Duaa I. Olwi, Lena R. Kaisinger, Katherine A. Kentistou, Marc Vaudel, Stasa Stankovic, Pål R. Njølstad, Stefan Johansson, John R. B. Perry, Felix R. Day, Ken K. Ong
{"title":"胰岛素抵抗和 IGF-1 生物作用对儿童和成人肥胖的可能因果效应:孟德尔随机研究。","authors":"Duaa I. Olwi, Lena R. Kaisinger, Katherine A. Kentistou, Marc Vaudel, Stasa Stankovic, Pål R. Njølstad, Stefan Johansson, John R. B. Perry, Felix R. Day, Ken K. Ong","doi":"10.1038/s41366-024-01605-4","DOIUrl":null,"url":null,"abstract":"Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear. We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and ‘biological effect’ filtering of fasting insulin and IGF-1 associated variants. Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10−3) and lower adult BMI (P = 1.4 × 10−5). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10−3), but effects on adult BMI were inconclusive. Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations.","PeriodicalId":14183,"journal":{"name":"International Journal of Obesity","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11502485/pdf/","citationCount":"0","resultStr":"{\"title\":\"Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study\",\"authors\":\"Duaa I. Olwi, Lena R. Kaisinger, Katherine A. Kentistou, Marc Vaudel, Stasa Stankovic, Pål R. Njølstad, Stefan Johansson, John R. B. Perry, Felix R. Day, Ken K. Ong\",\"doi\":\"10.1038/s41366-024-01605-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear. We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and ‘biological effect’ filtering of fasting insulin and IGF-1 associated variants. Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10−3) and lower adult BMI (P = 1.4 × 10−5). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10−3), but effects on adult BMI were inconclusive. Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. 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Likely causal effects of insulin resistance and IGF-1 bioaction on childhood and adult adiposity: a Mendelian randomization study
Circulating insulin and insulin-like growth factor-1 (IGF-1) concentrations are positively correlated with adiposity. However, the causal effects of insulin and IGF-1 on adiposity are unclear. We performed two-sample Mendelian randomization analyses to estimate the likely causal effects of fasting insulin and IGF-1 on relative childhood adiposity and adult body mass index (BMI). To improve accuracy and biological interpretation, we applied Steiger filtering (to avoid reverse causality) and ‘biological effect’ filtering of fasting insulin and IGF-1 associated variants. Fasting insulin-increasing alleles (35 variants also associated with higher fasting glucose, indicative of insulin resistance) were associated with lower relative childhood adiposity (P = 3.8 × 10−3) and lower adult BMI (P = 1.4 × 10−5). IGF-1-increasing alleles also associated with taller childhood height (351 variants indicative of greater IGF-1 bioaction) showed no association with relative childhood adiposity (P = 0.077) or adult BMI (P = 0.562). Conversely, IGF-1-increasing alleles also associated with shorter childhood height (306 variants indicative of IGF-1 resistance) were associated with lower relative childhood adiposity (P = 6.7 × 10−3), but effects on adult BMI were inconclusive. Genetic causal modelling indicates negative effects of insulin resistance on childhood and adult adiposity, and negative effects of IGF-1 resistance on childhood adiposity. Our findings demonstrate the need to distinguish between bioaction and resistance when modelling variants associated with biomarker concentrations.
期刊介绍:
The International Journal of Obesity is a multi-disciplinary forum for research describing basic, clinical and applied studies in biochemistry, physiology, genetics and nutrition, molecular, metabolic, psychological and epidemiological aspects of obesity and related disorders.
We publish a range of content types including original research articles, technical reports, reviews, correspondence and brief communications that elaborate on significant advances in the field and cover topical issues.