substrate (p = 0.04) compared to the Arg-allele.
The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homoeostasis and risk of T2D.
由LIPE基因编码的激素敏感性脂肪酶（HSL）参与脂肪分解。基于先前的动物和人体研究，在美国印第安人群体样本中，对LIPE基因作为2型糖尿病（T2D）发病候选基因进行了分析。
利用6782名有纵向临床测量数据参与者的全外显子组序列数据，来识别LIPE基因的变异。
在鉴定出的16个错义变异中，一个Arg611Cys变异（rs34052647；Cys等位基因频率 = 0.087）与T2D显著相关（OR [95% CI] = 1.38 [1.17 - 1.64]，p = 0.0002，经年龄、性别、出生年份和前五个遗传主成分校正），且与T2D发病年龄提前相关（HR = 1.22 [1.09 - 1.36]，p = 0.0005）。对该变异进一步分析了与T2D相关的数量性状。在非糖尿病的美国印第安人中，携带T2D风险Cys等位基因的个体，在口服葡萄糖耐量试验期间胰岛素水平升高（每个Cys等位基因升高0.07标准差，p = 0.04），在混合餐试验中也升高（每个Cys等位基因升高0.08 log μU/ml，p = 0.003），并且在吸收后和胰岛素输注期间脂质氧化率升高（两者均为每个Cys等位基因升高0.07 mg/[kg估计代谢体重{EMBS}]·min，p分别为0.01和0.009），与携带非风险Arg等位基因的个体相比。体外功能研究表明，与Arg等位基因相比，表达Cys等位基因的细胞在异丙肾上腺素刺激下脂肪分解降低17.2%（p = 0.03），以对硝基苯丁酸为底物测量的脂肪酶活性降低21.3%（p = 0.04）。
Arg611Cys变异导致脂肪分解有适度损害，从而影响葡萄糖稳态和T2D风险。
