Genetic determinants of extracellular magnesium concentration: analysis of multiple candidate genes, and evidence for association with the estrogen receptor alpha (ESR1) locus.

ABSTRACT

BACKGROUND: Serum magnesium concentration is a quantitative trait with substantial heritability. Although the pool of candidate genes continues to grow, only the histocompatibility locus has been associated with magnesium levels. To explore other possibilities, we targeted 6 candidate genes physiologically relevant to magnesium metabolism. METHODS: We studied a large cohort (n=471) derived from a well-characterized population of healthy Caucasian women 18 to 35 years. Total serum magnesium and calcium were measured by atomic absorption spectrophotometry (aaMg & aaCa). Genomic DNA was amplified and SNPs in candidate genes (CASR, VDR, ESR1, CLDN16, EGF1, TRPM6) genotyped by routine methods. RESULTS: We found a significant association between estrogen receptor alpha (ESR1) polymorphisms, PvuII and XbaI, and magnesium (r=-0.116, p=0.012 and r=-0.126, p=0.006, respectively). Stratifying by PvuII genotype (P/p alleles), the mean adjusted total magnesium (aaMg) concentration was significantly higher (p=0.01) in the pp group (0.823+/-0.005 mmol/l, n=130) than in PP homozygotes (0.805+/-0.006 mmol/l, n=70), and the mean in Pp heterozygotes was intermediate (0.810+/-0.005 mmol/l, n=180). No significant associations were observed with the other candidate genes tested. CONCLUSIONS: The significant association between magnesium and ESR1 polymorphisms supports previous studies linking physiologic changes in serum magnesium to estrogen status.