Thyroid hormones (THs) are key regulators of cellular growth, development, and metabolism. The thyroid gland secretes two THs, thyroxine (T4) and triiodothyronine (T3), into the plasma where they are almost all bound reversibly to plasma proteins. Free forms of THs are metabolically active, however, they represent a very small fraction of total TH levels. No genome-wide studies have been performed to date on total TH levels, comprising of protein-bound and free forms of THs. To detect genetic variants associated with total TH levels, we carried out the first GWAS meta-analysis of total T4 levels in 1121 individuals from two Croatian cohorts (Split and Korcula). We also performed GWAS analyses of total T3 levels in 577 individuals and T3/T4 ratio in 571 individuals from the Split cohort. The top association in GWAS meta-analysis of total T4 was detected for an intronic variant within SLC22A9 gene (rs12282281, P = 4.00 × 10−7). Within the same region, a genome-wide significant variant (rs11822642, P = 2.50 × 10−8) for the T3/T4 ratio was identified. SLC22A9 encodes for an organic anion transporter protein expressed predominantly in the liver and belongs to the superfamily of solute carriers (SLC), a large group of transport membrane proteins. The transport of THs across the plasma membrane in peripheral tissues is facilitated by the membrane proteins, and all TH transport proteins known to date belong to the same SLC superfamily as SLC22A9. These results suggest a potential role for SLC22A9 as a novel transporter protein of THs.
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Panicker V. Genetics of thyroid function and disease. Clin Biochem Rev. 2011;32:165–75.
Mondal S, Raja K, Schweizer U, Mugesh G. Chemistry and biology in the biosynthesis and action of thyroid hormones. Angew Chem Int Ed Engl. 2016;55:7606–30.
Hoermann R, Midgley JE, Larisch R, Dietrich JW. Relational stability in the expression of normality, variation, and control of thyroid function. Front Endocrinol. 2016;7:142.
Dayan CM, Panicker V. Novel insights into thyroid hormones from the study of common genetic variation. Nat Rev Endocrinol. 2009;5:211–8.
Larsen PR, Zavacki AM. Role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action. Eur Thyroid J. 2013;1:232–42.
Wilkin TJ, Isles TE. The behavior of the triiodothyronine/thyroxine (T3/T4) ratio in normal individuals, and its implications for the regulation of euthyroidism. J Endocrinol Investig. 1984;7:319–22.
Mortoglou A, Candiloros H. The serum triiodothyronine to thyroxine (T3/T4) ratio in various thyroid disorders and after Levothyroxine replacement therapy. Hormones. 2004;3:120–6.
Medici M, van der Deure WM, Verbiest M, Vermeulen SH, Hansen PS, Kiemeney LA, et al. A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels. Eur J Endocrinol. 2011;164:781–8.
Panicker V, Wilson SG, Spector TD, Brown SJ, Falchi M, Richards JB, et al. Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort. Clin Endocrinol. 2008;68:652–9.
Martin LJ, Crawford MH. Genetic and environmental components of thyroxine variation in Mennonites from Kansas and Nebraska. Hum Biol. 1998;70:745–60.
Samollow PB, Perez G, Kammerer CM, Finegold D, Zwartjes PW, Havill LM, et al. Genetic and environmental influences on thyroid hormone variation in Mexican Americans. J Clin Endocrinol Metab. 2004;89:3276–84.
Nielsen TR, Appel EV, Svendstrup M, Ohrt JD, Dahl M, Fonvig CE, et al. A genome-wide association study of thyroid stimulating hormone and free thyroxine in Danish children and adolescents. PLoS One. 2017;12:e0174204.
Porcu E, Medici M, Pistis G, Volpato CB, Wilson SG, Cappola AR, et al. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function. PLoS Genet. 2013;9:e1003266.
Rudan I, Marušić A, Janković S, Rotim K, Boban M, Lauc G, et al. “10 001 Dalmatians:” Croatia launches its national biobank. Croat Med J. 2009;50:4–6.
Matana A, Brdar D, Torlak V, Boutin T, Popović M, Gunjača I, et al. Genome-wide meta-analysis identifies novel loci associated with parathyroid hormone level. Mol Med. 2018;24:15.
Matana A, Popovic M, Boutin T, Torlak V, Brdar D, Gunjaca I, et al. Genome-wide meta-analysis identifies novel gender specific loci associated with thyroid antibodies level in Croatians. Genomics. 2018;18:30242–8.
Reinehr T, Andler W. Thyroid hormones before and after weight loss in obesity. Arch Dis Child. 2002;87:320–3.
Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007;23:1294–6.
Marchini J, Howie B, Myers S, McVean G, Donnelly P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet. 2007;39:906–13.
Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–1.
Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–7.
Ruffier M, Kähäri A, Komorowska M, Keenan S, Laird M, Longden I, et al. Ensembl core software resources: storage and programmatic access for DNA sequence and genome annotation. Database. 2017;2017:bax020.
Turner SD. qqman: an R package for visualizing GWAS results using Q–Q and Manhattan plots. J Open Source Softw. 2014;3:731.
Koepsell H. The SLC22 family with transporters of organic cations, anions and zwitterions. Mol Asp Med. 2013;34:413–35.
Shin HJ, Anzai N, Enomoto A, He X, Kim DK, Endou H, et al. Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate. Hepatology. 2007;45:1046–55.
