関節リウマチのGWAS結果
HLA DRB1とやはり関係があるという
RA is a chronic systemic inflammatory disease that primarily affects the small joints of the hands and feet, and results in a mean reduction in life expectancy of 3-10 years. RA is a multigene disorder with a substantial genetic component and a heritability estimate of 60%. Large-scale Genome-Wide Association Studies (GWAS) and meta-analyses have revealed common disease-associated variants in the population that may contribute cumulatively to RA pathogenesis. This review identifies the most significant genetic variants associated with RA susceptibility to date, with particular focus on the contribution of the HLA class II genes across different ethnic groups. Also discussed are the potential applications of pharmacogenomics to RA management by identifying polymorphisms associated with variation in treatment response or toxicity. The use of genetic variants to guide treatment strategy has the potential to not only reduce National Health Service costs, but also drastically improve patient experience and quality of life.
SNP.
Only rs660895 (p = 0.0003) had a p value for an association with radiographic progression that passed the pre-defined significance threshold when tested using the LME model (Table 2). This SNP tags *04:01; its β value of 1.07 (95% CI 1.03–1.12) indicated a 1.07-fold greater annual increase in Larsen scores per copy of the risk (G) allele carried, relative to the reference (A) allele (Figure 3). This SNP remained significant in a model including ACPA as a covariate in place of RF (p = 0.0003).
Significant genetic associations with Larsen score progression. Mean Larsen scores with standard error bars shown at each timepoint stratified by genotype (“best-guess” genotypes used for imputed data in this figure, but not in the statistical analysis). His13: histidine at position 13; Val11: valine at position 11.
Table 2.
Genetic variants attaining a significant association with radiological progression.
| SNP (Gene) or HLA-DRB1 Allele or HLA Amino Acid | All RA, n = 524 | ACPA+, n = 350 | ACPA−, n = 149 | |||
|---|---|---|---|---|---|---|
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| rs660895 (HLA-DRB1*04:01 tag) | 1.07 (1.03–1.12) | 0.0003 | 1.07 (1.02–1.13) | 0.0037 | 1.03 (0.96–1.11) | 0.4571 |
| HLA-DRB1*04:01 | 1.10 (1.05–1.15) | 0.0002 | 1.08 (1.02–1.14) | 0.0105 | 1.04 (0.94–1.16) | 0.4344 |
| Histidine at position 13 in HLA-DRβ1 | 1.07 (1.03–1.12) | 0.0005 | 1.07 (1.02–1.13) | 0.0060 | 1.02 (0.95–1.10) | 0.5590 |
| Valine at position 11 in HLA-DRβ1 | 1.07 (1.03–1.11) | 0.0012 | 1.07 (1.01–1.12) | 0.0111 | 1.02 (0.95–1.10) | 0.6130 |
p values from the linear-mixed effects model genotype*time interaction term. ACPA status missing in 25 patients. Bonferroni-corrected p value thresholds for SNP, HLA-DRB1 alleles, and HLA amino acid polymorphisms in all RA are 0.0007, 0.0033, and 0.0019, respectively. Bonferroni-corrected p value threshold for the 4 markers tested in ACPA-positive and ACPA-negative RA is 0.0125. SNP: single-nucleotide polymorphism; RA: rheumatoid arthritis; ACPA: anticitrullinated protein antibodies.
Restricting analyses to ACPA-positive patients (Table 2) provided similar findings for this SNP (β = 1.07, p = 0.0037). No significant association was seen in ACPA-negative patients (β = 1.03, p = 0.4571), although the sample size was substantially smaller. This suggested that rs660895’s effect on radiological progression was not mediated by ACPA; if rs660895 drove ACPA formation, which itself caused joint destruction, then no association between this SNP and radiographic progression would be seen in ACPA-positive patients. Results for all SNP are given in Supplementary Table 4 (available online at jrheum.org).
Using the ANOVA model to test the association between each SNP and the ∆Larsen, the 2 most strongly associated SNP — rs660895 (p = 0.0002) and rs7579944 (p = 0.0140) — were the same as those identified by the LME model. Only rs660895 was significant.
HLA-DRB1 alleles.
Only *04:01 (p = 0.0002) had a p value that passed the predefined significance threshold using the LME model (Table 2). Its β value of 1.10 (95% CI 1.05–1.15) indicated a 1.10-fold greater annual increase in Larsen scores per *04:01 allele copy carried, relative to a non-carrier. This allele remained significant in a model including ACPA as a covariate instead of RF (p = 0.0006). Restricting analyses to ACPA-positive patients revealed similar findings (β = 1.08, p = 0.0105). No significant effect was seen in ACPA-negative patients (β = 1.04, p = 0.4344). Results for all alleles are given in Supplementary Table 5 (available online at jrheum.org). Using the ANOVA model to test the association between HLA-DRB1 susceptibility alleles and the ∆Larsen, *04:01 remained significant (p = 0.0009).
