Kvaløy Kirsti, Holmen Jostein, Hveem Kristian, Holmen Turid Lingaas
HUNT Research Center, Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
PLoS One. 2015 Oct 7;10(10):e0139632. doi: 10.1371/journal.pone.0139632. eCollection 2015.
The complexity of obesity and onset and susceptibility of cardio-metabolic disorders are still poorly understood and is addressed here through studies of genetic influence on weight gain and increased metabolic risk longitudinally.
SUBJECTS/METHODS: Twenty seven previously identified obesity, eating disorder or metabolic risk susceptibility SNPs were tested for association with weight or metabolically related traits longitudinally in 3999 adults participating both in the HUNT2 (1995-97) and HUNT3 (2006-08) surveys. Regression analyses were performed with changes from normal weight to overweight/obesity or from metabolically healthy to adverse developments with regards to blood pressure, glucose, HDL cholesterol, triglycerides or metabolic syndrome as outcomes. Additionally, a sub-sample of 1380 adolescents was included for testing association of nine SNPs with longitudinal weight gain into young adulthood.
The most substantial effect on BMI-based weight gain from normal to overweight/obesity in adults was observed for the DRD2 variant (rs6277)(OR: 0.79, 95% CI: 0.69-0.90, P = 3.9x10(-4), adj. P = 0.015). DRD2 was not associated with BMI on a cross-sectional level. In the adolescent sample, FTO (rs1121980) was associated with change to overweight at adulthood in the combined male-female sample (OR: 1.27, 95% CI: 1.09-1.49, P = 3.0x10(-3), adj. P = 0.019) and in females (OR: 1.53, 95% CI: 1.23-1.91, P = 1.8x10(-4), adj. P = 0.003). When testing for association to longitudinal adverse developments with regard to blood pressure, blood lipids and glucose, only rs964184 (ZNF259/APOA5) was significantly associated to unfavourable triglyceride changes (OR: 1.66, 95% CI: 1.36-2.03, P = 5.7x10(-7), adj. P = 0.001). Pleiotropic effects on metabolic traits, however, were observed for several genetic loci cross-sectionally, ZNF259/APOA5, LPL and GRB14 being the most important.
DRD2 exhibits effects on weight gain from normal weight to overweight/obesity in adults, while, FTO is associated to weight gain from adolescence to young adulthood. Unhealthy longitudinal triglyceride development is strongly affected by ZNF259/APOA. Our main finding, linking the DRD2 variant directly to the longitudinal weight gain observed, has not previously been identified. It suggests a genetic pre-disposition involving the dopaminergic signalling pathways known to play a role in food reward and satiety linked mechanisms.
肥胖的复杂性以及心血管代谢紊乱的发病和易感性仍未得到充分理解，本文通过纵向研究基因对体重增加和代谢风险增加的影响来探讨这一问题。
受试者/方法：在参与HUNT2（1995 - 97年）和HUNT3（2006 - 08年）调查的3999名成年人中，对先前鉴定出的27个肥胖、饮食失调或代谢风险易感性单核苷酸多态性（SNP）进行纵向检测，以确定其与体重或代谢相关性状的关联。以体重从正常变为超重/肥胖，或血压、血糖、高密度脂蛋白胆固醇、甘油三酯或代谢综合征等代谢指标从代谢健康变为不良发展作为结局进行回归分析。此外，纳入1380名青少年的子样本，检测9个SNP与青年期纵向体重增加的关联。
在成年人中，观察到DRD2变体（rs6277）对基于BMI的体重从正常增加到超重/肥胖的影响最为显著（比值比：0.79，95%置信区间：0.69 - 0.90，P = 3.9×10⁻⁴，校正P = 0.015）。DRD2在横断面水平上与BMI无关联。在青少年样本中，FTO（rs1121980）在合并的男女样本中与成年期变为超重相关（比值比：1.27，95%置信区间：1.09 - 1.49，P = 3.0×10⁻³，校正P = 0.019），在女性中也相关（比值比：1.53，95%置信区间：1.23 - 1.91，P = 1.8×10⁻⁴，校正P = 0.003）。在检测与血压、血脂和血糖纵向不良发展的关联时，只有rs964184（ZNF259/APOA5）与甘油三酯的不利变化显著相关（比值比：1.66，95%置信区间：1.36 - 2.03，P = 5.7×10⁻⁷，校正P = 0.001）。然而，在横断面水平上，观察到几个基因位点对代谢性状有 pleiotropic 效应，其中ZNF259/APOA5、LPL和GRB14最为重要。
DRD2对成年人从正常体重增加到超重/肥胖有影响，而FTO与从青少年到青年期的体重增加有关。ZNF259/APOA对不健康的纵向甘油三酯发展有强烈影响。我们将DRD2变体直接与观察到的纵向体重增加联系起来的主要发现，此前尚未被发现。这表明存在一种遗传易感性，涉及已知在食物奖励和饱腹感相关机制中起作用的多巴胺能信号通路。
