Abstract
Different human leukocyte antigen (HLA) genotypes have been known to be associated with the risk of development of Sjögren's syndrome in different populations, but this association has never been reported in Taiwan. We enrolled 1044 subjects (673 patients, 371 controls) and tested their HLA‐DR genotypes. We found an increased risk of Sjögren's syndrome in patients carrying HLA‐DR8. DR1 and DR14 were associated with increased risk of eye involvement (uveitis, scleritis or optic neuritis), while DR15 was associated with increased risk of interstitial lung disease. DR8 was associated with increased risk of formation of multiple antibodies: anti‐Ro, rheumatoid factor and antinuclear antibodies (ANA) reaching titer 1:80 or above. DR9 was associated with decreased risk of formation of anti‐La antibodies and increased risk of formation of antithyroglobulin antibodies. DR10 was associated with risk of formation of anticyclic citrullinated peptide (anti‐CCP) antibodies, and DR11 was associated with increased risk of formation of anti‐La antibodies. Oral ulcer was found to be negatively associated with anti‐Ro antibodies and with anti‐ENA antibodies. Skin lesions were associated with ANA antibody titer elevation to 1:80 or above. Malignancies of any kind were associated with the presence of cryoglobulin. Females were more likely to be diagnosed at a younger age than males. There was no statistically significant relationship between HLA‐DR genotype and age at disease diagnosis. In patients with Sjögren's syndrome in Taiwan, the presence of HLA‐DR8 appeared to be a risk factor. In addition, we found several associations between HLA‐DR genotype, clinical presentation, and autoantibody status among them.
Keywords: genotype, human leukocyte antigen, Sjögren's syndrome
1. INTRODUCTION
Sjögren's syndrome is a chronic, progressive autoimmune disease that manifests primarily as the destruction of the salivary and lacrimal glands by infiltrating lymphocytes. 1 Sjögren's syndrome can also present with extraglandular manifestations, which include constitutional symptoms, arthritis, involvement of parenchymal organs such as the lungs and kidney, immune complex‐mediated diseases such as vasculitis and membranoproliferative glomerulonephritis, and, later in the disease course, lymphoma. 2 Sjögren's syndrome can occur per se (primary Sjögren's syndrome, hereafter referred to simply as Sjögren's syndrome) or in association with another autoimmune disease (secondary Sjögren's syndrome). Overall, the prevalence of Sjögren's syndrome is estimated to range from 0.01% to 0.05%. 3
The development of Sjögren's syndrome is affected by genetic, epigenetic and environmental factors that are not yet completely defined. Genetic factors affecting disease susceptibility include certain HLA genotypes, as well as various single nucleotide polymorphisms (SNPs); other genetic loci have been identified in genome‐wide association studies. 4 Defective epigenetic mechanisms, including abnormal DNA demethylation and abnormal microRNA expression, have been implicated in Sjögren's syndrome. 5 Proposed environmental factors affecting disease susceptibility include viruses, such as Epstein–Barr virus, cytomegalovirus, 6 and retroviral elements, 7 as well as declining estrogen levels, 8 which may explain the predominance of Sjögren's syndrome in postmenopausal women.
Of the genetic factors affecting susceptibility to Sjögren's syndrome, the best‐documented is HLA. Variations in the HLA genotype are long known to be associated with the susceptibility to, and presentation of, various autoimmune diseases in different populations. 9 , 10 , 11 Notably, Sjögren's syndrome is well‐known to be associated with HLA‐DR genotypes. 12 , 13 To the best of our knowledge, there have been no reported studies examining the association between the HLA‐DR genotype and the risk of Sjögren's syndrome in Taiwan. This study aims to investigate the three‐way association between HLA‐DR genotypes, clinical manifestations, and autoimmune serological statuses in Taiwanese patients with Sjögren's syndrome.
2. MATERIALS AND METHODS
We performed a review of 1044 subjects, including 673 patients with Sjögren's syndrome, comprising 630 females and 43 males enrolled from the Rheumatology clinic at Kaohsiung Medical University Hospital, and 371 healthy controls, to investigate the relationship between HLA‐DR genotypes, the risk of development of Sjögren's syndrome, the clinical manifestations of Sjögren's syndrome, and associated autoantibody serologies in Taiwanese patients.
