In PNAS, Yau et al. (1) identify a conserved 33-kb haplotype Ltab-Ncr3 across five genes, lymphotoxin-α (Lta), Tnf, lymphotoxin-β (Ltb), leukocyte-specific transcript 1 (Lst1), and natural cytotoxicity-triggering receptor 3 (Ncr3) in the MHC-III region in wild rats. The higher Ltb and Ncr3 expression, the lower Lst1 expression, and the expression of a shorter splice variant of Lst1 were associated with reduced arthritis severity in rats (1). Yau et al. (1) further analyzed the expression levels of LTB, LST1, and NCR3 using whole-blood samples from 32 patients with rheumatoid arthritis (RA) and 92 healthy controls (1). They identify significantly increased expression of these three genes in RA cases (1). The mild RA cases also showed lower expression of LST1 and higher expression of NCR3 than the severe RA cases (1).
Although these results are interesting, there are still two concerns to be mentioned. First, Yau et al. (1) report increased LST1 and NCR3 expression in RA cases. However, they did not investigate whether SNPs in LST1 and NCR3 genes could regulate the expression of both genes in RA cases. Second, Yau et al. (1) selected 13 SNPs and identified the Ltab-Ncr3 haplotype regulating arthritis severity in rats. However, they did not evaluate whether the SNPs in LST1 and NCR3 genes could regulate arthritis severity or susceptibility in humans. Thus, both of these concerns have prompted us to investigate these findings further.
Evidence shows that genetic variants modify gene expression and cause disease risk (2, 3). Here, we used a whole-genome expression quantitative trait loci (eQTL) dataset in whole blood to evaluate whether these eQTLs could regulate LST1 and NCR3 expression in 377 RA cases (4). We got the summary results about the cis-eQTL with a false discovery rate (FDR) of <5% in the original study (4). Interestingly, we identified 1,012 significant associations between 578 cis-eQTL and NCR3 expression, and 69 significant associations between 35 cis-eQTL and LST1 expression with an FDR of <5%.
We further investigated the potential association of these cis-eQTL with RA susceptibility using a large-scale RA genome-wide association studies (GWAS) dataset (19,234 RA cases and 61,565 controls) (5). We found that 415 of the 578 cis-eQTL and 34 of the 35 cis-eQTL were available in the RA GWAS dataset. Three hundred ninety-seven of these 415 cis-eQTL and 32 of these 34 cis-eQTL were significantly associated with RA susceptibility (P < 0.05). We further compared the findings from the RA GWAS and RA eQTL datasets. We found that the alleles of cis-eQTL significantly regulating increased LST1 and NCR3 expression were significantly associated with reduced RA susceptibility. In contrast, the alleles of cis-eQTL significantly regulating reduced LST1 and NCR3 expression were significantly associated with increased RA risk (28–35% for NCR3 and 6–19% for LST1). We list the top 10 significant association signals in Table 1.
Table 1.
Top 10 significant association signals in RA eQTLs dataset and RA GWAS dataset
| RA eQTL dataset | RA GWAS dataset | |||||||||
| SNP | Chr | Position (hg19) | A1 | A2 | Probe ID | Gene | Beta (A1) | P value | OR (A1) | P value |
| rs812561 | 6 | 31676641 | T | C | 211583_x_at | NCR3 | −0.32 | 5.26E-06 | 1.35 | 1.20E-106 |
| rs5872 | 6 | 31637734 | T | A | 211583_x_at | NCR3 | −0.33 | 4.99E-06 | 1.33 | 2.80E-101 |
| rs707919 | 6 | 31641139 | G | A | 211583_x_at | NCR3 | −0.33 | 4.99E-06 | 1.33 | 4.40E-101 |
| rs805299 | 6 | 31619652 | A | T | 211583_x_at | NCR3 | −0.33 | 4.99E-06 | 1.34 | 7.10E-101 |
| rs2736176 | 6 | 31587561 | C | G | 211583_x_at | NCR3 | −0.33 | 3.45E-06 | 1.33 | 1.00E-100 |
| rs755714 | 6 | 31609813 | T | C | 211583_x_at | NCR3 | −0.33 | 4.99E-06 | 1.34 | 1.00E-100 |
| rs805297 | 6 | 31622606 | A | C | 211583_x_at | NCR3 | −0.33 | 2.51E-06 | 1.34 | 1.10E-100 |
| rs2857698 | 6 | 31585084 | T | C | 211583_x_at | NCR3 | −0.33 | 3.45E-06 | 1.34 | 1.10E-100 |
| rs2844479 | 6 | 31572956 | C | A | 210763_x_at | NCR3 | −0.38 | 1.07E-07 | 1.30 | 1.10E-82 |
| rs2736178 | 6 | 31585821 | C | A | 211583_x_at | NCR3 | −0.32 | 8.30E-06 | 1.28 | 3.20E-80 |
| rs915654 | 6 | 31538497 | A | T | 210629_x_at | LST1 | −0.37 | 3.19E-07 | 1.19 | 5.30E-39 |
| rs73396237 | 6 | 31532490 | G | C | 210629_x_at | LST1 | −0.41 | 5.47E-06 | 1.16 | 8.50E-20 |
| rs9380261 | 6 | 31505784 | C | G | 210629_x_at | LST1 | −0.41 | 6.29E-06 | 1.15 | 5.00E-19 |
| rs6929796 | 6 | 31522669 | A | G | 210629_x_at | LST1 | −0.43 | 1.26E-06 | 1.11 | 7.60E-11 |
| rs2071596 | 6 | 31506691 | A | G | 210629_x_at | LST1 | −0.43 | 1.26E-06 | 1.11 | 1.90E-10 |
| rs2516493 | 6 | 31482714 | C | T | 210629_x_at | LST1 | −0.37 | 4.99E-07 | 1.09 | 1.30E-08 |
| rs2256974 | 6 | 31555392 | A | C | 210629_x_at | LST1 | −0.44 | 1.03E-06 | 1.08 | 2.70E-07 |
| rs2523500 | 6 | 31518354 | A | G | 210629_x_at | LST1 | −0.34 | 1.11E-06 | 1.06 | 1.80E-05 |
| rs2071590 | 6 | 31539768 | G | A | 210629_x_at | LST1 | −0.35 | 7.79E-07 | 1.06 | 4.20E-05 |
| rs2516492 | 6 | 31482727 | A | G | 210629_x_at | LST1 | 0.37 | 3.72E-07 | 1.06 | 5.30E-05 |
Chr, chromosome; ID, identification number; OR, odds ratio.
Taken together, we analyzed a large-scale eQTL dataset from 377 RA patients and RA GWAS from 19,234 RA cases. We found that SNPs in LST1 and NCR3 could regulate the expression of both genes in RA cases and that the increased LST1 and NCR3 expression was significantly associated with reduced RA susceptibility. We believe that our findings provide important supplementary information about the role of LST1 and NCR3 in human RA.
Acknowledgments
This work was supported by funding from the National Nature Science Foundation of China (Grants 81300945 and 61571152) and the Major State Research Development Program of China (2016YFC1202302).
Footnotes
The authors declare no conflict of interest.
References
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