Laboratory of Gene Expression Regulation in Development, Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
Center for Mathematical Modeling in Drug Development, Institute of Biodesign and Complex Systems Modeling, I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation, Moscow, Russia.
Biochimie. 2024 Mar;218:162-173. doi: 10.1016/j.biochi.2023.10.012. Epub 2023 Oct 19.
Cardiometabolic diseases (CMDs) are complex disorders with a heterogenous phenotype, which are caused by multiple factors including genetic factors. Single nucleotide polymorphisms (SNPs) rs45539933 (p.Ala64Thr), rs10011540 (c.-112A>C), rs3811791 (c.-1766A>G), and rs1800592 (c.-3826A>G) in the UCP1 gene have been analyzed for association with CMDs in many studies providing controversial results. However, previous studies only considered individual UCP1 SNPs and did not evaluate them in an integrated manner, which is a more powerful approach to uncover genetic component of complex diseases. This study aimed to investigate associations between UCP1 genotype combinations and CMDs or CMD risk factors in the context of non-genetic factors. We performed multiple logistic regression analysis and proposed new methodology of testing different combinations of SNP genotypes. We found that probability of CMDs increased in presence of the three-SNP combination of genotypes with minor alleles of c.-3826A>G and p.Ala64Thr and wild allele of c.-112A>C, with increasing age, body mass index (BMI), body fat percentage (BF%) and may differ between sexes and between countries. The combination of genotypes with c.-3826A>G minor allele and wild homozygotes of c.-112A>C and p.Ala64Thr was associated with increased probability of diabetes. While combination of genotypes with minor alleles of all three SNPs reduced the CMD probability. The present results suggest that age, BMI, sex, and UCP1 three-SNP combinations of genotypes significantly contribute to CMD probability. Varying of c.-112A>C alleles in the genotype combination with minor alleles of c.-3826A>G and p.Ala64Thr markedly changes CMD probability.
心血管代谢疾病（CMDs）是一种具有异质表型的复杂疾病，由遗传因素和多种因素共同引起。已有多项研究分析了 UCP1 基因中的单核苷酸多态性（SNPs）rs45539933（p.Ala64Thr）、rs10011540（c.-112A>C）、rs3811791（c.-1766A>G）和 rs1800592（c.-3826A>G）与 CMDs 的相关性，结果存在争议。然而，之前的研究仅考虑了 UCP1 基因的单个 SNP，并未进行综合评估，而综合评估是揭示复杂疾病遗传成分的更有力方法。本研究旨在探讨 UCP1 基因型组合与非遗传因素背景下 CMD 或 CMD 危险因素之间的相关性。我们进行了多元逻辑回归分析，并提出了一种新的 SNP 基因型组合检验方法。我们发现，在存在 c.-3826A>G 及 p.Ala64Thr 三个 SNP 基因型的次要等位基因和 c.-112A>C 野生等位基因，以及随着年龄、体重指数（BMI）、体脂肪百分比（BF%）增加的情况下，CMD 发生的概率会增加，而且这种增加可能存在性别和国家差异。c.-3826A>G 次要等位基因和 c.-112A>C 及 p.Ala64Thr 野生纯合子基因型组合与糖尿病发生概率增加相关。而所有三个 SNP 基因型的次要等位基因组合降低了 CMD 发生的概率。本研究结果表明，年龄、BMI、性别和 UCP1 基因三个 SNP 基因型组合显著影响 CMD 发生的概率。c.-112A>C 等位基因在 c.-3826A>G 和 p.Ala64Thr 三个 SNP 基因型的组合中发生变化，明显改变了 CMD 发生的概率。