The collection of subject data was performed in accordance with the WMA Declaration of Helsinki, with the approval of the Institutional Review Board at Kaohsiung Medical University Hospital. All patients met the 2016 ACR‐EULAR Classification Criteria for Primary Sjögren's Syndrome. 14 HLA‐DR genotyping was performed with the HLA FluoGene DRDQ kit (Inno‐Train Diagnostik GmbH, Kronberg, Germany). The medical records of each patient were reviewed to identify the disease manifestations, including parotid gland swelling, arthritis, oral ulcer, vasculitis, neuropathy, lymphadenopathy, annular erythematous skin lesions (including cutaneous lupus erythematosus (CLE)), eye involvement (including uveitis, scleritis or optic neuritis), interstitial lung disease, and malignancy. The autoimmune serologic profile for each patient was reviewed, including the serologic statuses for anti‐Ro antibody, anti‐La antibody, rheumatoid factor (RF), anticyclic citrullinated peptide (anti‐CCP) antibody, antinuclear antibody (ANA) (expressed in titer), anti‐double‐stranded DNA (anti‐dsDNA) antibody, antiextractable nuclear antigen (anti‐ENA) antibody, antithyroglobulin (ATG) antibody, antimicrosomal (AMS; antithyroid peroxidase) antibody, and cryoglobulins, as well as serum concentrations of complement C3 and complement C4. The biological gender and age at disease diagnosis for each patient were also reviewed.
Statistical analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria). Power analyses were performed using G*Power (Heinrich Heine University Düsseldorf, Düsseldorf, Germany). Alpha level was set at 0.05. p‐values were corrected for multiple comparisons using the Bonferroni and Benjamini‐Hochberg methods. Chi‐squared tests were performed to evaluate the association between each HLA‐DR genotype and disease status, between each genotype and the clinical manifestations, between each genotype and autoimmunity‐related markers, and between autoimmunity‐related markers and clinical manifestations. Two‐tailed t‐tests were performed to compare the mean ages at disease diagnosis between patients with and without each HLA‐DR genotype.
3. RESULTS
We tabulated the clinical manifestations (Table 1; Figure S1) and serological findings (Table 2; Figure S1) for the patient group, based on gender. We found that female patients were more likely to be diagnosed at an earlier age but found no significant difference in the frequencies of clinical manifestations and serological findings between the genders. The prevalence of each HLA‐DR genotype in the patient and control groups were also tabulated (Table 3; Figure S2). We found that HLA‐DR8 was associated with the occurrence of Sjögren's syndrome (odds ratio (OR) = 1.603, 95% confidence interval (CI) = 1.187–2.165, corrected p = 0.026). We then further compared the frequencies of each clinical manifestation for each genotype in patients with Sjögren's syndrome and found several associations between genotype and clinical manifestation (Table 4; Figure S3). DR1 and DR14 were associated with eye involvement (OR = 26.583, 95% CI = 2.576–274.348, corrected p = 0.00047; OR = 9.354, 95% CI = 1.541–56.766, corrected p = 0.0384 for DR1 and DR14, respectively). DR15 was associated with interstitial lung disease (OR = 4.731, 95% CI = 1.563–14.324, corrected p = 0.0312), while DR13 trended towards association (OR = 5.321, 95% CI 1.399–20.232, corrected p = 0.076). DR4 trended towards association with skin lesions (OR = 2.759, 95% CI = 1.333–5.709, corrected p = 0.055). DR8 trended towards association with lymphoma, but the odds ratio could not be calculated (corrected p = 0.086), since all study subjects who were diagnosed with lymphoma also carried DR8.
TABLE 1.
