HLA Class I, II, and III Polymorphism in Italian Patients With Sarcoidosis: Results

HLA Class I, II, and III Polymorphism in Italian Patients With Sarcoidosis: ResultsCharacteristics of Patients with Sarcoid
Data are described in Table 1. In our series, the female:male ratio was 1.48:1. The sample study enrolled a large majority of nonsmokers (69.15 percent). Only 37 patients (34.57 percent) were asymptomatic (chest radiographic abnormalities noticed during periodic screening), whereas most of patients (65.42 percent) had symptoms (dyspnea, fever, erythema nodosum, arthralgia, cough, chest pain, or ophthalmic symptoms). Radiologic stage II assembled 40 patients (37.38 percent), whereas 38 patients (35.51 percent) were assigned to stage I, and 25 (23.36 percent) were assigned to stage III. Finally, 38 patients (35.51 percent) had one or more extrapulmonary localizations of the disease.
HLA Polymorphisms
As reported in Table 2, we could confirm the positive association HLA-B8-sarcoidosis (p = 0.0127). Although the pc for this association was not significant in our study, we should bear in mind that the association HLA-B8-sarcoidosis in Caucasians was previously reported, and therefore, the significance for this association does not require a correction for number of antigens tested. In addition, we found a negative association with DR1 (x2 — 6.93, p = 0.0040, RR = 0.35) and CW6 (x2 = 7.83, p = 0.0024, RR = 0.37), but pc was not significant for both specificities. Among HLA class III we did not notice any different distribution of the C4A, C4B, and BF allele frequencies with respect to the controls.
Heterogeneity Analysis of Disease
When we analyzed the relationship of HLA heterogeneity and sarcoidosis (iie, sex of patients, age of onset, radiologic stage, and extrathoracic spread), we noticed several deviated frequencies. HLA-B35 was more frequent in {patients with an early onset of the disease than in those with a late onset (pc<0.05) (Table 3). The same trend was shared by HLA-DR5 (x2 = 5.99, p = 0.0122, pc = not significant [NS], RR = 2.75), whereas B40 was related to the subset of patients with an age of onset over 36 years (x2 = 8.91, p <0.05, pc = NS, RR = 3.97). The relationship between HLA polymorphisms and radiologic stage of sarcoidosis showed that HLA-DR3 was significantly more frequent in patients with stage 0 + 1 with respect to patients with stage III (pc <0.05, Table 4). B8 had the same trend (x2 = 9.93, p<0.05, RR = 2.96), but the pc was not significant. By contrast, DR5 and C4A3 showed a decreased frequency in stage I (x2 = 4.54, p = 0.0294, RR = 0.32 and x2 = 7.08, p<0.05, RR = 0.46, respectively; both pc = NS).
With regard to the other heterogeneity parameters analyzed, we found that HLA-BW22 was associated with the more extensive form of the disease (Table 5), occurring with extrapulmonary localizations (x2 = 11.54, p = 0.0015, RR = 5.40). We also noticed that the following antigens were positively associated with female sex (Table 6): B8 (x2 = 7.2, p<0.05, RR = 2.39), B40 (x2 = 7.3, p<0.05, RR = 3.51), CW2 (x2 = 7.3, p <0.05, RR = 2.65), and BFF (x2 = 5.99, p<0.05, RR=1.77). Interestingly, DR1 antigen was absent among male patients (vs female, x2 = 5.03, p = 0.02, R = 0.08). However, none of these associations reached a significant pc.

Table 1—Characteristics of Patients With Sarcoid

Characteristics No. (%)
No.-107: F 64 (59.81); M 43 (40.19)
Mean age, yr±SD-36.08± 12.4; F 39.3± 13.9, M 31.13±8.84
Smoke—Smokers 33 (30.84) (current 16 former 17) nonsmokers 74(69.16)
Disease onset—Asymptomatic* 37 (34.57); Symptomatic! 70 (65.43)
Radiologic stage—Stage 0, 4 (3.73) (F 3, M 1); stage I, 38 (35.51) (F 19, M 19); stage II, 40 (37.39) (F 24, M 16); stage III,25 (23.37) (F 18, M 7)
Site(s) of biopsy
Lung transbronchial 48 (44.38)
Scalene lymph node 40 (37.38)
Skin 7 (6.54)
Open lung 4 (3.73)
Peripheral lymph node 2 (1.86)
Parotid 1 (0.93)
Lung transbronchial + open lung 2 (1.86)
Lung transbronchial -1- skin 2 (1.86)
Scalene lymph node + liver 1 (0.93)
Scalene lymph node -1- skin 1 (0.93)
Scalene lymph node + lung transbronchial 1 (0.93)
Lung transbronchial + open lung -I- skin 1 (0.93)
Lung transbronchial + peripheral lymph node + liver + spleen 1 (0.93)
Extrapulmonary localizations, 38 (35.57)
Skin 12 (31.57)
Peripheral lymph node 5 (13.15)
Eyes 4 (10.52)
Liver 3 (7.89)
Heart 1 (2.63)
Parotid 1 (2.63)
Eyes 4- skin 3 (7.89)
Skin -1- joints 1 (2.63)
Eyes + parotid 1 (2.63)
Liver -1- parotid 1 (2.63)
Eyes + peripheral lymph node 1 (2.63)
Eyes -1- parotid + skin 1 (2.63)
Liver + parotid -1- peripheral lymph node + spleen 1 (2.63)
Bone marrow -1- retroperitoneal lymph node 1 (2.63)
Eyes + liver -1- skin -1- spleen + joints + peripheral lymph node 1 (2.63)

