Delplanque Jérôme, Le Collen Lauriane, Loiselle Hélène, Leloire Audrey, Toussaint Bénédicte, Vaillant Emmanuel, Charpentier Guillaume, Franc Sylvia, Balkau Beverley, Marre Michel, Henriques Emma, Buse Falay Emmanuel, Derhourhi Mehdi, Froguel Philippe, Bonnefond Amélie
Inserm/CNRS UMR 1283/8199, Institut Pasteur de Lille, EGID, Lille University Hospital, Lille, France; University of Lille, Lille, France.
Inserm/CNRS UMR 1283/8199, Institut Pasteur de Lille, EGID, Lille University Hospital, Lille, France; University of Lille, Lille, France; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, Nancy University Hospital, Nancy, France; Department of Metabolism, Nancy University Hospital, Nancy, France.
Am J Hum Genet. 2024 Dec 5;111(12):2668-2674. doi: 10.1016/j.ajhg.2024.10.014. Epub 2024 Nov 18.
Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous variants in LEPR and to evaluate their effect on obesity. We sequenced LEPR in ∼10,000 participants from the French RaDiO study. We found 86 rare heterozygous variants. Each identified variant was then investigated in vitro using luciferase and western blot assays. Using the criteria of the American College of Medical Genetics and Genomics (ACMG), including the strong criterion related to functional assays, we found 12 pathogenic LEPR variants. Most heterozygotes did not present with obesity, and we found no association between these pathogenic variants and body mass index (BMI). This lack of association between pathogenic LEPR variants and obesity risk or BMI was confirmed using exome data from 200,000 individuals in the UK Biobank. In the literature, among 55 reported heterozygotes for of a rare pathogenic LEPR variant, only 27% had obesity. In conclusion, monoallelic pathogenic LEPR variants were functionally tested, and they do not elevate the risk of obesity or BMI levels. This raises questions about the use of setmelanotide, a costly drug with potential side effects, based solely on the presence of a heterozygous LEPR variant.
由双等位基因致病性LEPR（瘦素受体）变异引起肥胖的个体可从新型MC4R激动剂setmelanotide中获益。一项正在进行的3期临床试验（NCT05093634）纳入了携带杂合LEPR变异的肥胖个体，尽管这些变异对致肥胖的影响仍未得到充分评估。本研究的目的是从功能上评估LEPR中的杂合变异，并评估它们对肥胖的影响。我们对来自法国RaDiO研究的约10,000名参与者的LEPR进行了测序。我们发现了86个罕见的杂合变异。然后使用荧光素酶和蛋白质印迹分析在体外对每个鉴定出的变异进行研究。根据美国医学遗传学与基因组学学会（ACMG）的标准，包括与功能分析相关的严格标准，我们发现了12个致病性LEPR变异。大多数杂合子没有肥胖表现，并且我们发现这些致病性变异与体重指数（BMI）之间没有关联。使用英国生物银行中200,000个人的外显子组数据证实了致病性LEPR变异与肥胖风险或BMI之间缺乏关联。在文献中，在55例报告的罕见致病性LEPR变异杂合子中，只有27%患有肥胖症。总之，对单等位基因致病性LEPR变异进行了功能测试，它们不会增加肥胖风险或BMI水平。这引发了关于仅基于杂合LEPR变异的存在就使用setmelanotide（一种有潜在副作用的昂贵药物）的问题。