Clinical manifestations in Sjögren's syndrome patients.
| Clinical manifestation | Female, n = 630 (%) | Male, n = 43 (%) | p a |
|---|---|---|---|
| Average diagnosis age b | 52.144 ± 13.646 | 58.113 ± 13.589 | 0.0077 |
| Parotid gland swelling | 14 (2.22) | 1 (2.33) | 1.000 |
| Arthritis | 226 (35.87) | 10 (23.26) | 0.172 |
| Oral ulcer | 74 (11.75) | 2 (4.65) | 0.270 |
| Vasculitis | 21 (3.33) | 0 (0) | 0.465 |
| Neuropathy | 20 (3.17) | 2 (4.65) | 0.892 |
| Lymphadenopathy | 10 (1.59) | 0 (0) | 0.878 |
| Skin lesions | 30 (4.76) | 1 (2.33) | 0.755 |
| Eye involvement | 5 (0.79) | 0 (0) | 1.000 |
| Interstitial lung disease | 12 (1.90) | 1 (2.33) | 1.000 |
| Malignancy | 53 (8.41) | 3 (6.98) | 1.000 |
| Malignancy (lymphoma) | 3 (0.48) | 0 (0) | 1.000 |
| Malignancy (nonlymphoma) | 50 (7.94) | 3 (6.98) | 1.000 |
p‐value for average age at diagnosis is that from t‐test, while p‐values for clinical manifestations are those from chi‐square tests.
Mean ± standard deviation.
TABLE 2.
Autoantibody serology in Sjögren's syndrome patients.
| Presence of autoantibody | Female, n = 630 (%) | Male, n = 43 (%) | p a |
|---|---|---|---|
| Anti‐Ro | 410 (65.08) | 25 (58.14) | 0.607 |
| Anti‐La | 152 (24.13) | 7 (16.28) | 0.371 |
| Anti‐ENA | 421 (66.83) | 25 (58.14) | 0.986 |
| Rheumatoid factor | 170 (26.98) | 7 (16.28) | 0.458 |
| Anti‐CCP | 15 (2.38) | 0 (0) | 0.675 |
| ANA≧1:80 | 265 (42.06) | 10 (23.26) | 0.084 |
| Anti‐dsDNA | 30 (4.76) | 2 (4.65) | 1.000 |
| Low C3 | 117 (18.57) | 7 (16.28) | 1.000 |
| Low C4 | 71 (11.27) | 5 (11.63) | 0.815 |
| ATG Ab | 72 (11.43) | 1 (2.33) | 0.265 |
| AMS Ab | 103 (16.35) | 5 (11.63) | 1.000 |
| Cryoglobulin | 13 (2.06) | 0 (0) | 0.967 |
Abbreviations: ATG, antithyroglobulin antibody; AMS, antimicrosomal (antithyroid peroxidase) antibody.
p‐values calculated for chi‐square tests.
TABLE 3.
HLA genotypes in Sjögren's syndrome patients versus controls.
| HLA genotype | Sjögren's, n = 673 (%) | Control, n = 371 (%) | Odds ratio, Sjögren/control (95% CI) | p a | Corrected p b |
|---|---|---|---|---|---|
| DR1 | 7 (1.04) | 3 (0.81) | 1.289 (0.331–5.016) | 0.713 | 0.927 |
| DR4 | 175 (26.00) | 98 (26.42) | 0.979 (0.734–1.306) | 0.885 | 0.929 |
| DR7 | 16 (2.38) | 14 (3.77) | 0.621 (0.300–1.287) | 0.196 | 0.510 |
| DR8 | 199 (29.57) | 77 (20.75) | 1.603 (1.187–2.165) | 0.0020 | 0.026 |
| DR9 | 145 (21.55) | 98 (26.42) | 0.765 (0.570–1.028) | 0.075 | 0.280 |
| DR10 | 10 (1.49) | 6 (1.62) | 0.918 (0.331–2.545) | 0.869 | 0.929 |
| DR11 | 110 (16.34) | 54 (15.56) | 1.147 (0.805–1.633) | 0.447 | 0.830 |
| DR12 | 170 (25.26) | 84 (22.64) | 1.155 (0.856–1.557) | 0.345 | 0.748 |
| DR13 | 39 (5.79) | 22 (5.93) | 0.976 (0.569–1.672) | 0.929 | 0.929 |
| DR14 | 96 (14.26) | 58 (15.63) | 0.898 (0.630–1.279) | 0.551 | 0.895 |
| DR15 | 136 (20.21) | 71 (19.14) | 1.070 (0.777–1.473) | 0.678 | 0.927 |
| DR16 | 71 (10.55) | 27 (7.28) | 1.503 (0.946–2.386) | 0.083 | 0.280 |
| DR17 | 88 (13.08) | 63 (16.98) | 0.735 (0.517–1.045) | 0.086 | 0.280 |
p‐values calculated for chi‐squared tests.
