HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women

Objectives. The aim of this study was to evaluate human leukocyte antigen (HLA) involvement in the disease expression and poor prognostic clinical features (pulmonary fibrosis and pulmonary arterial hypertension) in patients diagnosed with systemic sclerosis (SSc) in a multiethnic population. Methods. SSc patients followed up between 2008 and 2011 were included, and clinical data were obtained through records review. Molecular HLA typing was performed (polymerase chain reaction amplification technique using specific primer sequences). The statistical analysis involved Fisher's exact test and Pearson's corrected chi-square test. P values ≤ 0.05 were considered significant. The delta method was used to estimate the variance of the prevalence ratio (PR). Results. A total of 141 patients (120 women and 21 men) with SSc were studied, including 33.3% with diffuse cutaneous SSc (dcSSc), 62.4% with limited cutaneous SSc (lcSSc), and 4.3% with sine scleroderma. Pulmonary fibrosis was present in 61 patients (43.3%), and the HLA-A∗30 and DQB1∗04 alleles were related to susceptibility. In contrast, the HLA-DRB1∗01 and DQB1∗05 alleles were protective. Pulmonary arterial hypertension was diagnosed in 19 patients (13.5%) and was associated with HLA-B∗35 and C∗04; in contrast, C∗03 seemed to be protective. Conclusions. Our current study documents the association of some classes I and II HLA alleles with the most severe clinical manifestations in a multiethnic case series. Our findings differed slightly from the previous data in other populations.

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“…Our results did not support the previous reports of a higher skin score in the presence of the HLA-B*62, DRB1*11, and DRB1*07 alleles [4, 9]. …”

Section: Discussioncontrasting

confidence: 99%

“…Considering the clinical features, the HLA-DRB1 allele has been associated with the limited cutaneous form (lcSSc) [4] and B*62, DRB1*11 (DRB1*1104), and DRB1*07 with the diffuse cutaneous form (dcSSc) [4, 9]. An association between HLA alleles and visceral involvement in SSc is not well established.…”

Section: Introductionmentioning

confidence: 99%

HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

et al. 2013

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“…Comparing SSc patients with healthy controls, the overall distribution of 3rd HVR sequences was significantly different ( p = 0.007) (Table 2). The sequence “FLEDRRAA” (sequence category 5 in Table 1) was significantly enriched in SSc patients compared with controls ( p = 0.004, p value corrected for multiple comparisons p c = 0.032), primarily due to enrichment of DRB1*11:04 among SSc patients, as reported previously [3]. The sequence “FLEDRRAL” (sequence category 11 in Table 1) was also enriched in SSc patients ( p = 0.006, p c = 0.048) (Table 2), due to some increase of DRB1*08:01 and DRB1*08:02 in SSc patients.…”

Section: Resultssupporting

confidence: 78%

Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

et al. 2017

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BackgroundSpecific HLA class II alleles are associated with systemic sclerosis (SSc) risk, clinical characteristics, and autoantibodies. HLA nomenclature initially developed with antibodies as typing reagents defining DRB1 allele groups. However, alleles from different DRB1 allele groups encode the same third hypervariable region (3rd HVR) sequence, the primary T-cell recognition site, and 3rd HVR charge differences can affect interactions with T cells. We considered 3rd HVR sequences (amino acids 67–74) irrespective of the allele group and analyzed parental inheritance considered according to the 3rd HVR charge, comparing SSc patients with controls.MethodsIn total, 306 families (121 SSc and 185 controls) were HLA genotyped and parental HLA-haplotype origin was determined. Analysis was conducted according to DRβ1 3rd HVR sequence, charge, and parental inheritance.ResultsThe distribution of 3rd HVR sequences differed in SSc patients versus controls (p = 0.007), primarily due to an increase of specific DRB1*11 alleles, in accord with previous observations. The 3rd HVR sequences were next analyzed according to charge and parental inheritance. Paternal transmission of DRB1 alleles encoding a +2 charge 3rd HVR was significantly reduced in SSc patients compared with maternal transmission (p = 0.0003, corrected for analysis of four charge categories p = 0.001). To a lesser extent, paternal transmission was increased when charge was 0 (p = 0.021, corrected for multiple comparisons p = 0.084). In contrast, paternal versus maternal inheritance was similar in controls.ConclusionsSSc patients differed from controls when DRB1 alleles were categorized according to 3rd HVR sequences. Skewed parental inheritance was observed in SSc patients but not in controls when the DRβ1 3rd HVR was considered according to charge. These observations suggest that epigenetic modulation of HLA merits investigation in SSc.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1253-9) contains supplementary material, which is available to authorized users.

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“…Clinical characteristics of the patients and controls have been published elsewhere. ( 12,13 ) The ethics review boards at the participating institutions approved the study protocol. Informed consent was obtained from all subjects.…”

Section: Methodsmentioning

confidence: 99%

Skewed X-Chromosome Inactivation in Scleroderma

Loubière

Gadi

et al. 2007

Clinic Rev Allerg Immunol

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Scleroderma is a female-prevalent autoimmune disease of unclear etiology. Two fundamental gender differences, skewed X-chromosome inactivation (XCI) and pregnancy-related microchimerism have been implicated in scleroderma. We investigated the XCI patterns of female scleroderma patients and the parental origin of the inactive X chromosome in those patients having skewed XCI patterns (>80%). In addition, we investigated whether a correlation exists between XCI patterns and microchimerism in a well-characterized cohort. 195 female scleroderma patients and 160 female controls were analyzed for the androgen receptor locus to assess XCI patterns in the DNA extracted from peripheral blood cells. Skewed XCI was observed in 67 (44.9%) of 149 informative patients and in 10 of 124 healthy controls (8.0%) [odds ratio (OR) = 9.3 (95% confidence interval (CI) 4.3-20.6, P<0.0001)]. Extremely skewed XCI (>90%) was present in 44 of 149 patients (29.5%) but only in 3 of 124 controls (2.4%) (OR=16.9; 95% CI 4.8-70.4, P<0.0001). Parental origin of the inactive X chromosome was investigated for 10 patients for whom maternal DNA was informative, and the inactive X chromosome was of maternal origin in 8 patients and of paternal origin in 2 patients. Skewed XCI mosaicism could be considered as an important risk factor in scleroderma.

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HLA allelic variants encoding DR11 in diffuse and limited systemic sclerosis in Caucasian women

Cited by 28 publications

References 27 publications

HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

HLA Markers for Poor Prognosis in Systemic Sclerosis Brazilian Patients

Characterization of the HLA-DRβ1 third hypervariable region amino acid sequence according to charge and parental inheritance in systemic sclerosis

Skewed X-Chromosome Inactivation in Scleroderma

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