Disease relevance of SLC22A4

• We report here that two variants in the organic cation transporter cluster at 5q31 (a missense substitution in SLC22A4 and a G-->C transversion in the SLC22A5 promoter) form a haplotype associated with susceptibility to Crohn disease [1].
• Evidence for association of OCTN genes and IBD5 with ulcerative colitis [2].
• BACKGROUND AND AIMS: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions [3].
• METHODS: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a_1, IGR2198a_1, and IGR2230a_1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls [4].
• Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no association with SNPs within SLC22A4 and SLC22A5 [5].

Psychiatry related information on SLC22A4

• METHODS: In a model we studied: 1) The influence on ETT-Res caused by different connectors and secretions; 2) Direct Trach-P measurements with a catheter (o.d. 2 mm, i.d. 0.9 mm) with either end or side hole, filled with either air or liquid, introduced through the ETT lumen and evaluated regarding response time and position [6].

High impact information on SLC22A4

• Functional variants of OCTN cation transporter genes are associated with Crohn disease [1].
• Our data indicate that the regulation of SLC22A4 expression by RUNX1 is associated with susceptibility to rheumatoid arthritis, which may represent an example of an epistatic effect of two genes on this disorder [7].
• Here we report that there is significant association between rheumatoid arthritis and the organic cation transporter gene SLC22A4 (P = 0.000034) [7].
• A SNP affects the transcriptional efficiency of SLC22A4 in vitro, owing to an allelic difference in affinity to Runt-related transcription factor 1 (RUNX1), a transcriptional regulator in the hematopoietic system [7].
• The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease [8].

Chemical compound and disease context of SLC22A4

• Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease [9].
• In this study, the characteristics of L-carnitine transport into hepatocytes were studied by use of cultured human hepatoma HLF cells, which expressed OCTN2 mRNA to a greater extent than OCTN1 mRNA [10].
• CONCLUSIONS: These data show benefits of using an alkalinized lidocaine-filled ETT cuff in combination with water-soluble gel lubrication in preventing post-intubation sore throat [11].
• The factor analysis yielded three factors that accounted for 58.7% of the total variance in the data: Factor 1, "Dyspnea with Laboratory Exercise" comprised ETT SOB end, ETT SOB isotime, ITTSOB end, ITT SOB isotime, ITT SOB/Time and ETT SOB/Time [12].
• PURPOSE: To study the delivery efficiency of procaterol aerosols administered through the tracheal tube (ETT) with a metered-dose inhaler (MDI) during apnea [13].

Biological context of SLC22A4

• There was no significant interaction between the SLC22A4/SLC22A5 diplotype and the three CD-associated CARD15 SNPs [14].
• Little correlation was seen with regard to clinical phenotype and the SLC22A4/SLC22A5 diplotype [14].
• Two variants, 1672C>T in SLC22A4 and -207G>C in SLC22A5, were shown to alter these genes' functions and were identified as genetic susceptibility factors for Crohn's disease (CD) [15].
• There was a significant difference in the allele frequency (0.444 vs 0.519; P = 0.041) of the 1672T polymorphism in the SLC22A4 gene between controls and patients with CD [16].
• We performed a comprehensive analysis of OCTN variants in an independent, exclusively pediatric onset CD cohort and examined the genotype/phenotype correlations [14].

Anatomical context of SLC22A4

• The organic cation transporter OCTN1 (SLC22A4) is expressed ubiquitously, with strong expression in kidney, trachea, bone marrow, and fetal liver, and it mediates transport of organic cations in a pH-dependent manner [17].
• OCTN1 (SLC22A4) transports cationic compounds such as tetraethylammonium in a pH-sensitive and sodium-independent manner in cultured cells, and is expressed in wide variety of tissues, including kidney, muscle, placenta, heart, and others [18].
• The real-time PCR expression profile of human ETT, with strong expression in CD71+ cells, is consistent with a pivotal function of ET in erythrocytes [19].
• By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound [19].
• Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders [19].

Associations of SLC22A4 with chemical compounds

• Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1 [19].
• The hMATE1 and hMATE2-K, but not hOCTN1 and OCTN2, mediated the cellular accumulation of cisplatin and oxaliplatin without a marked release of lactate dehydrogenase [20].
• OCTN1-mediated [14C]TEA uptake was inhibited by various organic cations such as cimetidine, procainamide, pyrilamine, quinidine, quinine, and verapamil [21].
• This impairment of l-carnitine transport by OCTN1 may respond to high-dose l-carnitine therapy [22].
• The group differences in ET values were maintained after adjustment for disease-related anthropometric and clinical variables (age, sex, body mass index, smoking, duration of disease, hemoglobin, C-reactive protein, and medication) and were also independent of erythrocyte glutathione levels and of polymorphisms of the OCTN1 gene [23].
• Subcellular localization and ergothioneine inhibition kinetics were similar among the common amino-acid sequence variants of OCTN1 [24].

Physical interactions of SLC22A4

• These findings suggested that OCTN1 transports compound(s) that are required for erythroid differentiation, maturation, and/or growth [25].

Regulatory relationships of SLC22A4

• RESULTS: No statistically significant differences between patients with RA and healthy controls were observed when comparing the distribution of the genotypes or alleles of any of the SLC22A4 polymorphisms tested [26].

Other interactions of SLC22A4

• There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD [2].
• The SLC22A4 gene has also been associated with rheumatoid arthritis [27].
• SLC22A4 is an organic cation transporter with unknown physiological function, and RUNX1 is a hematological transcriptional regulator that has been shown to be responsible for acute myelogenic leukemia [28].
• Both carried a CARD15 R702W variant, but had normal alleles in TLR4 and OCTN [29].
• Uptake of tetraethylammonium by OCTN1 was much higher in HEK293/PDZK1 cells, compared with that in the parent HEK293 cells, the uptake in HEK293/PDZK1-E195K cells showing middle range between the two values [30].

Analytical, diagnostic and therapeutic context of SLC22A4

• We show that expression of SLC22A4 is specific to hematological and immunological tissues and that SLC22A4 is also highly expressed in the inflammatory joints of mice with collagen-induced arthritis [7].
• Evidence for the association of the SLC22A4 and SLC22A5 genes with type 1 diabetes: a case control study [9].
• Site-directed mutagenesis and introduction of residues nonconserved between OCTN1 and OCTN2 in the OCTN2 cDNA indicated that the R341A, L409W, L424Y, and T429I substitutions significantly decreased carnitine transport [31].
• We demonstrate that the organic cation/carnitine transporters, OCTN1, OCTN2, and OCTN3, are expressed in sperm as three distinct proteins with an expected molecular mass of 63 kDa, using Western blot analysis and our transporter-specific antibodies [32].
• After a short training programme 11 naval medical trainees inserted a laryngeal mask airway (LMA) and a tracheal tube (ETT) in random order in a total of 110 anaesthetised patients [33].

References