HLA amino acids.
Two amino acid polymorphisms — histidine at position 13 (His13; β = 1.07, p = 0.0005) and valine at position 11 (Val11; β = 1.07, p = 0.0012) in HLA-DRβ1 — had p values that passed the predefined significance threshold using the LME model (Table 2). Repeating the analysis with ACPA as a covariate instead of RF revealed similar results (His13 p = 0.0006, Val11 p = 0.0012). Restricting analyses to ACPA-positive patients showed similar findings; no significant association was seen in ACPA-negative patients (Table 2). Using the ANOVA model, His13 (p = 0.0002) and Val11 (p = 0.0002) in HLA-DRβ1 remained the most significant markers. Results for all amino acids are given in Supplementary Table 6 (available online at jrheum.org).
Because His13 and Val11 were in tight LD (r2 = 0.943), a conditional analysis was undertaken. Conditioning on His13 eliminated the effect of Val11 (LME p = 0.5547, ANOVA p = 0.4851). Conditioning on Val11 eliminated the effect of His13 (LME p = 0.1699, ANOVA p = 0.8697). This indicated the significance at both these markers was driven by their high LD, although it was not possible to establish which variant drove their association with Larsen scores.
None of the tested polymorphisms in the shared epitope (SE) region (positions 71 and 74) were significant (Supplementary Table 6 available online at jrheum.org); the lowest p value was for lysine at position 71 (p = 0.0293). However, the SE itself (sequences QRRAA, RRRAA, and QKRAA in positions 70–7429) significantly associated with radiological progression when the classical SE alleles (*01:01, *01:02, *04:01, *04:04, *04:05, *04:08, *10:01) were grouped together (LME p = 0.0003, ANOVA p = 0.0001).
Although His13 and Val11 are not in LD with positions 71 and 74, there is a marked correlation between their presence and carrying an SE sequence. His13 and Val11 are encoded by the SE alleles *04:01, *04:04, *04:05, *04:08, and *10:0112. A conditional analysis incorporating the SE as a modeling covariate was therefore undertaken. Conditioning on the SE eliminated the effect of His13 (LME p = 0.1996, ANOVA p = 0.1346) and Val11 (LME p = 0.3593, ANOVA p = 0.1224). Conditioning on His13 (LME p = 0.08301, ANOVA p = 0.0842) and Val11 (LME p = 0.05345, ANOVA p = 0.1023) eliminated the effect of the SE. This suggests that the association of His13, Val11, and the SE with joint destruction was driven by a high correlation between them, although it was not possible to establish which variant drove the association.
wGRS.
The full wGRS (LME p = 0.0428) and HLA wGRS (LME p < 0.0001), but not the non-HLA wGRS (LME p = 0.6720), associated with radiological progression (Supplementary Table 7, available online at jrheum.org).
Associations with disease activity.
Ten SNP, 1 HLA-DRB1 allele, and 4 HLA amino acid polymorphisms had p values < 0.05 for an association with the intercept and/or slope 1 and/or slope 2 DAS28 latent growth factor means (Supplementary Table 8, available online at jrheum.org). None were significant after Bonferroni correction.
The HLA wGRS associated with the intercept DAS28 latent growth factor means (β = 0.09, p = 0.041), but not those for slope 1 or slope 2 (Supplementary Table 7, available online at jrheum.org). No associations were seen between the full wGRS or non-HLA wGRS and DAS28.
Associations with disability.
From all tested variants, 2 SNP had p values for an association with HAQ score slope 2 latent growth factor means that passed the predefined significance threshold (Supplementary Table 9, available online at jrheum.org). These were composed of rs11889341 in STAT4 (β = 0.142, p = 0.0001) and rs653178 in SH2B3-PTPN11 (β = –0.109, p = 0.0004). Although the rs11889341 RA risk (T) allele associated with greater HAQ score increases over months 6–24, mean HAQ scores were lower at all timepoints in T allele carriers (Figure 4). Similarly, although the rs653178 RA risk (C) allele associated with an improvement in HAQ scores over months 6–24, at all timepoints except 24 months, mean HAQ scores were higher in CC homozygotes (Figure 4).
Significant genetic associations with HAQ scores over 6–24 months. Mean HAQ scores with standard error bars shown at each timepoint stratified by genotype. HAQ: Health Assessment Questionnaire.
A significant association was observed between the full wGRS (β = −0.08, p = 0.015) and HLA wGRS (β = −0.05, p = 0.026) and latent growth factor means of HAQ score slope 1. The non-HLA wGRS did not associate with HAQ scores (Supplementary Table 7, available online at jrheum.org).
2024年7月14日 | カテゴリー：関節リウマチ リウマチ外来 |
