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

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. (C) 2009 Elsevier B.V. All rights reserved.