rs115239632 (ALPL): Alkaline phosphatase & kidney stones

Key takeaways

• This variant sits near ALPL, the gene encoding tissue-nonspecific alkaline phosphatase, a standard blood test marker for bone, liver, and kidney function
• Large-scale genetic studies of 35 blood and urine biomarkers across 363,228 UK Biobank participants have mapped the genetic architecture of alkaline phosphatase and related metabolic traits at loci across the genome
• Serum calcium, a closely related metabolic pathway in which ALPL participates, has been shown to mediate 12%-15% of the kidney stone disease risk attributable to central adiposity, with central adiposity raising serum calcium by approximately 0.12 mmol/L
• The alternate allele at this locus increases expression of the nearby NBPF2P pseudogene in esophagus mucosa, artery aorta, and lung tissue
• A direct association between this variant and kidney stone disease has not been reported in the available studies; the pathway connection is inferred from the ALPL gene's role in calcium metabolism

What the research says A genome-wide association study of 35 blood and urine biomarkers in 363,228 UK Biobank participants identified 1,857 loci containing 3,374 fine-mapped associations, characterizing the genetic architecture of routinely measured laboratory values including alkaline phosphatase at the NBPF3 - ALPL region. A complementary study using Mendelian randomization meta-analyzed across UK Biobank and FinnGen cohorts found that higher waist-to-hip ratio (WHR, a marker of central adiposity), independent of body mass index (BMI), increases kidney stone disease risk by approximately 24% per one standard deviation increase in WHR, with approximately 12%-15% of that effect mediated through elevated serum calcium concentrations (beta approximately 0.12 mmol/L per standard deviation of WHR), while BMI independently increases kidney stone risk by approximately 21% per standard deviation through mechanisms other than serum calcium. GTEx v11 eQTL data (953 donors, FDR<0.05) show that the alternate allele at rs115239632 is associated with increased expression of NBPF2P across three tissue types and increased expression of CELA3A and CELA3B in cultured fibroblasts GTEx Portal.

Reported associations

• Serum alkaline phosphatase and blood biomarkers: This locus, containing the ALPL gene which encodes tissue-nonspecific alkaline phosphatase, was among 1,857 loci identified in a GWAS of 35 routinely measured blood and urine laboratory values in 363,228 participants across five population groups
• Kidney stone disease pathway - serum calcium mediation: Research using Mendelian randomization found that central adiposity (WHR) raises serum calcium by approximately 0.12 mmol/L, with this calcium elevation mediating 12%-15% of WHR's total effect on kidney stone disease risk; WHR independently increases kidney stone risk by approximately 24% per standard deviation, while BMI independently increases risk by approximately 21% per standard deviation through separate mechanisms
• NBPF2P expression (esophagus mucosa, artery aorta, lung): The alternate allele increases NBPF2P expression across three tissue types, with the strongest signals in esophagus mucosa and artery aorta GTEx Portal
• CELA3B expression (cultured fibroblasts): The alternate allele increases CELA3B expression in cultured fibroblasts GTEx Portal
• CELA3A expression (cultured fibroblasts): The alternate allele increases CELA3A expression in cultured fibroblasts GTEx Portal

Evidence quality The biomarker GWAS (Nature genetics, 2021) included 363,228 unrelated UK Biobank individuals spanning five population groups (White British n=318,953; non-British White n=23,582; African n=6,019; South Asian n=7,338; East Asian n=1,082), applying Bonferroni-corrected thresholds (meta-analysis p<5 x 10^-9 for imputed variants) and producing 3,374 fine-mapped credible associations; effect size estimates showed high agreement across 42 previously published study cohorts. The kidney stone disease study (Journal of the American Society of Nephrology, 2023) used observational UK Biobank data over a mean of 11.6 years per person, with multivariable and mediation Mendelian randomization meta-analyzed with FinnGen data; the approximately 24% and 21% kidney stone risk estimates and the 12%-15% calcium mediation figure are genome-wide causal inference results and are not effect sizes specific to rs115239632. The available study excerpts do not report this variant by rsID, meaning the connection between this locus and kidney stone disease rests on pathway reasoning (ALPL and serum calcium) rather than a direct genetic association study of kidney stone outcomes; this link should be treated as preliminary and inferential. GTEx eQTL findings from 953 donors at FDR<0.05 represent tissue-specific regulatory signals and should not be interpreted as clinical outcome predictors on their own.

Tissue-specific expression effects

• NBPF2P: The alternate allele is associated with increased expression in esophagus mucosa, artery aorta, and lung tissue; the signal is strongest in esophagus mucosa and artery aorta GTEx Portal
• CELA3B: The alternate allele is associated with increased expression in cultured fibroblasts GTEx Portal
• CELA3A: The alternate allele is associated with increased expression in cultured fibroblasts GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.