BMI is a strong indicator of complications from type I diabetes, especially under intensive treatment. We have genotyped 435 type 1 diabetics using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed mitoGWAS on BMI. We identified additive interactions between mitochondrial and nuclear variants in genes associated with mitochondrial functioning MitoCarta2.0 and confirmed and refined the results on external cohorts: the Framingham Heart Study (FHS) and GTEx data. Linear mixed model analysis was performed using the GENESIS package in R/Bioconductor. We find a borderline significant association between the mitochondrial variant rs28357980, localized to MT-ND2, and BMI (β = − 0.69, p = 0.056). This BMI association was confirmed on 1889 patients from FHS cohort (β = − 0.312, p = 0.047). Next, we searched for additive interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with variants in the genes SIRT3, ATP5B, CYCS, TFB2M and POLRMT. TFB2M is a mitochondrial transcription factor and together with TFAM creates a transcription promoter complex for the mitochondrial polymerase POLRMT. We have found an interaction between rs3021088 in MT-ND2 and rs6701836 in TFB2M leading to BMI decrease (inter_pval = 0.0241), while interaction of rs3021088 in MT-ND2 and rs41542013 in POLRMT led to BMI increase (inter_pval = 0.0004). The influence of these interactions on BMI was confirmed in external cohorts. Here, we have shown that variants in the mitochondrial genome as well as additive interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general cohorts.

中文翻译：

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T1DM 患者线粒体 GWAS 以及核线粒体上位性与 BMI 的关联。


BMI 是 I 型糖尿病并发症的有力指标，尤其是在强化治疗下。我们使用 Illumina Infinium Omni Express Exome-8 v1.4 芯片对 435 名 1 型糖尿病患者进行了基因分型，并对 BMI 进行了 mitoGWAS。我们确定了与线粒体功能 MitoCarta2.0 相关的基因中线粒体和核变异之间的附加相互作用，并确认和完善了外部队列的结果：弗雷明汉心脏研究 (FHS) 和 GTEx 数据。使用 R/Bioconductor 中的 GENESIS 包进行线性混合模型分析。我们发现定位于 MT-ND2 的线粒体变异 rs28357980 与 BMI 之间存在显着相关性（β = − 0.69，p = 0.056）。这种 BMI 关联在 FHS 队列的 1889 名患者中得到证实（β = − 0.312，p = 0.047）。接下来，我们寻找线粒体和核变异之间的附加相互作用。 MT-ND2 变体与 SIRT3、ATP5B、CYCS、TFB2M 和 POLRMT 基因中的变体相互作用。 TFB2M 是一种线粒体转录因子，与 TFAM 一起创建线粒体聚合酶 POLRMT 的转录启动子复合物。我们发现MT-ND2中的rs3021088和TFB2M中的rs6701836之间的相互作用导致BMI下降（inter_pval = 0.0241），而MT-ND2中的rs3021088和POLRMT中的rs41542013之间的相互作用导致BMI增加（inter_pval = 0.0004）。这些相互作用对 BMI 的影响在外部队列中得到了证实。在这里，我们发现线粒体基因组的变异以及线粒体和核 SNP 之间的附加相互作用会影响 T1DM 和一般人群的 BMI。