Fig. 2: LAG3 5′ UTR variant rs781745126-T creates a novel upstream open reading frame (uORF) and associates with lower plasma levels of LAG-3.
a rs781745126-T creates a novel start codon, thereby generating a novel upstream open reading frame (uORF), that contains a STOP codon after 84 codons or 51 bp upstream of LAG-3 protein translation initiation site. rs781745126-T generates a stronger Kozak sequence than the reference LAG3 start codon has, which might reduce the use of the canonical start site, that could result in reduced levels of the LAG-3 protein. b Plasma levels of LAG-3 were measured using a proteome-wide screening with the aptamer-based SomaScan® platform in 37,943 Icelanders. rs781745126-T had the largest effect on LAG-3 levels (top cis-pQTL). The distribution of standardized beta adjusted values in two homozygote rs781745126-T carriers (TT), 93 heterozygote carriers (CT), and 37,848 non-carriers (CC) is shown by box-plots (outliers, 10th-90th percentile, interquartile range, median levels) and statistical comparison is calculated using linear regression of log-transformed protein levels against SNP allele count (see also Table 1). c Lower plasma levels in 66 rs781745126-T carriers (CT, median 841 pg/ml) than in 66 age and sex-matched non-carriers (CC, median 1589 pg/ml) were confirmed in Icelanders by another method, the antibody-based MSD assay (R-PLEX # F213Y-3, Meso Scale Diagnostics) and the distribution is shown as in figure b. The correlation (Spearman) between the two methods was high (R = 0.93, P < 2.2 × 10−16). All P-values are two-sided.
