Malic enzyme gene polymorphism is associated with responsiveness in circulating parathyroid hormone after long-term calcium supplementation

Abstract

Objective: To identify genetic variations associated with parathyroid hormone (PTH) suppression after long-term calcium supplementation. Design and Participants: For high throughput SNP screening, subjects consisted of 171 postmenopausal women without osteoporosis at the lumbar spine. A separate group of 19 premenpausal women were recruited for calcium absorption study. Postmenopausal women in the screening group were given 500 mg/day calcium supplementation. Setting: Bangkok, Thailand. Measurements: Parathyroid hormone (PTH) and bone mineral density (BMD) were measured at baseline and 2 years after calcium supplementation. High throughput single-nucleotide polymorphism (SNP) screening was performed by comparing estimated allele frequencies derived from hybridization signal intensities of pooled DNA samples on Affymetrix's 10K SNP genotyping microarrays based responsiveness in PTH after calcium supplementation. Genotyping of SNP rs1112482 in malic enzyme gene (ME1) gene, a SNP among those with highest odds ratio of being related to PTH suppression after calcium, was performed in all postmenopausal subjects in the screening group and premenopausal women in the calcium absorption study group in which fractional calcium absorption was assessed by stable isotope dilution. Data were expressed as mean +/- SEM. Results: PTH significantly decreased after 2 years of calcium supplementation (4.7 + 1.9 vs. 4.4 + 1.6 pmol/L, P < 0.01). There was a significant increase in lumbar spine BMD (1.03 + 0.01 vs. 1.01 + 0.01 g/cm 2 , P < 0.001) but not femoral neck BMD. In 108 subjects whose PTH levels decreased after calcium, the suppression of PTH was higher in those with at least one C allele in rs1112482 of ME1 gene (-26.3 ± 2.1 vs. -16.9 ± 1.4%, P < 0.001). Fractional calcium absorption also tends to the higher in subjects in the calcium absorption study group with at least one C allele (n = 6) compared to those without the C allele (n = 13) (58.0 ± 4.9 vs. 49.3 ± 2.8%, P = 0.054). Conclusion: Cytosolic malic enzyme 1 gene polymorphism is associated with the degree of suppression of parathyroid hormone after long-term calcium supplementation. The effect is probably mediated through an increase in intestinal calcium absorpti on.