Table 2—HLA Deviated Frequencies in Sarcoidosis

HLAAntigens Control Subjects (n = 510), % Sarcoidosis (n = 107), % X2 p Value pc RR
B8 13.10 22.40 6.07 0.0127 NS 1.91
CW6 19.8 8.4 7.83 0.0024 NS 0.37
DR1 16.5 6.5 6.93 0.0040 NS 0.35

Table 3—HLA Markers and Onset of Clinical Signs andJor Symptoms of Sarcoidosis

HLAAntigen Controls (%) n = 510 Patients (%)
Age <36 yr n = 56 Age >36 yr n = 51
A3 24.7 28.6 11.6
B8 13.1 19.6 27.9
B35 28.8 32.1 9.3
B40 4.0 5.4 14.0
CW4 32.3 37.5 16.3
DR5 47.9 64.3 39.5
Sarcoid patients >36 yr vs controls Sarcoid patients <36 yr vs >36 yr
B8 X27.06 p<0.05 pc = NS RR 2.56 A3 x2 4.18 p = 0.034 pc = NS RR 3.04
B35 X2 7.61 p<0.05 pc = NS RR 0.25 B35 v2 7.34 p = 0.0056 pc<0.05 RR 4.62
B40 X2 8.91 p<0.05 pc = NS RR 3.97 CW4 x2 5.40 p = 0.0167 pc = NS RR 3.09
DR5 x2 599 p = 0.0122 pc= NS RR 2.75

Table 4—HLA Markers and Radiologic Stage of Sarcoidosis

HLAAntigen Controls (%) n = 510 (382 for BF, 370 for C4) Patients (%)
Stage 0 +1 n = 42 Stage II n = 40 Stage III n = 25
B8 13.1 31.0 20.0 12.0
DR3 19.7 38.1 15.0 8.0
DR5 47.9 45.2 47.5 72.0
C4A3 76.3 60.0 79.7 77.5
BFF 20.16 14.71 30.26 29.17
Stage 0 +1 vs controls Stage I vs Stage III
B8 X29.93 p<0.05 pc= NS RR 2.96 DR3 y2 7.22 p = 0.0061 pc <0.05 RR 7.08
C4A3 X27.08 p<0.05 pc= NS RR 0.46 DR5 X24.54 p = 0.0294 pc = NS RR 0.32

Table 5—HLA Markers and Extrapulmonary Localizations of Sarcoidosis

HLAAntigen Controls (%) n = 510 Patients (%)
With Extrapulmonary Location n = 38 Without Extrapulmonary Location n = 69
B8 13.1 34.2 15.9
BW22 3.4 15.8 0
With extrapulmonary location vs controls Without extrapulmonary location vs with extrapulmonary location
B8 X212.59 p<0.01 pc = NS RR 3.43 BW22 X211.54 p = 0.0015 pc= NS RR 0.03
BW22 X213.60 p<0.01 pc = NS RR 5.41

Table 6—HLA Markers and Sex in Sarcoidosis

HLAAntigen Controls (%) n = 510 Patients (%)
Male n = 43 Female n = 64
B8 13.1 16.3 26.6
B40 4.0 2.3 12.5
CW2 7.3 14.0 17.2
DR1 16.5 0 10.9
DR7 24.8 16.6 25.0
Males vs controls Females vs controls
DR1 X2 8.3 p<0.05 pc = NS RR 0.05 B8 X2 7.2 p<0.05 pc = NS RR 2.39
Males vs females B40 X2 7.3 p<0.05 pc = NS RR 3.51
CW2 X27.3 p<0.05 pc = NS RR 2.65
DR1 X2 5 03 p = 0.02 pc= NS RR 0.08
DR7 X2 7.26 p = 0.006 pc = NS RR 0.23
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