Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Broad Institute, Cambridge, MA, USA.
Int J Obes (Lond). 2024 May;48(5):694-701. doi: 10.1038/s41366-024-01470-1. Epub 2024 Jan 24.
While environmental factors play an important role in weight loss effectiveness, genetics may also influence its success. We examined whether a genome-wide polygenic score for BMI was associated with weight loss effectiveness and aimed to identify common genetic variants associated with weight loss.
Participants in the ONTIME study (n = 1210) followed a uniform, multimodal behavioral weight-loss intervention. We first tested associations between a genome-wide polygenic score for higher BMI and weight loss effectiveness (total weight loss, rate of weight loss, and attrition). We then conducted a genome-wide association study (GWAS) for weight loss in the ONTIME study and performed the largest weight loss meta-analysis with earlier studies (n = 3056). Lastly, we ran exploratory GWAS in the ONTIME study for other weight loss outcomes and related factors.
We found that each standard deviation increment in the polygenic score was associated with a decrease in the rate of weight loss (Beta (95% CI) = -0.04 kg per week (-0.06, -0.01); P = 3.7 × 10) and with higher attrition after adjusting by treatment duration. No associations reached genome-wide significance in meta-analysis with previous GWAS studies for weight loss. However, associations in the ONTIME study showed effects consistent with published studies for rs545936 (MIR486/NKX6.3/ANK1), a previously noted weight loss locus. In the meta-analysis, each copy of the minor A allele was associated with 0.12 (0.03) kg/m higher BMI at week five of treatment (P = 3.9 × 10). In the ONTIME study, we also identified two genome-wide significant (P < 5×10) loci for the rate of weight loss near genes implicated in lipolysis, body weight, and metabolic regulation: rs146905606 near NFIP1/SPRY4/FGF1; and rs151313458 near LSAMP.
Our findings are expected to help in developing personalized weight loss approaches based on genetics.
Obesity, Nutrigenetics, Timing, and Mediterranean (ONTIME; clinicaltrials.gov: NCT02829619) study.
虽然环境因素在减肥效果中起着重要作用，但遗传因素也可能影响减肥效果。我们研究了 BMI 的全基因组多基因评分是否与减肥效果有关，并旨在确定与减肥相关的常见遗传变异。
ONTIME 研究（n=1210）的参与者遵循统一的多模式行为减肥干预措施。我们首先测试了更高 BMI 的全基因组多基因评分与减肥效果（总减重、减重率和脱落）之间的关联。然后，我们在 ONTIME 研究中进行了全基因组关联研究（GWAS）以研究体重减轻，并与早期研究（n=3056）进行了最大的体重减轻荟萃分析。最后，我们在 ONTIME 研究中对其他体重减轻结果和相关因素进行了探索性 GWAS。
我们发现，多基因评分每增加一个标准差，与减重率下降相关（Beta（95%CI）=-0.04kg/周[-0.06，-0.01]；P=3.7×10），并且在调整治疗持续时间后，脱落率更高。在与以前的 GWAS 研究的荟萃分析中，没有关联达到全基因组显著水平。然而，ONTIME 研究中的关联结果与已发表的研究结果一致，rs545936（MIR486/NKX6.3/ANK1）是一个先前注意到的减肥基因座。在荟萃分析中，每周治疗 5 周时，每个次要 A 等位基因的拷贝与 BMI 增加 0.12（0.03）kg/m 相关（P=3.9×10）。在 ONTIME 研究中，我们还在与脂肪分解、体重和代谢调节相关的基因附近鉴定出两个与减重率相关的全基因组显著（P<5×10）位点：rs146905606 附近的 NFIP1/SPRY4/FGF1 基因和 rs151313458 附近的 LSAMP 基因。
我们的发现有望帮助根据遗传学制定个性化的减肥方法。
肥胖、营养遗传学、时间和地中海（ON TIME；clinicaltrials.gov：NCT02829619）研究。
