A replication study for three nephrolithiasis loci at 5q35.3, 7p14.3 and 13q14.1 in the Japanese population

Abstract

A previous genome-wide association study (GWAS) reported three novel nephrolithiasis-susceptibility loci at 5q35.3, 7p14.3 and 13q14.1. Here, we investigated the association of these loci with nephrolithiasis by using an independent Japanese sample set. We performed case-control association analysis using 601 patients with nephrolithiasis and 201 control subjects. We selected seven single-nucleotide polymorphisms (SNPs): rs12654812 and rs11746443 from 5q35.3 (RGS14-SLC34A1-PFN3-F12); rs12669187 and rs1000597 from 7p14.3 (INMT-FAM188B-AQP1); and rs7981733, rs1170155, and rs4142110 from 13q14.1 (DGKH (diacylglycerol kinase)), which were previously reported to be significantly associated with nephrolithiasis. rs12654812, rs12669187 and rs7981733 were significantly associated with nephrolithiasis after Bonferroni's correction (P=3.12 × 10(-3), odds ratio (OR)=1.43; P=6.40 × 10(-3), OR=1.57; and P=5.00 × 10(-3), OR=1.41, respectively). Meta-analysis of current and previous GWAS results indicated a significant association with nephrolithiasis (P=7.65 × 10(-15), 7.86 × 10(-14) and 1.06 × 10(-9), respectively). We observed a cumulative effect with these three SNPs; individuals with three or more risk alleles had a 5.9-fold higher risk for nephrolithiasis development than those with only one risk allele. Our findings elucidated the significance of genetic variation at these three loci in nephrolithiasis in the Japanese population.

Association Study of Reported Significant Loci at 5q35.3, 7p14.3, 13q14.1 and 16p12.3 with Urolithiasis in Chinese Han Ethnicity

“…In the replication study, SNP rs12669187, located on FAM188B gene, also showed a significant association with nephrolithiasis7. The role of FAM118B in the pathogenesis of nephrolithiasis has not been fully elucidated so far.…”

“…conducted a GWAS using a total of 5892 nephrolithiasis cases and 17809 controls of Japanese population and found three novel loci for nephrolithiasis, including rs11746643 on 5q35.3, rs100597 on 7p14.3 and rs4142110 on 13q14.1. Yasui et al 7. performed a replication study for these three loci and their results have reported that rs12654812 on 5q35.3, rs12669187 on 7p14.3 and rs7981733 on 13p14.1 were significantly associated with nephrolithiasis.…”

“…We selected a total of eight single-nucleotide polymorphisms (SNPs) at four loci on 5q35.3, 7p14.3, 13q14.1, and 16p12.3, which were previously reported to be significantly associated with nephrolithiasis6789. We genotyped these SNPs on the MassARRAY iPLEX platform (Sequenom, Inc., San Diego, CA) at the Fudan-VARI Center for Genetic Epidemiology at Fudan University.…”

“…In order to evaluate the role of these genetic factors, a validation study has been performed in 2013 by using an independent Japanese cohort, including 601 nephrolithiasis and 201 control subjects. Their findings elucidate the significance of genetic variation at these 3 loci in nephrolithiasis in Japanese population7. In 2014, an association study of DGKH genetic polymorphisms with calcium oxalate nephrolithiasis has been performed in Chinese population, and their findings also implicate a link between nucleotide variant of DGKH and nephrolithiasis8.…”

Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation

“…Interestingly, renal Mws sorted from op/op mice expressed lower levels of stone-and M2-related genes based on microarray analysis. Some genes listed in Figure 10A (such as Aqp1, Aurka, and Slc34a1) inhibit the development of renal stones, 53,54 suggesting that CSF-1 deficiency resulted in severely impaired defense against crystal formation in Mws. hi M2-like Mws by CSF-1 treatment reduced renal crystal deposition and CaOx crystal formation.…”