TABLE 8

Nonsynonymous genetic variants of human organic cation transporters with analyzed impact on function and/or expression

MAFs reported from different groups are presented in the order of their appearance in the literature. Superscript letters indicate the numbers of employed individuals in the studies: a, 200; b, 60; c, 20; d, 455; e, 570; f, 220; g, 116; h, 240; i, 3023; k, 125; l, 150; m, 96; n, 7968; o, 160; p, 120; q, 100; r, 623; s, 89; t, 136; u, 68. References in which the indicated MAFs are reported are printed in italics. SLC22A1: Ser14Phe: Shu et al., 2003; More et al., 2010; Seitz et al., 2015, Ser29Leu: Seitz et al., 2015, Phe41Leu: Itoda et al., 2004, Arg61Cys: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b, 2017b; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2013, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Matthaei et al., 2016, 2019, Leu85Phe: Shu et al., 2003, Leu85Phe: Shu et al., 2003, Cys88Arg: Kerb et al., 2002; Saadatmand et al., 2012; Dujic et al., 2015; Seitz et al., 2015, Gln97Lys: Chen et al., 2010b, Pro117Leu: Itoda et al., 2004; Seitz et al., 2015, Phe160Leu: Kerb et al., 2002; Shu et al., 2003; Itoda et al., 2004; Sakata et al., 2004; Kang et al., 2007; Chen et al., 2010b, Ser189Leu: Shu et al., 2003; More et al., 2010; Seitz et al., 2015, Pro197Ser: Herraez et al., 2013; Seitz et al., 2015, Arg206Cys: Yoon et al., 2013; Seitz et al., 2015, Gly220Val: Shu et al., 2003; Chen et al., 2010b; More et al., 2010; Seitz et al., 2015, Thr245Met: Seitz et al., 2015, Pro283Leu: Sakata et al., 2004; Kang et al., 2007, Glu284Lys: Seitz et al., 2015, Arg287Gly: Sakata et al., 2004, Pro341Leu: Shu et al., 2003; Itoda et al., 2004; Kang et al., 2007; Chen et al., 2010b; More et al., 2010; Yoon et al., 2013, Arg342His: Shu et al., 2003; Gly401Ser: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b, 2017b; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Matthaei et al., 2019, Met408Val: Kerb et al., 2002; Shu et al., 2003; Itoda et al., 2004; Kang et al., 2007; Chen et al., 2010b; More et al., 2010, Gly414Ala: Kerb et al., 2002, Met420del: Kerb et al., 2002; Shu et al., 2003, 2007; More et al., 2010; Saadatmand et al., 2012; Tzvetkov et al., 2012, 2013, 2018; dos Santos Pereira et al., 2014; Dujic et al., 2015; Seitz et al., 2015; Chen et al., 2017b; Liang et al., 2018; Matthaei et al., 2019, Met440Ile: Shu et al., 2003, Ile449Thr: Seitz et al., 2015, Val461Ile: Shu et al., 2003, Gly465Arg: Kerb et al., 2002; Shu et al., 2003; Chen et al., 2010b; More et al., 2010; Saadatmand et al., 2012; Dujic et al., 2015; Arg488Met: Shu et al., 2003. SLC22A2: Pro54Ser: Leabman et al., 2002, Pro160Ser: Leabman et al., 2002, Phe161Leu: Leabman et al., 2002, Met165Val: Leabman et al., 