Ryckman Kelli K, Smith Caitlin J, Jelliffe-Pawlowski Laura L, Momany Allison M, Berberich Stanton L, Murray Jeffrey C
Department of Epidemiology, University of Iowa, Iowa City, IA, 52242, USA,
Hum Genet. 2014 Aug;133(8):1049-57. doi: 10.1007/s00439-014-1450-4. Epub 2014 May 22.
Recent genome-wide association studies of the adult human metabolome have identified genetic variants associated with relative levels of several acylcarnitines, which are important clinical correlates for chronic conditions such as type 2 diabetes and obesity. We have previously shown that these same metabolite levels are highly heritable at birth; however, no studies to our knowledge have examined genetic associations with these metabolites measured at birth. Here, we examine, in 743 newborns, 58 single nucleotide polymorphisms (SNPs) in 11 candidate genes previously associated with differing relative levels of short-chain acylcarnitines in adults. Six SNPs (rs2066938, rs3916, rs3794215, rs555404, rs558314, rs1799958) in the short-chain acyl-CoA dehydrogenase gene (ACADS) were associated with neonatal C4 levels. Most significant was the G allele of rs2066938, which was associated with significantly higher levels of C4 (P = 1.5 × 10(-29)). This SNP explains 25 % of the variation in neonatal C4 levels, which is similar to the variation previously reported in adult C4 levels. There were also significant (P < 1 × 10(-4)) associations between neonatal levels of C5-OH and SNPs in the solute carrier family 22 genes (SLC22A4 and SLC22A5) and the 3-methylcrotonyl-CoA carboxylase 1 gene (MCCC1). We have replicated, in newborns, SNP associations between metabolic traits and the ACADS and SLC22A4 genes observed in adults. This research has important implications not only for the identification of rare inborn errors of metabolism but also for personalized medicine and early detection of later life risks for chronic conditions.
近期针对成年人类代谢组的全基因组关联研究已经确定了与几种酰基肉碱相对水平相关的基因变异，这些酰基肉碱是2型糖尿病和肥胖症等慢性疾病的重要临床关联指标。我们之前已经表明，这些相同的代谢物水平在出生时具有高度遗传性；然而，据我们所知，尚无研究探讨与出生时测量的这些代谢物的基因关联。在此，我们在743名新生儿中检测了11个候选基因中的58个单核苷酸多态性（SNP），这些基因之前与成年人中短链酰基肉碱的不同相对水平相关。短链酰基辅酶A脱氢酶基因（ACADS）中的6个SNP（rs2066938、rs3916、rs3794215、rs555404、rs558314、rs1799958）与新生儿C4水平相关。最显著的是rs2066938的G等位基因，它与显著更高的C4水平相关（P = 1.5 × 10⁻²⁹）。该SNP解释了新生儿C4水平变异的25%，这与之前报道的成人C4水平变异相似。新生儿C5 - OH水平与溶质载体家族22基因（SLC22A4和SLC22A5）以及3 - 甲基巴豆酰辅酶A羧化酶1基因（MCCC1）中的SNP之间也存在显著（P < 1 × 10⁻⁴）关联。我们在新生儿中重复了在成年人中观察到的代谢性状与ACADS和SLC22A4基因之间的SNP关联。这项研究不仅对罕见先天性代谢缺陷的识别具有重要意义，而且对个性化医疗以及慢性疾病后期生活风险的早期检测也具有重要意义。
