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Genome-Wide Meta-Analysis Unravels Interactions Between Magnesium Homeostasis and Metabolic Phenotypes

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META-ANALYSIS www.jasn.org Genome-Wide Meta-Analysis Unravels Interactions between Magnesium Homeostasis and Metabolic Phenotypes Tanguy Corre,1,2,3 Francisco J. Arjona,4 Caroline Hayward,5 Sonia Youhanna,6 Jeroen H.F. de Baaij,4 Hendrica Belge,6 Nadine Nägele,6 Huguette Debaix,6 Maxime G. Blanchard,4 Michela Traglia,7 Sarah E. Harris,8,9 Sheila Ulivi,10 Rico Rueedi,2,3 David Lamparter,2,3 Aurélien Macé,1,3 Cinzia Sala,7 Stefania Lenarduzzi,10 Belen Ponte,11 Menno Pruijm,12 Daniel Ackermann,13 Georg Ehret,14 Daniela Baptista,14 Ozren Polasek,15 Igor Rudan,16 Toby W. Hurd,5 Nicholas D. Hastie,5 Veronique Vitart,5 Geràrd Waeber,17 Zoltán Kutalik,1,3 Sven Bergmann,2,3,18 Rosa Vargas-Poussou,19,20 Martin Konrad,21 Paolo Gasparini,22,23 Ian J. Deary,9,24 John M. Starr,8,25 Daniela Toniolo,7 Peter Vollenweider,17 Joost G.J. Hoenderop,4 René J.M. Bindels,4 Murielle Bochud,1 and Olivier Devuyst6 Due to the number of contributing authors, the affiliations are listed at the end of this article. ABSTRACT Magnesium (Mg2+) homeostasis is critical for metabolism. However, the genetic determinants of the renal handling of Mg2+, which is crucial for Mg2+ homeostasis, and the potential influence on metabolic traits in the general population are unknown. We obtained plasma and urine parameters from 9099 individuals from seven cohorts, and conducted a genome-wide meta-analysis of Mg2+ homeostasis. We identified two 2 loci associated with urinary magnesium (uMg), rs3824347 (P=4.4310 13)nearTRPM6, which encodes an 2 epithelial Mg2+ channel, and rs35929 (P=2.1310 11), a variant of ARL15, which encodes a GTP-binding protein. Together, these loci account for 2.3% of the variation in 24-hour uMg excretion. In human kidney cells, ARL15 regulated TRPM6-mediated currents. In zebrafish, dietary Mg2+ regulated the expression of the highly conserved ARL15 ortholog arl15b,andarl15b knockdown resulted in renal Mg2+ wasting and metabolic disturbances. Finally, ARL15 rs35929 modified the association of uMg with fasting insulin and fat mass in a general population. In conclusion, this combined observational and experimental approach uncovered a gene–environment interaction linking Mg2+ deficiency to insulin resistance and obesity. J Am Soc Nephrol 29: 335–348, 2018. doi: https://doi.org/10.1681/ASN.2017030267 Magnesium (Mg2+) is an essential cation for mul- Received March 11, 2017. Accepted July 19, 2017. tiple enzymatic reactions, including those involving T.C., F.J.A., and C.H. contributed equally to this work. DNA and protein synthesis and energy metabo- O.D., M.B., and R.J.M.B. have codirected this study. lism.1 Abnormal Mg2+ levels in serum are associ- ated with common diseases such as diabetes and Published online ahead of print. Publication date available at metabolic disorders.2 Interventional and longitudi- www.jasn.org. nal observational studies in humans show that high Correspondence: Prof. Dr. Olivier Devuyst, Institute of Physiology, dietary Mg2+ protects against the risk of developing Mechanisms of Inherited Kidney Disorders Group, University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Email: 3–6 type 2 diabetes, and improves glycemic control [email protected] or Prof. Murielle Bochud, IUMSP, Route de la in patients with diabetes7 as well as in overweight Corniche 10, 1010 Lausanne, Switzerland. Email: murielle.bochud@ META-ANALYSIS nondiabetic people.8–10 In young adults, high Mg2+ chuv.ch intake is significantly associated with lower Copyright © 2018 by the American Society of Nephrology J Am Soc Nephrol 29: 335–348, 2018 ISSN : 1046-6673/2901-335 335 META-ANALYSIS www.jasn.org incidence of metabolic syndrome.11 Further, there is evidence Significance Statement linking Mg2+ intake to body weight regulation, with low intake potentially impairing lean body mass growth,12,13 whereas Mg2+ Magnesium (Mg2+) is essential for many enzymatic reactions in- 2+ supplementation may increase lean body mass and decrease fat volved in energy metabolism, and abnormal Mg levels are associ- 14 ated with diabetes and metabolic disorders. The genetic factors mass in overweight women. 