p‐values corrected using Bonferroni method.
TABLE 4.
HLA genotypes and associated clinical manifestations in Sjögren's syndrome patients (condensed). a
| HLA genotype | Associated clinical manifestation | Odds ratio (95% CI) b | p c | Corrected p d |
|---|---|---|---|---|
| DR1 | Eye involvement | 26.583 (2.576–274.348) | 0.000039 | 0.00047 |
| DR4 | Skin lesions | 2.759 (1.333–5.709) | 0.0046 | 0.055 |
| DR8 | Malig. (lymphoma) | Inf (NaN‐Inf) | 0.0072 | 0.086 |
| DR13 | Interstitial lung disease | 5.321 (1.399–20.232) | 0.0063 | 0.076 |
| DR14 | Eye involvement | 9.354 (1.541–56.766) | 0.0032 | 0.0384 |
| DR15 | Interstitial lung disease | 4.731 (1.563–14.324) | 0.0026 | 0.0312 |
Only results with significant or near‐significant (i.e., between 0.05 and 0.10) corrected p‐values are shown here. See Table 4 in Supplementary information for the full table.
Some values could not be determined due to very low, very high, or lack of incidence. NaN, not a number; Inf: infinity.
p‐values calculated for chi‐square tests.
p‐values corrected with Benjamini‐Hochberg method.
We further examined the relationship between HLA‐DR genotype and autoantibody serology in patients (Table 5; Figure S4). DR8 was associated with anti‐Ro antibodies (OR = 2.169, 95% CI = 1.462–3.218, corrected p = 0.0012), RF (OR = 1.705, 95% CI = 1.170–2.485, corrected p = 0.0208), and the elevation of ANA titer above 1:80 (OR = 1.802, 95% CI = 1.243–2.611, corrected p = 0.0108). DR9 was associated with the presence of ATG antibodies (OR = 2.397, 95% CI = 1.389–4.138, corrected p = 0.0168), and negatively associated with anti‐La antibodies (OR = 0.480, 95% CI = 0.290–0.794, corrected p = 0.0222). DR10 was associated with anti‐CCP antibody (OR = 15.769, 95% CI = 2.646–93.971, corrected p = 0.00068). DR11 was associated with the presence of anti‐La antibodies (OR = 2.250, 95% CI = 1.448–3.498, corrected p = 0.0030). In addition, there was a trend towards negative association between DR4 and anti‐La antibodies (OR = 0.528, 95% CI 0.336–0.831, corrected p = 0.062), association between DR8 and anti‐La antibodies (OR = 1.582, 95% CI 1.083–2.311, corrected p = 0.051), and negative association between DR9 and RF (OR = 0.584, 95% CI 0.370–0.922, corrected p = 0.084).
TABLE 5.
HLA genotypes and serology in Sjögren's syndrome patients (condensed). a
| HLA genotype | Serology | Odds ratio (95% CI) b | p c | Corrected p d |
|---|---|---|---|---|
| DR4 | Anti‐La | 0.528 (0.336–0.831) | 0.0052 | 0.062 |
| DR8 | Anti‐Ro | 2.169 (1.462–3.218) | 0.000096 | 0.0012 |
| Anti‐La | 1.582 (1.083–2.311) | 0.0171 | 0.051 | |
| Rheumatoid factor | 1.705 (1.170–2.485) | 0.0052 | 0.0208 | |
| ANA≧1:80 | 1.802 (1.243–2.611) | 0.0018 | 0.0108 | |
| DR9 | Anti‐La | 0.480 (0.290–0.794) | 0.0037 | 0.0222 |
| ATG Ab | 2.397 (1.389–4.138) | 0.0014 | 0.0168 | |
| DR10 | Anti‐CCP | 15.769 (2.646–93.971) | 0.000062 | 0.00068 |
| DR11 | Anti‐La | 2.250 (1.448–3.498) | 0.00025 | 0.0030 |
Only results with significant or near‐significant (i.e., between 0.05 and 0.10) corrected p‐values are shown here. See Table 5 in Supplementary information for the full table.
