Abstract
Serum hepcidin concentration is regulated by iron status, inflammation, erythropoiesis and numerous other factors, but underlying processes are incompletely understood. We studied the association of common and rare single nucleotide variants (SNVs) with serum hepcidin in one Italian study and two large Dutch population-based studies. We genotyped common SNVs with genome-wide association study (GWAS) arrays and subsequently performed imputation using the 1000 Genomes reference panel. Cohort-specific GWAS were performed for log-transformed serum hepcidin, adjusted for age and gender, and results were combined in a fixed-effects meta-analysis (total N 6,096). Six top SNVs (p<5x10-6) were genotyped in 3,821 additional samples, but associations were not replicated. Furthermore, we meta-analyzed cohort-specific exome array association results of rare SNVs with serum hepcidin that were available for two of the three cohorts (total N 3,226), but no exome-wide significant signal (p<1.4x10-6) was identified. Gene-based meta-analyses revealed 19 genes that showed significant association with hepcidin. Our results suggest the absence of common SNVs and rare exonic SNVs explaining a large proportion of phenotypic variation in serum hepcidin. We recommend extension of our study once additional substantial cohorts with hepcidin measurements, GWAS and/or exome array data become available in order to increase power to identify variants that explain a smaller proportion of hepcidin variation. In addition, we encourage follow-up of the potentially interesting genes that resulted from the gene-based analysis of low-frequency and rare variants.
Highlights
Iron is an essential trace element for fundamental metabolic processes in humans [1, 2]
For hepcidin/transferrin saturation (TS), nine and 16 genes were significant in all individuals and in the subset, respectively, but none overlapped. This is the first meta-analysis of genome-wide association study (GWAS) and exome array results for serum hepcidin
The fact that our meta-analysis revealed no single nucleotide variants (SNVs) that were significantly associated with serum hepcidin suggests that there are no common, low-frequency or rare variants that explain a large proportion of phenotypic variation in serum hepcidin
Summary
Iron is an essential trace element for fundamental metabolic processes in humans [1, 2]. The iron balance in the human body is tightly controlled, with the peptide hormone hepcidin as key regulator of systemic iron homeostasis [7]. Storage and tissue distribution of iron by binding to the cellular iron exporter ferroportin and inducing its internalization and degradation [8]. In this way, hepcidin regulates the uptake of dietary iron from the intestine and the release of iron from macrophages involved in recycling of iron from senescent erythrocytes [7]
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