2+ 2+ regulating Mg homeostasis are poorly characterized. Using ge- Plasma Mg levels are closely regulated and remain con- nome-wide association studies (GWAS) in European populations, we 2+ stant throughout life, despite the fact that dietary Mg intake discovered two loci significantly associated with urinary Mg2+:the and intestinal absorption decrease with age.15 The control of TRPM6 gene coding for a Mg2+ channel and the ARL15 gene, which is Mg2+ balance is ensured by a tightly regulated reabsorption of linked to lipid levels, type 2 diabetes and cardiovascular disease. We fi fl 2+ Mg2+ in the distal tubular segments of the kidney. In particu- nd that ARL15 in uences Mg reabsorption through regulation of fi 2+ TRPM6, suggesting a genetic mechanism for the association of urinary lar, the ltered Mg is reabsorbed in the proximal tubule and Mg2+ excretion with metabolic phenotypes. These findings suggest thick ascending loop of Henle (TAL) via paracellular routes, that gene-diet interactions may contribute to the link between Mg2+ whereas downstream, in the distal convoluted tubule (DCT), homeostasis and metabolic disorders in the general population. Mg2+ is efficiently reabsorbed through transcellular mecha- nisms involving the transient receptor potential cation chan- nel, subfamily M, member 6 (TRPM6).2 The reabsorption of RESULTS Mg2+ in the DCT determines the final urinary magnesium (uMg) excretion because no reabsorption of Mg2+ occurs in Meta-Analyses of GWAS for Mg2+ Homeostasis posterior segments. People harboring inherited or acquired The initial discovery phase consisted of a GWAS (2.5 M mark- dysfunctions of the renal tubular handling of Mg2+ show in- ers) performed on the population-based CoLaus cohort appropriate urinary loss of Mg2+, causing chronic hypomag- (5150 samples) testing for association with urinary Mg2+-to- nesemia and severe, multisystemic manifestations.2,16,17 creatinine ratio. The analysis revealed a single, genome-wide 2 The genetic component of Mg2+ homeostasis is indicated significant signal at rs3824347 (P=3.6310 8), corresponding by a significant heritability (15%–39%) of serum Mg2+18,19 to the TRPM6 locus on chromosome 9, and six suggestive loci 2 and by rare monogenic disorders disturbing renal tubular with P values ,10 5 (Supplemental Figure 1). These associ- transport of Mg2+.20–23 However, most of the regulatory genes ation results were combined with the genome-wide associa- of renal Mg2+ channels and transporters remain unknown. A tion scans from six additional European cohorts (LBC1936, genome-wide association study (GWAS) on serum Mg2+ in CROATIA-Split, CROATIA-Vis, Carlantino, CROATIA- European ancestry adults identified six loci, one of which in- Korcula, and Val Borbera) into a single meta-analysis (9099 cluded the gene encoding TRPM6.24 Two more recent studies samples). As shown on the Manhattan plot (Figure 1A), two 2 in children25 and in blacks26 did not reveal additional loci. signals showed a P value ,5310 8. The QQ plot showed no 2 However, changes in uMg excretion precede changes in circu- problematic inflation (l=1.014, se=3.16310 5) (Supplemen- lating serum Mg2+ levels, thus being a more sensitive indicator tal Figure 2A). Both the forest plots (Figure 1B) and the low I2 of any disturbance in Mg2+ homeostasis.27 Further, Mg2+ de- values (Table 1) indicated little heterogeneity across cohorts. pletion can be found in individuals with apparently normal No secondary signals were detected in the approximate con- total serum Mg2+ levels,28 which underscores the limitations ditional analysis, using the lead single nucleotide polymor- of total serum Mg2+ as a marker of Mg2+ status. Assessment of phisms (SNPs) as covariates in the