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Common genetic variants associate with serum phosphorus concentration.

ABSTRACT: Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk in Communities Study, Framingham Offspring Study, and the Rotterdam Study. We excluded participants with an estimated GFR <45 ml/min per 1.73 m(2) to focus on phosphorus metabolism under normal conditions. We imputed genotypes to approximately 2.5 million single-nucleotide polymorphisms in the HapMap and combined study-specific findings using meta-analysis. We tested top polymorphisms from discovery cohorts in a 5444-person replication sample. Polymorphisms in seven loci with minor allele frequencies 0.08 to 0.49 associate with serum phosphorus concentration (P = 3.5 x 10(-16) to 3.6 x 10(-7)). Three loci were near genes encoding the kidney-specific type IIa sodium phosphate co-transporter (SLC34A1), the calcium-sensing receptor (CASR), and fibroblast growth factor 23 (FGF23), proteins that contribute to phosphorus metabolism. We also identified genes encoding phosphatases, kinases, and phosphodiesterases that have yet-undetermined roles in phosphorus homeostasis. In the replication sample, five of seven top polymorphisms associate with serum phosphorous concentrations (P < 0.05 for each). In conclusion, common genetic variants associate with serum phosphorus in the general population. Further study of the loci identified in this study may help elucidate mechanisms of phosphorus regulation.

SUBMITTER: Kestenbaum B

PROVIDER: S-EPMC3152230 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Common genetic variants associate with serum phosphorus concentration.

Kestenbaum Bryan B Glazer Nicole L NL Köttgen Anna A Felix Janine F JF Hwang Shih-Jen SJ Liu Yongmei Y Lohman Kurt K Kritchevsky Stephen B SB Hausman Dorothy B DB Petersen Ann-Kristin AK Gieger Christian C Ried Janina S JS Meitinger Thomas T Strom Tim M TM Wichmann H Erich HE Campbell Harry H Hayward Caroline C Rudan Igor I de Boer Ian H IH Psaty Bruce M BM Rice Kenneth M KM Chen Yii-Der Ida YD Li Man M Arking Dan E DE Boerwinkle Eric E Coresh Josef J Yang Qiong Q Levy Daniel D van Rooij Frank J A FJ Dehghan Abbas A Rivadeneira Fernando F Uitterlinden André G AG Hofman Albert A van Duijn Cornelia M CM Shlipak Michael G MG Kao W H Linda WH Witteman Jacqueline C M JC Siscovick David S DS Fox Caroline S CS

Journal of the American Society of Nephrology : JASN 20100617 7

Phosphorus is an essential mineral that maintains cellular energy and mineralizes the skeleton. Because complex actions of ion transporters and regulatory hormones regulate serum phosphorus concentrations, genetic variation may determine interindividual variation in phosphorus metabolism. Here, we report a comprehensive genome-wide association study of serum phosphorus concentration. We evaluated 16,264 participants of European ancestry from the Cardiovascular Heath Study, Atherosclerosis Risk i ...[more]

PMID: 20558539

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Project description:Hypo- and hyperphosphatemia have each been associated with increased mortality in maintenance hemodialysis (MHD) patients. There has not been previous evaluation of a differential relationship between serum phosphorus level and death risk across varying age groups in MHD patients.In a 6-year cohort of 107,817 MHD patients treated in a large dialysis organization, we examined the association between serum phosphorus levels with all-cause and cardiovascular mortality within 5 age categories (15 to <45, 45 to <65, 65 to <70, 70 to <75, and ?75 years old) using Cox proportional hazards models adjusted for case-mix covariates and malnutrition inflammation complex syndrome (MICS) surrogates.All-cause and cardiovascular mortality.The overall mean age of the cohort was 60 ± 16 years, among whom there were 45% women, 35% Blacks, and 58% diabetics. The time-averaged serum phosphorus level (mean ± SD) within each age category was 6.26 ± 1.4, 5.65 ± 1.2, 5.26 ± 1.1, 5.11 ± 1.0, and 4.88 ± 1.0 mg/dL, respectively (P for trend <.001). Hyperphosphatemia (>5.5 mg/dL) was consistently associated with increased all-cause and cardiovascular mortality risks across all age categories, including after adjustment for case-mix and MICS-related covariates. In fully adjusted models, a low serum phosphorus level (<3.5 mg/dL) was associated with increased all-cause mortality only in elderly MHD patients ?65 years old (hazard ratio [95% confidence interval]: 1.21 [1.07-1.37], 1.13 [1.02-1.25], and 1.28 [1.2-1.37] for patients 65 to <70, 70 to <75, and ?75 years old, respectively), but not in younger patients (<65 years old). A similar differential cardiovascular mortality risk for low serum phosphorus levels between old and young age groups was observed.The association between hyperphosphatemia and mortality is similar across all age groups of MHD patients, whereas hypophosphatemia is associated with increased mortality only in elderly MHD patients. Preventing very low serum phosphorus levels in elderly dialysis patients may be associated with better outcomes, which needs to be examined in future studies.

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Common genetic variants associate with serum phosphorus concentration.

Publications

Common genetic variants associate with serum phosphorus concentration.

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