Some values could not be determined due to very low incidence. NaN, not a number; Inf, infinity.
p‐values calculated for chi‐square tests.
p‐values corrected with Benjamini‐Hochberg method.
We also examined the relationship between serological status and clinical presentations in Sjögren syndrome patients (Table 6; Figure S5). Perhaps unsurprisingly, arthritis was positively associated with the presence of anti‐CCP antibodies (OR = 9.672, 95% CI 2.155–43.417, corrected p = 0.0041). Interestingly, oral ulcer was negatively associated with the presence of anti‐Ro antibodies (OR = 0.437, 95% CI 0.268–0.713, corrected p = 0.0043) and anti‐ENA antibodies (OR = 0.330, 95% CI 0.178–0.613, corrected p = 0.0032); in addition, there was a trend towards negative association with C4 hypocomplementemia (OR = 0.258, 95% CI 0.078–0.849, corrected p = 0.068). Skin lesions were associated with elevation of ANA titers to above 1:80 (OR = 3.552, 95% CI 1.548–8.150, corrected p = 0.0180). Nonlymphoma malignancies were associated with the presence of cryoglobulin (OR = 8.906, 95% CI 1.970–40.265, corrected p = 0.0168).
TABLE 6.
Serologies and clinical manifestations in Sjögren syndrome patients (listed in order: odds ratio, 95% confidence interval, p‐value a , corrected p‐value b ) (condensed). c
| Arthritis | Oral ulcer | |
|---|---|---|
| Anti‐Ro | 1.116 (0.790–1.577), 0.533, 0.914 | 0.437 (0.268–0.713), 0.00072, 0.0043 |
| Anti‐ENA | 0.817 (0.501–1.332), 0.418, 0.836 | 0.330 (0.178–0.613), 0.00027, 0.0032 |
| Anti‐CCP | 9.672 (2.155–43.417), 0.00034, 0.0041 | 1.048 (0.230–4.774), 0.952, 0.952 |
| Skin lesions | ||
|---|---|---|
| ANA≧1:80 | 3.552 (1.548–8.150), 0.0015, 0.0180 |
| Malignancy (total) | Malignancy (nonlymphoma) | |
|---|---|---|
| Cryoglobulin | 8.906 (1.970–40.265), 0.0014, 0.0168 | 8.906 (1.970–40.265), 0.0014, 0.0168 |
p‐values calculated for chi‐square tests.
p‐values corrected using Benjamini‐Hochberg method.
Only results with significant or near‐significant (i.e., between 0.05 and 0.10) corrected p‐values are shown here. See Table 6 in Supplementary information for the full table.
Finally, we compared the mean ages at disease diagnosis for each genotype in Sjögren's syndrome patients (Table 7; Figure S6). After correcting for multiple comparisons, we found no statistically significant association between HLA‐DR genotype and age at diagnosis. As we had found DR8 to be associated with an increased occurrence of Sjögren's syndrome, we performed a power analysis (post‐hoc 2‐tailed z‐test with an alpha of 0.05) to confirm whether we achieved adequate power to detect a difference in the proportion of DR8 in patients and controls and found that we achieved a power of 0.8805.
TABLE 7.