regression (Supplemental 2 uMg in GWAS is therefore crucial to elucidate new genes in- Figure 2, B and C). The lowest combined P value (4.4310 13) volved in Mg2+ homeostasis. Further, studying the association was observed for the SNP rs3824347 on chromosome 9, at a between the genetic determinants of uMg and metabolic pheno- locus comprising five genes: TRPM6, C9orf40, C9orf41, types linked to disturbed Mg2+ balance (e.g.,obesityanddiabetes) NMRK1,andOSTF1 (Figure 1C). The second strongest signal 2 may provide novel insights into links between Mg2+ and common maps to chromosome 5, with a P value of 2.1310 11 for the diseases. Indeed, plasma triglycerides and glucose are major de- lead SNP rs35929 (Figure 1D). This SNP and all other genome- terminants of the Mg2+ balance in patients with diabetes.29 wide significant SNPs at this locus lie in the first intron of To shed light on the genetic factors and molecular mecha- the ADP ribosylation factor like GTPase 15 (ARL15) gene. None nisms linking Mg2+ handling and metabolic disorders, we of the two signals showed significant association with urinary performed a meta-analysis of GWAS for the renal handling creatinine. of Mg2+ by combining genetic isolates and population-based Results from the versatile gene-based association study (VE- studies, and investigating the biologic relevance of the identified GAS analysis)30 of urinary Mg2+-to-creatinine ratio identified loci using cellular systems and model organisms. Given the known C9orf40, C9orf41,andTRPM6 as the only genes with a statis- 2 relationships of Mg2+ intake with metabolic disorders, we also ex- tically significant result (P,2.8310 6); however, these signals plored whether the identified loci modified these relationships. are overlapping with the one SNP association in the meta- These studies establish a novel biologic control of renal Mg2+ han- analysis (rs3824347). None of the discovered SNPs tag copy dling, and a novel gene–environment interaction sustaining the link number variations (CNVs). A pathway analysis was per- between Mg2+ homeostasis, insulin resistance, and obesity.
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  • OSTF1 (AT9G4): Sc-517418

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    SAN TA C RUZ BI OTEC HNOL OG Y, INC . OSTF1 (AT9G4): sc-517418 BACKGROUND PRODUCT OSTF1 (osteoclast-stimulating factor 1) is a 214 amino acid cytoplasmic pro - Each vial contains 100 µg IgG 2a kappa light chain in 1.0 ml of PBS with tein that contains 3 ANK repeats and one SH3 domain. The SH3 domain < 0.1% sodium azide and 0.1% gelatin. mediates interaction of OSTF1 with SMN. In addition to SMN, OSTF1 inter - acts with Src and FAS-L. In osteoclasts, OSTF1 is thought to induce bone APPLICATIONS resorption most likely through a signaling cascade that results in the secre - OSTF1 (AT9G4) is recommended for detection of OSTF1 of mouse, rat and tion of factors that enhance osteoclast formation and activity. The gene that human origin by Western Blotting (starting dilution 1:200, dilution range encdoes OSTF1 consists of almost 59,000 bases and maps to human chro mo - 1:100-1:1000), immunoprecipitation [1-2 µg per 100-500 µg of total protein some 9q21.13. Housing over 900 genes, chromosome 9 comprises nearly 4% (1 ml of cell lysate)], immunofluorescence (starting dilution 1:50, dilution of the human genome. Hereditary hemorrhagic telangiectasia, which is char - range 1:50-1:500), flow cytometry (1 µg per 1 x 10 6 cells) and solid phase acterized by harmful vascular defects, and familial dysautonomia, are both ELISA (starting dilution 1:30, dilution range 1:30-1:3000). associated with chromosome 9. Notably, chromosome 9 encompasses the largest interferon family gene cluster. Suitable for use as control antibody for OSTF1 siRNA (h): sc-92800, OSTF1 siRNA (m): sc-151336, OSTF1 shRNA Plasmid (h): sc-92800-SH, OSTF1 REFERENCES shRNA Plasmid (m): sc-151336-SH, OSTF1 shRNA (h) Lentiviral Particles: sc-92800-V and OSTF1 shRNA (m) Lentiviral Particles: sc-151336-V.
