Metabolic heritability at birth: implications for chronic disease research

Abstract

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.

Brain carnitine deficiency causes nonsyndromic autism with an extreme male bias: A hypothesis

“…Short‐chain acyl‐CoA dehydrogenase deficiency is caused by mutations in ACADS and one partially inactivating SNP in the gene is particularly common. Although six SNPs in ACADS are associated with increased levels of plasma butyrlcarnitine , the great majority of deficient patients detected by newborn screening experience a benign course . We suggest that heterozygous or homozygous genotypes for partial or complete ACADS deficiency could be a common risk factor or modifier for NoMeND autism.…”

A pilot data analysis of a metabolomic HPLC-MS/MS study of patients with COPD

“…27,31 Metabolic heritability may be implicated in aberrant levels of some acylcarnitines, as it was shown that some metabolite levels are inheritable at birth and that some genes are associated with acylcarnitines. 32 The role of inherited fatty acid oxidation deficiency and genetics in COPD may be further implicated by the higher levels of the acylated C8/C2 carnitines ratio in COPD patients. The C8/C2 ratio and the C8 levels are the most accurate markers of medium-chain acyl-CoA dehydrogenase deficiency (MCADD), the most common inherited defect in the fatty acid oxidation pathway marked by an inability to break down medium-chain fatty acids during periods of fasting.…”

Acylcarnitine Profiles in HIV-Exposed, Uninfected Neonates in the United States

“…46,47 Moreover, it is not yet known whether having abnormal acylcarnitine levels at birth has implications for the development of chronic diseases, as is the case in adults with elevated acylcarnitines. 48 For these reasons it will be important to follow the health of HEU newborns with abnormal ACP beyond early childhood. This is especially crucial in a world in which access to ARV for pregnant HIV-positive women is increasing 49 and the reduction of chronic disease-related morbidity and mortality is a global health priority.…”