2002, Met165Ile: Leabman et al., 2002, Thr199Ile: Kang et al., 2007; Song et al., 2008a, Yoon et al., 2013, Thre201Met: Kang et al., 2007; Song et al., 2008a; Yoon et al., 2013, Ala270Ser: Leabman et al., 2002; Kang et al., 2007; Song et al., 2008a,b; Chen et al., 2009a, 2017b; Zolk et al., 2009a; Yoon et al., 2013; Teft et al., 2017, Ala297Gly: Leabman et al., 2002, Arg400Cys: Leabman et al., 2002, Lys432Gln: Leabman et al., 2002. SLC22A3: Thr44Met: Chen et al., 2010a, Ala116Ser: Chen et al., 2010a, Leu186Phe: Chen et al., 2010a, Met370Ile: Lazar et al., 2008, Val388Met: Chen et al., 2010a, Thr400Ile: Chen et al., 2010a; Yoon et al., 2013, Val423Phe: Chen et al., 2010a; Yoon et al., 2013, Ala439Val: Nies et al., 2011b, Gly475Ser: Nies et al., 2011b. SLC22A4: Val159Met: Urban et al., 2007, Asp165Gly: Urban et al., 2007, Met205Ile: Urban et al., 2007; Dujic et al., 2015, Arg282Stop: Urban et al., 2007, Ile306Thr: Urban et al., 2007; Toh et al., 2009; Yoon et al., 2013; Futatsugi et al., 2016, Gly462Glu: Kawasaki et al., 2004, Leu503Phe: Peltekova et al., 2004; Newman et al., 2005b; Taubert et al., 2005; Urban et al., 2007, 2008; Toh et al., 2009; Pochini et al., 2012; Yoon et al., 2013; Dujic et al., 2015; Futatsugi et al., 2016. SLC22A5: Phe17Leu: Urban et al., 2006, Trp132Stop: Koizumi et al., 1999; Tang et al., 1999, Leu144Phe: Urban et al., 2006, Met179Leu: Koizumi et al., 1999, Tyr211Cys: Vaz et al., 1999, Arg282Stop: Vaz et al., 1999; Wang et al., 1999, Trp283Cys: Koizumi et al., 1999, Met352Arg: Seth et al., 1999, Tyr401Stop: Wang et al., 1999, Tyr449Asp: Urban et al., 2006; Amat di San Filippo et al., 2008, Ser467Cys: Koizumi et al., 1999; Ohashi et al., 2002, Glu475Arg: Wang et al., 2000a, Pro478Leu: Seth et al., 1999; Tang et al., 1999; Urban et al., 2006, Val481Phe: Urban et al., 2006, Val481Ile: Urban et al., 2006, Phe508Leu: Urban et al., 2006, Met530Val: Urban et al., 2006, Pro549Ser: Urban et al., 2006. SLC47A1: Val10Leu: Kajiwara et al., 2009, Gly64Asp: Chen et al., 2009b; Kajiwara et al., 2009; Yoon et al., 2013, Leu125Phe: Chen et al., 2009b, Kim et al., 2013; Yoon et al., 2013, Thr159Met: Meyer zu Schwabedissen et al., 2010, Ala310Val: Kajiwara et al., 2009, Asp328Ala: Kajiwara et al., 2009; Meyer zu Schwabedissen et al., 2010, Val338Ile: Chen et al., 2009b; Meyer zu Schwabedissen et al., 2010, Asn474Ser: Kajiwara et al., 2009, Val480Met: Chen et al., 2009b, Cys497Ser: Chen et al., 2009b, Cys497Phe: Meyer zu Schwabedissen et al., 2010, Gln519His: Chen et al., 2009b. SLC47A2: Lys64Asn: Kajiwara et al., 2009; Yoon et al., 2013, Pro162Leu: Choi et al., 2011, Gly211Val: Kajiwara et al., 2009; Yoon et al., 2013, Gly393Arg: Choi et al., 2011, Thr505Ile: Choi et al., 2011, Ala525Thr: Choi et al., 2011.