  • Massive Parallel Sequencing As a New Diagnostic Approach For

    Massive Parallel Sequencing As a New Diagnostic Approach For

    Chaiyasap et al. BMC Medical Genetics (2017) 18:102 DOI 10.1186/s12881-017-0464-x RESEARCH ARTICLE Open Access Massive parallel sequencing as a new diagnostic approach for phenylketonuria and tetrahydrobiopterin-deficiency in Thailand Pongsathorn Chaiyasap1, Chupong Ittiwut1,2, Chalurmpon Srichomthong1,2, Apiruk Sangsin3, Kanya Suphapeetiporn1,2,4* and Vorasuk Shotelersuk1,2 Abstract Background: Hyperphenylalaninemia (HPA) can be classified into phenylketonuria (PKU) which is caused by mutations in the phenylalanine hydroxylase (PAH) gene, and BH4 deficiency caused by alterations in genes involved in tetrahydrobiopterin (BH4) biosynthesis pathway. Dietary restriction of phenylalanine is considered to be the main treatment of PKU to prevent irreversible intellectual disability. However, the same dietary intervention in BH4 deficiency patients is not as effective, as BH4 is also a cofactor in many neurotransmitter syntheses. Method: We utilized next generation sequencing (NGS) technique to investigate four unrelated Thai patients with hyperphenylalaninemia. Result: We successfully identified all eight mutant alleles in PKU or BH4-deficiency associated genes including three novel mutations, one in PAH and two in PTS, thus giving a definite diagnosis to these patients. Appropriate management can then be provided. Conclusion: This study identified three novel mutations in either the PAH or PTS gene and supported the use of NGS as an alternative molecular genetic approach for definite diagnosis of hyperphenylalaninemia, thus leading to proper management of these patients in Thailand. Keywords: Next generation sequencing, Exome, Hyperphenylalaninemia, Phenylketonuria, Tetrahydrobiopterin deficiency, Newborn screening Background 120 μmol/l (2 mg/dl), the individual is considered to be Phenylketonuria (PKU) is an autosomal recessive metabolic hyperphenylalaninemia (HPA) and needs further diagnosis disorder, characterized by progressive intellectual disability, [4].
  • Supplementary Table 1

    Supplementary Table 1

    Supplementary Table 1. Large-scale quantitative phosphoproteomic profiling was performed on paired vehicle- and hormone-treated mTAL-enriched suspensions (n=3). A total of 654 unique phosphopeptides corresponding to 374 unique phosphoproteins were identified. The peptide sequence, phosphorylation site(s), and the corresponding protein name, gene symbol, and RefSeq Accession number are reported for each phosphopeptide identified in any one of three experimental pairs. For those 414 phosphopeptides that could be quantified in all three experimental pairs, the mean Hormone:Vehicle abundance ratio and corresponding standard error are also reported. Peptide Sequence column: * = phosphorylated residue Site(s) column: ^ = ambiguously assigned phosphorylation site Log2(H/V) Mean and SE columns: H = hormone-treated, V = vehicle-treated, n/a = peptide not observable in all 3 experimental pairs Sig. column: * = significantly changed Log 2(H/V), p<0.05 Log (H/V) Log (H/V) # Gene Symbol Protein Name Refseq Accession Peptide Sequence Site(s) 2 2 Sig. Mean SE 1 Aak1 AP2-associated protein kinase 1 NP_001166921 VGSLT*PPSS*PK T622^, S626^ 0.24 0.95 PREDICTED: ATP-binding cassette, sub-family A 2 Abca12 (ABC1), member 12 XP_237242 GLVQVLS*FFSQVQQQR S251^ 1.24 2.13 3 Abcc10 multidrug resistance-associated protein 7 NP_001101671 LMT*ELLS*GIRVLK T464, S468 -2.68 2.48 4 Abcf1 ATP-binding cassette sub-family F member 1 NP_001103353 QLSVPAS*DEEDEVPVPVPR S109 n/a n/a 5 Ablim1 actin-binding LIM protein 1 NP_001037859 PGSSIPGS*PGHTIYAK S51 -3.55 1.81 6 Ablim1 actin-binding