HLA genotypes and mean age of diagnosis in Sjögren's syndrome patients.
| HLA genotype | Mean age at diagnosis if positive (95% CI) | Mean age at diagnosis if negative (95% CI) | 95% confidence interval for difference | p a | Corrected p b |
|---|---|---|---|---|---|
| DR1 | 53.932 (44.021–63.842) | 52.525 (51.459–53.591) | −11.667, 8.853 | 0.750 | 0.949 |
| DR4 | 52.246 (50.204–54.288) | 52.644 (51.403–53.884) | −1.987, 2.782 | 0.743 | 0.949 |
| DR7 | 51.857 (44.090–59.624) | 52.555 (51.484–53.626) | −7.178, 8.574 | 0.852 | 0.949 |
| DR8 | 50.967 (49.040–52.893) | 53.217 (51.952–54.482) | −0.050, 4.551 | 0.055 | 0.358 |
| DR9 | 52.434 (50.029–54.838) | 52.569 (51.388–53.749) | −2.539, 2.809 | 0.921 | 0.949 |
| DR10 | 51.073 (42.254–59.892) | 52.563 (51.495–53.631) | −7.497, 10.477 | 0.718 | 0.949 |
| DR11 | 52.442 (49.366–55.518) | 52.559 (51.442–53.676) | −3.151, 3.386 | 0.944 | 0.949 |
| DR12 | 51.609 (49.611–53.607) | 52.843 (51.598–54.087) | −1.116, 3.583 | 0.302 | 0.785 |
| DR13 | 50.474 (45.519–55.429) | 52.669 (51.585–53.752) | −2.874, 7.262 | 0.387 | 0.839 |
| DR14 | 54.868 (52.003–57.734) | 52.150 (51.011–53.288) | −5.796, 0.359 | 0.083 | 0.360 |
| DR15 | 53.672 (51.423–55.920) | 52.248 (51.048–53.448) | −3.967, 1.120 | 0.271 | 0.785 |
| DR16 | 52.437 (49.063–55.811) | 52.552 (51.435–53.669) | −3.433, 3.663 | 0.949 | 0.949 |
| DR17 | 55.608 (52.898–58.318) | 52.077 (50.932–53.221) | −6.467, −0.595 | 0.019 | 0.247 |
p‐values calculated for two‐tailed t‐tests.
p‐values corrected using Benjamini‐Hochberg method.
4. DISCUSSION
In our study, we found that HLA‐DR8 was associated with the incidence of Sjögren's syndrome, as well as with the presence of anti‐Ro antibodies. In addition, we found several other associations between HLA‐DR genotype, autoantibody serology, and clinical manifestations.
A link between risk for Sjögren's syndrome and HLA serotype was first reported by Manthorpe et al., 15 in addition to a link between anti‐SSB/La and HLA serotype. Moriuchi et al. 16 reported an increased frequency of HLA‐DRw53 (a supertype that includes HLA‐DR4, DR7, and DR9) in Japanese patients, while Kang et al. 12 reported association between Sjögren's syndrome and HLA‐DR3 in Caucasian patients, HLA‐DR4 in Japanese patients, and HLA‐DR8 in Chinese patients.
Sjögren's syndrome is known to occur predominantly in women. In our study, in addition to confirming increased disease incidence in women, we found that the average age at which a patient was diagnosed with Sjögren's syndrome was significantly lower in women than in men, a finding that is compatible with previous epidemiological studies. 17 It is currently unknown exactly why, among patients with Sjögren's syndrome, male patients seem to be diagnosed at older ages compared with female patients, although it has been proposed that since Sjögren's syndrome is much more prevalent in females than in males overall, there could be delayed recognition and diagnosis in male patients (interestingly, the US‐based Sjögren's Foundation further hypothesizes that the female‐to‐male ratio in Sjögren's syndrome could be reduced in the future, owing to increased clinical awareness of the disease in males). 18 Additionally, it has also been proposed that males may be less likely to report or seek medical attention for early symptoms of Sjögren's syndrome, such as dry eyes and dry mouth, leading to under‐diagnosis. However, apart from this finding, we found neither any significant association between biological gender and clinical manifestation, nor any significant association between biological gender and autoantibody serological status. In contrast, Chatzis et al. 19 reported an increased risk of lymphoma and an increased prevalence of serum anti‐La/SSB antibodies among male Sjögren's syndrome patients.