GeneAmino Acid Exchange (MAF in Different Populations)In Vitro Uptake Compared with WT [% of WT]
Substrate: Effect on Uptake Measured Below Km, Effect onVmax, (Effect on Km)
SLC22A1Ser14Phe (Af: 0.031a, 0.012d; Eu: 0a, 0e; As: 0b, 0.002f, Me: 0c)TEA: ∼190, ∼100; MPP: ∼190; metformin: ∼60; picoplatin: ∼70
Ser29Leu (Af: 0d; Eu: 0e; As: 0f)TEA: 0; MPP: 0; metformin: 0; tropisetron: 0
Phe41Leu (Ja: 0.004g)
Arg61Cys (Af: 0a, 0.010d; Eu: 0.156h, 0.072a, 0.009e; As: 0b, 0.0166f; Me: 0.056c)TEA: ∼30; MPP: ∼30, ∼50, (∼100, 640); metformin: ∼5; 22, (103); picoplatin: ∼20; tropisetron: ∼10; debrisoquine: ∼37, (100); proguanil: ∼50; cycloguanil ∼80; fenoterol: ∼30; sumatriptan: 54; ipratropium: 43; amilsulpride: ∼30; sulpride: <5
Leu85Phe (Af: 0.01a; Eu: 0a, 0.004h; As: 0b; Me: 0c)MPP: ∼100
Cys88Arg (Af: 0.002d; Eu: 0.012h, 0.0005e, 0.004i; As: 0.0009f)TEA: ∼6; MPP: ∼2, serotonin: ∼12; debrisoquine: 0
Gln97Lys (EA: 0.017k)TEA: ∼60; MPP: ∼60; metformin: ∼60, 88, (280)
Phe160Leu (Af: 0.005a; Eu: 0.340h, 0.065a, 4.6; As: 0.017b; EA: 0.12k; Me: 0.05c; Ko: 13l; Ja: 0.086g)TEA: ∼100, ∼100, (100); MPP: ∼100, ∼100, (60)
Pro117Leu (Af: 0d; Eu: 0e; As: 0.002f; Ja: 0.004g)TEA: ∼45; MPP: ∼50; metformin: ∼55, 51, (128)
Ser189Leu (Af: 0a, 0d; Eu: 0.005a, 0e; As: 0b, 0f; Me: 0c)TEA: ∼100, ∼20; MPP: ∼100; metformin: ∼20; picoplatin: ∼60
Pro197SerTEA: ∼100
Arg206Cys (Af: 0d; Eu: 0e; As: 0.001f; Ko: 0m)TEA: ∼20; MPP: ∼25; metformin: ∼20, 20, (111)
Gly220Val (Af: 0.005a, 0d; Eu: 0a, 0e; As: 0b, 0f; Me: 0c)TEA: 0; MPP: ∼7; metformin: 0, picoplatin: ∼10
Thr245Met (Af: 0d; Eu: 0e; As: 0.002f)
Pro283Leu (Ko: 0.02l)TEA: 0; MPP: 0;
Glu284Lys (Af: 0d; Eu: 0e; As: 0f, 0.14)TEA: 0; MPP: 0; metformin: 0; tropisetron: 0
Arg287GlyTEA: 0; MPP: 0;
Pro341Leu (Af: 0.082a; Eu: 0a; As: 0.117b; EA: 0.19k; Me: 0c; Ja: 0.168g; Ko: 0.16l, 0.135m)TEA: ∼65, 56, (63); MPP: 60–100, 56, (180); metformin: ∼100; picoplatin: ∼100
Arg342His (Af: 0.031a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100; 1–8; picoplatin: ∼100
Gly401Ser (Af: 0.007a, 0.0009d; Eu: 0.065h, 0.011a, 0.0047e, 0.0024i; As: 0b, 0f; Me: 0c)TEA: 1–8; MPP: <2; serotonin: ∼10; metformin: ∼10; picoplatin: ∼30; tropisetron 0; debrisoquine: ∼9, (100); proguanil: ∼30; cycloguanil ∼60; fenoterol: ∼30; sumatriptan: 13; ipratropium: 10; amilsulpride: ∼20; sulpride: ∼30
Met408Val (Af: 0.74a; Eu: 0.60a; As: 0.76b; EA: 0.81k; Me: 0.79c; Ko: 74l; Ja: 0.81g)MPP: ∼100; picoplatin: ∼140
Gly414Ala (Eu: 0.004h)
Met420del (Af: 0.029a, 0.040d; Eu: 0.263h, 0.185a, 0.027e; 0.191i; As: 0b, 0.065f; Me: 0.21c)TEA: ∼100; MPP: ∼100, ∼100, (100); metformin: ∼30; picoplatin: ∼61; morphine: 25, (147); tropisetron: ∼5; debrisoquine: ∼50, (100); proguanil: ∼70; cycloguanil ∼100; fenoterol: ∼70; sumatriptan: ∼100, 66; ipratropium: 55; thiamine: ∼60, 30, (150); amilsulpride: ∼30; sulpride: ∼30
