Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine

Abstract

The nature and importance of genetic factors regulating the differential handling of Ca and Mg by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg over Ca in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.

Claudin-14 Gene Polymorphisms and Urine Calcium Excretion

“…These findings suggest that minor alleles of CLDN14 SNPs might play a protective role against hypercalciuria and kidney stones as described in populations of different origin (4,(14)(15)(16)30). We confirmed the association of CLDN14 39 region SNPs with 24-hour calcium excretion, but different SNPs were implicated with respect to previous studies (4,(14)(15)(16).…”

“…Claudins (CLDNs) are a family of transmembrane proteins that interact with each other and other proteins to form barriers or pores regulating paracellular solute transport in tight junctions (1)(2)(3)(4). Different CLDNs are expressed in specific segments of the kidney tubule and contribute to the development of distinctive properties of each tubular portion (2,3).…”

Magnesium supplementation to prevent recurrence of renal stones

“…The selectivity of the paracellular pathway is determined by claudins which form a cation -selective tight junction through which the Mg paracellular transport is done 23,24 . Three claudin proteins, claudin -14, claudin -16 and claudin -19, make the cation -selective paracellular pathway for Ca and Mg. Claudin -16 and claudin -19 form the pores and claudin -14 inhibits the cation selectivity of that pore 25,26 .…”

“…Genome--wide association studies have identified several candidate genes implicated in renal tubular handling of lithogenic elements, such as calcium, phosphate and oxalate, and inhibitors of lithogenesis, such as Mg and citrate 28 . A genome -wide association study suggested that variants in the claudin -14 gene are associated with the ratio of urinary excretion of Mg and to the urinary stone risk 30,26 .…”

Heterogeneity of tight junctions in the thick ascending limb

“…Claudin‐14 has been shown to interfere with claudin‐16 and claudin‐19 complexes to reduce cation selectivity, and it regulates paracellular Ca 2+ transport subsequent to CaSR stimulation . Interestingly, claudin‐14 variants not only associate with renal calcifications but also strongly with urinary Mg 2+ /Ca 2+ ratio in healthy humans, indicating that there is a differential effect of claudin‐14 on Ca 2+ versus Mg 2+ transport . The investigation of the underlying mechanism on the level of claudin regulation in the renal tubule under defined dietary Mg 2+ /Ca 2+ conditions could provide a first clue toward understanding the independent control of the transport of these two essential divalent cations.…”