TY - JOUR
T1 - Polymorphisms in Renal Ammonia Metabolism Genes Correlate With 24-Hour Urine pH
AU - Canales, Benjamin K.
AU - Smith, Jennifer A.
AU - Weiner, I. David
AU - Ware, Erin B.
AU - Zhao, Wei
AU - Kardia, Sharon L.R.
AU - Curhan, Gary C.
AU - Turner, Stephen T.
AU - Perinpam, Majuran
AU - Lieske, John C.
N1 - Publisher Copyright:
© 2017 International Society of Nephrology
PY - 2017
Y1 - 2017
N2 - Introduction Urine pH is critical for net acid and solute excretion, but the genetic factors that contribute to its regulation are incompletely understood. Methods We tested the association of single nucleotide polymorphisms (SNPs) from 16 genes related to ammonia (NH3) metabolism (15 biological candidates selected a priori, 1 selected from a previous genome-wide association study analysis) to that of 24-hour urine pH in 2493 individuals of European descent across 2 different cohorts using linear regression, adjusting for age, sex, and body mass index. Results Of 2871 total SNPs in these genes, 13 SNPs in ATP6V0A4 (a4 subunit of hydrogen− adenosine triphosphatase), SLC9A3 (sodium/hydrogen exchanger, isoform 3), and RHCG (Rhesus C glycoprotein), and 12 SNPs from insulin-like growth factor binding protein 7 (IGFBP7) had a meta-analysis P value <0.01 in the joint analysis plus a consistent direction of effect and at a least suggestive association (P < 0.1) in both cohorts. The maximal effect size (in pH units) for each additional minor allele of the identified SNPs was −0.13 for IGFBP7, −0.08 for ATP6V0A4, 0.06 for RHCG, and −0.06 for SLC9A3; SNP rs34447434 in IGFBP7 had the lowest meta-analysis P value (P = 7.1 × 10−8). After adjusting for net alkali absorption, urine pH remained suggestively associated with multiple SNPs in IGFBP, 1 SNP in ATP6V0A4, and a new SNP in GLS (phosphate-dependent glutaminase). Discussion Overall, these findings suggest that variants in common genes involved in ammonia metabolism may substantively contribute to basal urine pH regulation. These variations might influence the likelihood of developing disease conditions associated with altered urine pH, such as uric acid or calcium phosphate kidney stones.
AB - Introduction Urine pH is critical for net acid and solute excretion, but the genetic factors that contribute to its regulation are incompletely understood. Methods We tested the association of single nucleotide polymorphisms (SNPs) from 16 genes related to ammonia (NH3) metabolism (15 biological candidates selected a priori, 1 selected from a previous genome-wide association study analysis) to that of 24-hour urine pH in 2493 individuals of European descent across 2 different cohorts using linear regression, adjusting for age, sex, and body mass index. Results Of 2871 total SNPs in these genes, 13 SNPs in ATP6V0A4 (a4 subunit of hydrogen− adenosine triphosphatase), SLC9A3 (sodium/hydrogen exchanger, isoform 3), and RHCG (Rhesus C glycoprotein), and 12 SNPs from insulin-like growth factor binding protein 7 (IGFBP7) had a meta-analysis P value <0.01 in the joint analysis plus a consistent direction of effect and at a least suggestive association (P < 0.1) in both cohorts. The maximal effect size (in pH units) for each additional minor allele of the identified SNPs was −0.13 for IGFBP7, −0.08 for ATP6V0A4, 0.06 for RHCG, and −0.06 for SLC9A3; SNP rs34447434 in IGFBP7 had the lowest meta-analysis P value (P = 7.1 × 10−8). After adjusting for net alkali absorption, urine pH remained suggestively associated with multiple SNPs in IGFBP, 1 SNP in ATP6V0A4, and a new SNP in GLS (phosphate-dependent glutaminase). Discussion Overall, these findings suggest that variants in common genes involved in ammonia metabolism may substantively contribute to basal urine pH regulation. These variations might influence the likelihood of developing disease conditions associated with altered urine pH, such as uric acid or calcium phosphate kidney stones.
KW - acid-base
KW - diabetes mellitus
KW - genetics
KW - kidney stone disease
KW - uric acid
KW - urine pH
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U2 - 10.1016/j.ekir.2017.06.009
DO - 10.1016/j.ekir.2017.06.009
M3 - Article
AN - SCOPUS:85040730330
SN - 2468-0249
VL - 2
SP - 1111
EP - 1121
JO - Kidney International Reports
JF - Kidney International Reports
IS - 6
ER -