Sjögren's syndrome primarily involves exocrine glands, especially the lacrimal and salivary glands, but can involve other organ systems as well. For each HLA‐DR genotype, we investigated the relationship between the genotype and several clinical manifestations of Sjögren's syndrome (namely, parotid gland swelling, arthritis, oral ulcer, vasculitis, neuropathy, lymphadenopathy, skin lesions, eye involvement (uveitis, scleritis, or optic neuritis), interstitial lung disease, and malignancy).
Different HLA genotypes are known to be associated with different risks for various forms of uveitis. Zamecki and Jabs 20 found that different HLA antigens were correlated with different presentations of uveitis. We found DR1 and DR14 to be associated with an increased risk of eye involvement in patients with Sjögren's syndrome.
Prior studies have established links between carriage of certain HLA genotypes and risk for interstitial lung disease. Xue et al. 21 reported that DRB1*15:01 was over‐represented in patients with idiopathic pulmonary fibrosis, while Mori et al. 22 reported that in patients with rheumatoid arthritis (RA) that DRB1*15:02 was positively associated with interstitial lung disease, but was negatively associated with airway disease. Furukawa et al. 23 reported that, among Japanese patients with RA, the DRB1 shared epitope was negatively associated with risk for interstitial lung disease, while the DR2 serological group (DRB1*15 and *16) were positively associated. Fingerlin et al. 24 performed a genome‐wide association study in non‐Hispanic White cases of fibrotic idiopathic interstitial pneumonia, and found that DRB1*15:01 and DQB1*06:02 were highly associated. The effects of HLA genotype on risk for pulmonary fibrosis are incompletely understood, but there appears to be an indirect association between the two. For example, in RA, there is an association between HLA epitopes and production of anti‐CCP antibodies, and an association between anti‐CCP antibodies and risk for pulmonary fibrosis; HLA and risk for pulmonary fibrosis are thus indirectly associated through anti‐CCP antibodies. 25 In our study, we found that DR15 was significantly associated with interstitial lung disease in patients with Sjögren's syndrome; however, DR15 was not found to be associated with anti‐CCP antibody or anti‐Ro antibody, and anti‐CCP antibody and anti‐Ro antibody were not found to be associated with interstitial lung disease. It is possible that Sjögren's syndrome and RA cause interstitial lung disease via different pathogenic mechanisms; future work is needed to investigate these differences.
It is well‐established that certain HLA genotypes are correlated with risk for lymphoma. 26 Among our subjects, we found no statistically significant correlation between malignancy (including lymphomas) and any of the HLA genotypes we tested for. DR8 trended towards association with increased risk of lymphoma. However, it should be noted that, of all our study subjects who simultaneously had Sjögren's syndrome and any form of malignancy, the most commonly occurring malignancy appeared to be solid organ cancers, rather than lymphomas. Our findings that no statistically significant link could be established between HLA genotype and malignancy could be due to the relatively low proportion of patients who simultaneously had Sjögren's syndrome and malignancy.
Different HLA genotypes are associated with different risks for SCLE and DLE in different populations. DLE is associated with HLA‐A28 in Black patients, and HLA‐B5 in White patients. However, the exact genotypes associated with each ethnic group can be controversial 27 , 28 ; on the other hand, it is less clear whether there is an association with Sjögren syndrome‐related skin lesions. We noted a trend towards association between DR4 and the presence of skin lesions, which includes CLE, although this association was not statistically significant.
No association was found between HLA‐DR genotype and the risks for parotid gland swelling, arthritis, and oral ulcer.
We examined the relationship between HLA‐DR genotype and various markers related to autoimmunity. Terao et al. 29 reported that the SNP rs2395185 in the HLA locus, which is in linkage disequilibrium with HLA‐DRB1*0405, was significantly associated with ANA seropositivity. In our study, we found that HLA‐DR8 was significantly associated with an increase of ANA titer to 1:80 and above.
Anti‐CCP antibodies are highly specific for RA. van Drongelen and Holoshitz 30 reviewed HLA disease associations in RA, and reported that patients carrying DR1, DR4, or DR10 (all of which encode a “shared epitope”) were more likely to carry anti‐CCP antibodies. We found in our study that anti‐CCP seropositivity was associated with DR10 but found no such association with DR1 or DR4 in Sjögren's syndrome.
