Bordoni Laura, Marchegiani Francesca, Piangerelli Marco, Napolioni Valerio, Gabbianelli Rosita
School of Advanced Studies, University of Camerino, Via Gentile III da Varano, Camerino, MC, Italy.
Clinical Laboratory and Molecular Diagnostics, INRCA-IRCCS, Ancona, Italy.
IUBMB Life. 2017 Feb;69(2):98-105. doi: 10.1002/iub.1596. Epub 2017 Jan 16.
Pediatric obesity develops when a complex biological predisposition collides with an obesogenic environment. To further elucidate the role of genetics in obesity onset, we performed a candidate-gene association study in a young and sportive Italian population by testing the association of functional polymorphisms in ACE (rs4646994), FTO (rs9939609), MC4R (rs17782313) and PPARG (rs1801282) genes with body mass index (BMI) and waist-to-height ratio (WHtR). We also tested the combinations of identified risk genotypes and epistatic interactions among them to determine the existence of cumulative effects in predicting the predisposition to gain weight. Our results confirm a significant direct influence of MC4R rs17782313 and PPARG rs1801282 on body composition, that is, minor allele homozygotes showed significantly higher BMI (rs17782313, β = 1.258, P = 0.031; rs1801282, β = 6.689, P = 1.2 × 10 ) and WHtR (rs17782313, β = 0.021, P = 0.005; rs1801282, β = 0.069, P = 0.003) values. Moreover, by leveraging multifactor dimensionality reduction and general linear model (GLM) approaches we identified an epistatic interaction between ACE and MC4R, where heterozygosity at ACE rs4646994 seems to protect from the unfavorable predisposition to gain weight given by C/C genotype at MC4R rs17782313 (GLM, P = 0.004). In conclusion, to clarify the role of genetics in multifactorial diseases remains a difficult goal, even for the most investigated polymorphisms and in controlled populations. Further studies on epistasis and gene-gene interaction will help to elucidate this complex scenario. © 2017 IUBMB Life, 69(2):98-105, 2017.
当复杂的生物易感性与致肥胖环境相互作用时，儿童肥胖就会发生。为了进一步阐明遗传学在肥胖发病中的作用，我们在年轻且热爱运动的意大利人群中开展了一项候选基因关联研究，检测了ACE（rs4646994）、FTO（rs9939609）、MC4R（rs17782313）和PPARG（rs1801282）基因中的功能多态性与体重指数（BMI）和腰高比（WHtR）之间的关联。我们还测试了已识别的风险基因型的组合及其上位性相互作用，以确定在预测体重增加易感性方面是否存在累积效应。我们的结果证实了MC4R rs17782313和PPARG rs1801282对身体组成有显著的直接影响，即次要等位基因纯合子的BMI（rs17782313，β = 1.258，P = 0.031；rs1801282，β = 6.689，P = 1.2×10）和WHtR（rs17782313，β = 0.021，P = 0.005；rs1801282，β = 0.069，P = 0.003）值显著更高。此外，通过利用多因素降维和通用线性模型（GLM）方法，我们发现ACE和MC4R之间存在上位性相互作用，其中ACE rs4646994的杂合性似乎可以抵御MC4R rs17782313的C/C基因型所带来的体重增加的不利易感性（GLM，P = 0.004）。总之，即使对于研究最多的多态性以及在受控人群中，阐明遗传学在多因素疾病中的作用仍然是一个艰巨的目标。对上位性和基因 - 基因相互作用的进一步研究将有助于阐明这一复杂情况。© 2017国际生物化学与分子生物学联盟生命科学，69(2):98 - 105，2017。