Met440Ile (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
Ile449Thr (Af: 0d; Eu: 0e; As: 0f)
Val461Ile (Af: 0.001a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
Gly465Arg (Af: 0a, 0.002d; Eu: 0.003h, 0.04a, 0.003e, 0.0032i; As: 0b, 0.004f; Me:0c)TEA: 0; MPP: ∼7; metformin: 0; picoplatin: ∼8; debrisoquine: 0
Arg488Met (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100; picoplatin: ∼120
SLC22A2Pro54Ser (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼150
Pro160Ser (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)
Phe161Leu (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c)MPP: ∼100
Met165Val (Af: 0.005a; Eu: 0a; As: 0b; Me: 0c)MPP: ∼100
Met165Ile (Af: 0.01a; Eu: 0a; As: 0b; Me: 0c)TEA: decrease; MPP: ∼50, (100)
Thr199Ile (Ko: 0.01l, 0m)TEA: ∼30; MPP: ∼3, ∼30, 4, (372), metformin: 3, 14, (50)
Thr201Met (Ko: 0.02l, 0.005m)TEA: ∼50, ∼30; MPP: ∼2, ∼40, 5, (509); metformin: 1, 15, (40)
Ala270Ser (Af: 0.11a; Eu 0.157a, 0.11n; As: 0.086a; Me: 0.15a; Ko: 0.14l, 0.078m)TEA: ∼40; MPP: ∼6, ∼40, 9, 70, (100), (200); metformin: 150, 9, 53, 135, (100); propranolol: 44, (50); ipratropium: 121, (∼200); TMAO: ∼100
Ala297Gly (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c)MPP: ∼80
Arg400Cys (Af: 0.015a; Eu: 0a; As: 0b; Me: 0c)TEA: decrease; MPP: ∼30, (100)
Lys432Gln (Af: 0.01a; Eu: 0a; As: 0b; Me: 0.05c)MPP: (∼56)
SLC22A3Thr44Met (Af: 0.006a; Eu: 0.006a; As: 0b; Me: 0c)Metformin: 136, (105)
Ala116Ser (Af: 0.02a; Eu: 0a; As: 0b; Me: 0c)Metformin: 92, (94)
Leu186PheMetformin: 97, (95)
Met370IleNorepinephrine: 60, 280, (210)
Val388MetMetformin: 105, (104)
Thr400Ile (Af: 0a; Eu: 0.005a; As: 0b; Me: 0c; Ko: 0m)Metformin: 71, (350)
Val423Phe (Ko: 0m)Metformin: 75, (271)
Ala439Val
Gly475Ser
SLC22A4Val159Met (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)TEA: ∼100; betaine: ∼80
Asp165Gly (Af: 0°; Eu: 0°; As: 0.008p; Me: 0q)TEA: <10; betaine: 0
Met205Ile (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)TEA: ∼60; betaine: ∼60
Arg285Stop (Af: 006°; Eu: 0°; As: 0p; Me: 0q)TEA: 0; betaine: 0
Thr306Ile (Af: 0.27°; Eu: 0.34°, 0.41n; As: 0.64p; Me: 0.24q; CS: 0.40m; IS: 0.14m; Ko: 0.63m)TEA: ∼70; betaine: ∼110; ergothioneine: 95, (106); gabapentin: 66, (129)
Gly462GluTEA: 0
Leu503Phe (Af: 0.09°; Eu: 0.41°, 0.39n; As: 0p; Me: 0.23p; Ca: 0.43r; CS: 0m; IS: 0.07m; Ko: 0m)Ergothioneine: 52, 63, (34), (47); L-carnitine: 46, (238); TEA: ∼240, 133, 316, (17), (39); gabapentin: ∼50, 273, (453); acetylcholine: ∼100, ∼100; betaine: ∼30; metformin: ∼30; buformin: ∼30; phenformin: ∼30
SLC22A5Phe17Leu (Af: 0°; Eu: 0°; As: 0.0.7p; Me: 0q)L-carnitine: 60, 52, (93); TEA: 10, 65, (206)
Trp132StopL-carnitine: 0
Leu144Phe (Af: 0.075°; Eu: 0°; As: 0p; Me: 0.01q)L-carnitine: ∼100, ∼100, (∼100); TEA: ∼100, ∼100, (∼100)
Met179LeuL-carnitine: ∼70
Tyr211CysL-carnitine: 0
Arg282StopL-carnitine: 0
Trp283CysL-carnitine: ∼2
