Abstract
Our study investigated the association of rare allelic variants with extremes of 24-hour urinary calcium excretion because higher urinary calcium excretion is a dominant risk factor for calcium-based kidney stone formation. We resequenced 40 candidate genes potentially related to urinary calcium excretion in individuals from the Nurses' Health Studies I & II and the Health Professionals Follow-up Study. A total of 960 participants were selected based on availability of 24-hour urine collection data and level of urinary calcium excretion (low vs. high). We utilized DNA sample pooling, droplet-based target gene enrichment, multiplexing, and high-throughput sequencing. Approximately 64% of samples (n = 615) showed both successful target enrichment and sequencing data with >20-fold deep coverage. A total of 259 novel allelic variants were identified. None of the rare gene variants (allele frequencies <2%) were found with increased frequency in the low vs. high urinary calcium groups; most of these variants were only observed in single individuals. Unadjusted analysis of variants with allele frequencies ≥2% suggested an association of the Claudin14 SNP rs113831133 with lower urinary calcium excretion (6/520 versus 29/710 haplotypes, P value = 0.003). Our data, together with previous human and animal studies, suggest a possible role for Claudin14 in urinary calcium excretion. Genetic validation studies in larger sample sets will be necessary to confirm our findings for rs113831133. In the tested set of candidate genes, rare allelic variants do not appear to contribute significantly to differences in urinary calcium excretion between individuals.
Highlights
Kidney stone disease is a major cause of morbidity associated with tremendous pain, suffering, and substantial economic impact [1,2,3]
Nephrolithiasis is a multifactorial disease with genetic and environmental factors determining the likelihood of stone formation [5]
We and other investigators have identified multiple environmental risk factors associated with increased risk including lower dietary Ca2+ intake [6,7,8], lower fluid intake [6,7,8,9], and higher body mass index [8,10]
Summary
Kidney stone disease is a major cause of morbidity associated with tremendous pain, suffering, and substantial economic impact [1,2,3]. Higher urinary Ca2+ excretion is associated with higher risk of calcium-containing kidney stone formation. Nephrolithiasis is a multifactorial disease with genetic and environmental factors determining the likelihood of stone formation [5]. Genes for rare Mendelian forms of nephrolithiasis and increased urinary Ca2+ excretion have been identified; mutations in these genes explain only a very small fraction of kidney stone disease in the general population. Inactivating (loss-of-function) mutations in the calcium-sensing receptor (CaSR) cause autosomal-dominant hypocalcemia and hypercalciuria [14]. Another example is familial hypomagnesemia associated with hypercalciuria and nephrocalcinosis (mutations in Claudin16) [15]. Additional genes were identified in various animal models such as the renal epithelial Ca2+ transporter gene (TRPV5), which when mutated causes severe hypercalciuria in the mouse [16]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