Provost and Watson 31 postulated that the association between HLA‐DR3 and Sjögren's syndrome is related to anti‐Ro/SSA. Miyagawa et al. 32 reported in a study of Japanese women that a possible link exists between HLA class II genotype and the development of anti‐Ro and/or anti‐La antibodies. In our study, we found an association between the presence of anti‐Ro antibodies and DR8. This finding was consistent with those reported by Miyagawa et al. in Japanese subjects. In addition, we found a positive association between the presence of anti‐La antibodies and DR11, as well as a negative association with DR9.
Sjögren's syndrome is the most common rheumatic disease to be associated with autoimmune thyroid diseases, and HLA genotypes have long been known to be associated with thyroid disorders. The HLA haplotypes B8 and DR3 are frequently seen in both autoimmune thyroid disease and Sjögren's syndrome, and have been proposed to participate in both diseases. 33 Thompson and Farid 34 reported that Hashimoto's thyroiditis is associated with DR4, while Tachi et al. 35 reported that patients with DRw9 and/or B51 and who had higher titers of ATG antibody were more likely to develop permanent hypothyroidism. Our results showed that DR9 was positively associated with the production of ATG antibodies. No similar associations were found for AMS antibodies.
Previous studies have investigated the association between HLA genotype and the presence of RF. Nelson et al. 36 reported an association between DR4 and RF seropositivity in women with recent‐onset RA. We found DR8 to be significantly associated with the production of RF; DR9 trended towards negative association with RF.
We examined the relationship between various autoimmune markers and clinical manifestations of Sjögren's syndrome. We focus on anti‐Ro and anti‐La antibodies, which are frequently associated with Sjögren's syndrome. Anti‐Ro antibodies play a central role in the pathogenesis of Sjögren's syndrome. Over the past several decades, various associations have been reported between anti‐Ro/La serological status and the extraglandular manifestations of Sjögren's syndrome. Of these, an association between anti‐Ro/La serological status and skin manifestations, such as annular erythema, has been frequently reported. 37 Initially, the association between anti‐Ro/La serological status and skin manifestations was believed to occur in patients of Asian descent. Brito‐Zerón et al. 38 performed a retrospective study of non‐Asian primary Sjögren's syndrome patients who had presented with annular erythema, and found that annular erythema was strongly associated with anti‐Ro antibodies, but only weakly associated with other markers of immunity. However, in our study, no significant association between anti‐Ro or anti‐La with skin manifestations was detected.
In addition, we found that the presence of anti‐Ro antibodies was negatively associated with the incidence of oral ulcers. However, this finding remains unexplained, and to our knowledge, no mechanism for this finding has been proposed.
Finally, we examined the relationship between HLA‐DR genotype and age at disease diagnosis in Sjögren's syndrome patients. There is relatively scant information regarding the relationship between HLA genotype and age of onset in patients with Sjögren's syndrome. Thorlacius et al. 39 found a correlation between HLA‐DQA1 and age at symptom onset. However, Cruz‐Tapias et al. 40 reported no relationship between HLA and age at disease diagnosis in their review. In our study, we found no association between HLA genotype and the age at disease diagnosis.
In conclusion, HLA‐DR8 was found to be associated with a higher disease incidence and a higher percentage of anti‐Ro seropositivity. Several associations between HLA‐DR genotype, clinical presentation, and autoantibody status were uncovered. Further study is needed to explore the mechanistic link between HLA‐DR genotype and the overall clinical picture in Sjögren's syndrome in Taiwan.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Supporting information
Data S1. Supporting information.
Yen C‐Y, Wang P‐Y, Chen K‐Y, Tseng C‐C, Wu C‐C, Ou T‐T, et al. HLA‐DR genotypes in patients with primary Sjögren's syndrome in Taiwan. Kaohsiung J Med Sci. 2024;40(10):934–941. 10.1002/kjm2.12885
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Supplementary Materials
Data S1. Supporting information.