Met352ArgL-carnitine: 0; TEA: ∼10
Tyr401StopL-carnitine: 0
Tyr449Asp (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼80; TEA: ∼170
Glu452ArgL-carnitine: ∼4, ∼6, (∼100)
Ser467CysL-carnitine: 9.9, 150, (1660); acetyl-L-carnitine: 13; TEA: 105, 180, (122); pyrilamine: 74; quinidine: 88; verapamil: 10
Pro478LeuL-carnitine: ∼4; TEA: ∼370
Val481Phe (Af: 0°; Eu: 0.006°; As: 0p; Me: 0q)L-carnitine: ∼80; TEA: ∼30
Val481Ile (Af: 0.006°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼100; TEA: ∼100
Phe508Leu (Af: 0°; Eu: 0°; As: 0p; Me: 0.01q)L-carnitine: ∼10; TEA: ∼100
Met530Val (Af: 0°; Eu: 0°; As: 0.008p; Me: 0q)L-carnitine: ∼80; TEA: ∼150
Pro549Ser (Af: 0.10°; Eu: 0°; As: 0p; Me: 0q)L-carnitine: ∼100, ∼100, (∼100); TEA: ∼100, ∼100, (∼100)
SLC47A1Val10Leu (Ja: 0.022s)TEA: ∼100; metformin: ∼100
Gly64Asp (Af: 0t; Eu: 0t; As: 0.007t; Me: 0t; Ja: 0.006s; Ko: 0.005m)TEA: 0, ∼10; metformin: ∼2, ∼7; paraquat: 0; oxaliplatin: 0
Leu125Phe (Af: 0t; Eu: 0t; As: 0.007t; Me: 0.05t; Ko: 0.005m)TEA: ∼50; metformin: ∼60, 78, (126); paraquat: ∼70, 114, (116); oxaliplatin: ∼90
Thr159MetTEA: ∼45; metformin: ∼45
Ala310Val (Ja: 0.0022s)TEA: ∼20, 38, (∼376); metformin: ∼40
Asp328Ala (Ja: 0.006s)TEA: ∼20, ∼100, 27, (∼129); metformin: ∼27, ∼100
Val338Ile (Af: 0.05t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼40, ∼50; metformin: ∼50, ∼60, 89, (116); paraquat: ∼100; oxaliplatin: ∼80
Asn474Ser (Ja: 0.006s)TEA: ∼64, 70, (∼143); metformin: ∼98
Gly480Ala (Af: 0t; Eu: 0t; As: 0.008t; Me: 0t)TEA: 0; metformin: ∼5; paraquat: ∼5; oxaliplatin: 0
Cys497PheTEA: ∼100; metformin: ∼80, ∼120
Cys497Ser (Af: 0.02t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼80; metformin: ∼80; paraquat: ∼120; oxaliplatin: ∼170
Gln519His (Af: 0.08t; Eu: 0t; As: 0t; Me: 0t)TEA: ∼90; metformin: ∼80; paraquat: ∼100; oxaliplatin: ∼90
SLC47A2Lys64Asn (Ja: 0.006s; Ko: 0m)TEA: ∼50, 37, (∼57); metformin: ∼70
Pro162Leu (Af: 0.06u; Eu: 0u; As: 0.09u; Me: 0u)TEA: ∼20; metformin: ∼25; amiloride: ∼50; trospium: ∼15
Gly211Val (Ja: 0.017s; Ko: 0m)TEA: ∼2; metformin: 0
Gly393Arg (Af: 0u; Eu: 0.009u; As: 0u; Me: 0.008u)TEA: ∼25, metformin: ∼40, amiloride: ∼50, trospium: ∼35
Thr505Ile (Af: 0.07u; Eu: 0u; As: 0u; Me: 0u)TEA: ∼80, metformin: ∼60, amiloride: ∼105, trospium: ∼115
Ala525Thr (Af: 0.07u; Eu: 0u; As: 0u; Me: 0u)TEA: ∼80, metformin: ∼75, amiloride: ∼130, trospium: ∼90
  • Af, Africans i.e., American Africans (research group of K. Giacomini) or Africans from North Africa, Sub-Sahara and Middle East (Seitz et al., 2015); As, American Asians (research group of K. Giacomini) or Asians from Central Asia (Seitz et al., 2015); Ca, Canadians; C/J, mixed Chinese and Japanese population; CS, Chinese from Singapore; EA, Asians from East Asia; Eu, Europeans or American Europeans; IS, Indians from Singapore; Ja, Japanese; Ko, Koreans; Me, American Mexicans.