NFAT5 and SLC4A10 Loci Associate with Plasma Osmolality

被引：24

作者：

Boger, Carsten A. ^{[1
]}

Gorski, Mathias ^{[1
]}

McMahon, Gearoid M. ^{[1
]}

Xu, Huichun ^{[1
]}

Chang, Yen-Pei C. ^{[1
]}

van der Most, Peter J. ^{[1
]}

Navis, Gerjan ^{[1
]}

Nolte, Ilja M. ^{[1
]}

de Borst, Martin H. ^{[1
]}

Zhang, Weihua ^{[1
]}

Lehne, Benjamin ^{[1
]}

Loh, Marie ^{[1
]}

Tan, Sian-Tsung ^{[1
]}

Boerwinkle, Eric ^{[1
]}

Grams, Morgan E. ^{[1
]}

Sekula, Peggy ^{[1
]}

Li, Man ^{[1
]}

Wilmot, Beth ^{[1
]}

Moon, James G. ^{[1
]}

Scheet, Paul ^{[1
]}

Cucca, Francesco ^{[1
]}

Xiao, Xiangjun ^{[1
]}

Lyytikainen, Leo-Pekka ^{[1
]}

Delgado, Graciela ^{[1
]}

Grammer, Tanja B. ^{[1
]}

Kleber, Marcus E. ^{[1
]}

Sedaghat, Sanaz ^{[1
]}

Rivadeneira, Fernando ^{[1
]}

Corre, Tanguy ^{[1
]}

Kutalik, Zoltan ^{[1
]}

Bergmann, Sven ^{[1
]}

Nielson, Carrie M. ^{[1
]}

Srikanth, Priya ^{[1
]}

Teumer, Alexander ^{[1
]}

Muller-Nurasyid, Martina ^{[1
]}

Brockhaus, Anne Catharina ^{[1
]}

Pfeufer, Arne ^{[1
]}

Rathmann, Wolfgang ^{[1
]}

Peters, Annette ^{[1
]}

Matsumoto, Martha ^{[1
]}

de Andrade, Mariza ^{[1
]}

Atkinson, Elizabeth J. ^{[1
]}

Robinson-Cohen, Cassianne ^{[1
]}

de Boer, Ian H. ^{[1
]}

Hwang, Shih-Jen ^{[1
]}

Heid, Iris M. ^{[1
]}

Gogele, Martin ^{[1
]}

Concas, Maria Pina ^{[1
]}

Tanaka, Toshiko ^{[1
]}

Bandinelli, Stefania ^{[1
]}

机构：

[1] Oregon Hlth & Sci Univ, Div Nephrol & Hypertens, Mailcode SJH6,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA

来源：

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY | 2017年 / 28卷 / 08期

关键词：

NEPHROGENIC DIABETES-INSIPIDUS; TRANSCRIPTION FACTOR-BINDING; CELL-TYPES; INAPPROPRIATE ANTIDIURESIS; INTRONIC ENHANCERS; GENE-EXPRESSION; PRIMARY-CARE; HYPONATREMIA; PROTEIN; IDENTIFICATION;

D O I：

10.1681/ASN.2016080892

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Disorders of water balance, an excess or deficit of total body water relative to body electrolyte content, are common and ascertained by plasma hypo- or hypernatremia, respectively. We performed a two-stage genome-wide association study meta analysis on plasma sodium concentration in 45,889 individuals of European descent (stage 1 discovery) and 17,637 additional individuals of European descent (stage 2 replication), and a transethnic meta-analysis of replicated single-nucleotide polymorphisms in 79,506 individuals (63,526 individuals of European descent, 8765 individuals of Asian Indian descent, and 7215 individuals of African descent). In stage 1, we identified eight loci associated with plasma sodium concentration at P<5.0 x 10(-6). Of these, rs9980 at NFAT5 replicated in stage 2 meta-analysis (P=3.1 x 10(-5)), with combined stages 1 and 2 genome-wide significance of P=5.6 x 10(-10). Transethnic meta-analysis further supported the association at rs9980 (P=5.9 x 10(-12)). Additionally, rs16846053 at SLC4A10 showed nominally, but not genome-wide, significant association in combined stages 1 and 2 meta-analysis (P=6.7 x 10(-8)). NFAT5 encodes a ubiquitously expressed transcription factor that coordinates the intracellular response to hypertonic stress but was not previously implicated in the regulation of systemic water balance. SLC4A10 encodes a sodium bicarbonate transporter with a brain-restricted expression pattern, and variant rs16846053 affects a putative intronic NFAT5 DNA binding motif. The lead variants for NFAT5 and SLC4A10 are cis expression quantitative trait loci in tissues of the central nervous system and relevant to transcriptional regulation. Thus, genetic variation in NFAT5 and SLC4A10 expression and function in the central nervous system may affect the regulation of systemic water balance.

引用

页码：2311 / 2321

页数：11

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