Association analysis of 10 candidate genes causing Mendelian calcium nephrolithiasis in the INCIPE study: a South European general population cohort

Abstract

Background Idiopathic calcium nephrolithiasis (ICN) is a common condition with different a complex phenotype influenced by both environmental and genetic factors. In our study we investigated the association of allelic variants with the history of nephrolithiasis. Methods We genotyped and selected 10 candidate genes potentially related to risk of ICN from 3046 subjects participating in the INCIPE survey (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a cross-sectional study enrolling subjects from the general population in the Veneto region in Italy. Results Overall, 66 224 variants mapping on the 10 candidate genes were studied. 69 and 18 variants in INCIPE-1 and INCIPE-2, respectively, were significantly associated with stone history (SH). Only 2 variants, rs36106327 (chr20:54 171 755, intron variant) and rs35792925 (chr20:54 173 157, intron variant) of the CYP24A1 gene were observed to be consistently associated with SH. Both variants have not been previously reported in association with renal stones or other conditions. Carriers of CYP24A1 variants showed a significant increase in ratio 1,25 (OH)2 D/25 OH D compared with controls (P = 0.043). Although not associated with SH in this study, the rs4811494 CYP24A1 variant that was reported to be causative of nephrolithiasis was very prevalent in heterozygosity (20%). Conclusion Our data suggest a possible role for CYP24A1 variants in the risk of nephrolithiasis. Genetic validation studies in larger sample sets will be necessary to confirm our findings.

Vitamin D and Calcium Supplementation and Urolithiasis: A Controversial and Multifaceted Relationship

“…In their seminal study, Schlingmann and co-workers found recessive mutations in CYP24A1, the gene encoding 25-hydroxyvitamin D 24-hydroxylase, the key enzyme involved in the degradation of 1,25-dihydroxy vitamin D3, in six children with spontaneous hypercalcemia and also in a cohort of neonates in whom severe hypercalcemia developed after vitamin D administration [ 98 ]. Since then, many studies have reported a strong association between an increased risk of forming urinary stones and some genetic variants in the CYP24A1 gene, VDR gene polymorphisms, or other genetic variants of some specific solute transporters (SLC34A1, SLC34A3), suggesting that some individuals may be more prone than others to suffer from pro-lithogenic effects of vitamin D administration [ 99 , 100 , 101 , 102 , 103 , 104 , 105 ].…”

Predictive value of single-nucleotide polymorphism signature for nephrolithiasis recurrence: a 5-year prospective study

“…Prior studies have suggested that certain clinical and radiologic features of kidney stones are associated with disease recurrence [ 7–9 ]. In addition to traditional risk factors, genetics also play a key role in nephrolithiasis [ 10 ]. Single nucleotide polymorphism (SNP) is one of the most common types of genetic differences among humans.…”