Schweizer U, Johannes J, Bayer D, Braun D. Structure and function of thyroid hormone plasma membrane transporters. Eur Thyroid J. 2014;3:143–53.
Bernal J, Guadano-Ferraz A, Morte B. Thyroid hormone transporters—functions and clinical implications. Nat Rev. 2015;11:406–17.
Visser WE, Friesema EC, Visser TJ. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011;25:1–14.
Roth M, Obaidat A, Hagenbuch B. OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol. 2012;165:1260–87.
Hsiang B, Zhu Y, Wang Z, Wu Y, Sasseville V, Yang WP, et al. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999;274:37161–8.
Konig J, Cui Y, Nies AT, Keppler D. A novel human organic anion transporting polypeptide localized to the basolateral hepatocyte membrane. Am J Physiol Gastrointest Liver Physiol. 2000;278:G156–64.
Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, et al. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001;142:2005–12.
Kullak-Ublick GA, Ismair MG, Stieger B, Landmann L, Huber R, Pizzagalli F, et al. Organic anion-transporting polypeptide B (OATP-B) and its functional comparison with three other OATPs of human liver. Gastroenterology. 2001;120:525–33.
van der Deure WM, Peeters RP, Visser TJ. Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters. J Mol Endocrinol. 2010;44:1–11.
Pizzagalli F, Varga Z, Huber RD, Folkers G, Meier PJ, St-Pierre MV. Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab. 2003;88:3902–12.
van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema ECH, Hegedüs L, et al. Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation. Endocrinology. 2008;149:5307–14.
van der Deure WM, Friesema ECH, de Jong FJ, de Rijke YB, de Jong FH, Uitterlinden AG, et al. Organic anion transporter 1B1: an important factor in hepatic thyroid hormone and estrogen transport and metabolism. Endocrinology. 2008;149:4695–701.
Roef GL, Rietzschel ER, De Meyer T, Bekaert S, De Buyzere ML, Van daele C, et al. Associations between single nucleotide polymorphisms in thyroid hormone transporter genes (MCT8, MCT10 and OATP1C1) and circulating thyroid hormones. Clin Chim Acta. 2013;425:227–32.
Lago-Leston R, Iglesias MJ, San-Jose E, Areal C, Eiras A, Araujo-Vilar D, et al. Prevalence and functional analysis of the S107P polymorphism (rs6647476) of the monocarboxylate transporter 8 (SLC16A2) gene in the male population of north-west Spain (Galicia). Clin Endocrinol. 2009;70:636–43.
Jacobsson JA, Haitina T, Lindblom J, Fredriksson R. Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family. Genomics. 2007;90:595–609.
Nigam SK, Bush KT, Martovetsky G, Ahn S-Y, Liu HC, Richard E, et al. The organic anion transporter (OAT) family: a systems biology perspective. Physiol Rev. 2015;95:83–123.
Sun W, Wu RR, van Poelje PD, Erion MD. Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun. 2001;283:417–22.
Volk C. OCTs, OATs, and OCTNs: structure and function of the polyspecific organic ion transporters of the SLC22 family. Wiley Interdiscip Rev: Membr Transp Signal. 2014;3:1–13.
Ruth KS, Campbell PJ, Chew S, Lim EM, Hadlow N, Stuckey BG, et al. Genome-wide association study with 1000 genomes imputation identifies signals for nine sex hormone-related phenotypes. Eur J Hum Genet. 2016;24:284–90.
Zhang X, Li D, Li M, Ye M, Ding L, Cai H, et al. MicroRNA‐146a targets PRKCE to modulate papillary thyroid tumor development. Int J Cancer. 2014;134:257–67.
Li X, Thyssen G, Beliakoff J, Sun Z. The novel PIAS-like protein hZimp10 enhances Smad transcriptional activity. J Biol Chem. 2006;281:23748–56.
Tuccilli C, Baldini E, Sorrenti S, Di Gioia C, Bosco D, Ascoli V, et al. Papillary thyroid cancer is characterized by altered expression of genes involved in the sumoylation process. J Biol Regul Homeost Agents. 2015;29:655–62.
Gerondopoulos A, Langemeyer L, Liang JR, Linford A, Barr FA. BLOC-3 mutated in Hermansky–Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. Curr Biol. 2012;22:2135–9.
Seto S, Tsujimura K, Koide Y. Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. Traffic. 2011;12:407–20.
Takeda S, Fujiwara T, Shimizu F, Kawai A, Shinomiya K, Okuno S, et al. Isolation and mapping of karyopherin alpha 3 (KPNA3), a human gene that is highly homologous to genes encoding Xenopus importin, yeast SRP1 and human RCH1. Cytogenet Cell Genet. 1997;76:87–93.
The Croatian Science Foundation funded this work under the project “Identification of new genetic loci implicated in the regulation of thyroid and parathyroid function” (Grant 1498). The “10 001 Dalmatians” project was funded by the Medical Research Council UK, The Croatian Ministry of Science, Education and Sports (Grant 216-1080315-0302), and the Croatian Science Foundation (Grant 8875).
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Gunjača, I., Matana, A., Boutin, T. et al. Genome-wide association meta-analysis for total thyroid hormone levels in Croatian population. J Hum Genet 64, 473–480 (2019). https://doi.org/10.1038/s10038-019-0586-4