Abstract
IntroductionHuman leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results. These studies need to consider the genetic admixture of the studied population. Here we used our previously reported definition of genetic admixture of Mexicans using HLA class I and II DNA blocks to map genetic susceptibility to develop SSc and its complications.MethodsWe included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population.ResultsOur study revealed that class I block HLA-C*12:03-B*18:01 was important to map susceptibility to diffuse cutaneous (dc) SSc, HLA-C*07:01-B*08:01 block to map the susceptibility role of HLA-B*08:01 to develop SSc, and the C*07:02-B*39:05 and C*07:02-B*39:06 blocks to map the protective role of C*07:02 in SSc. We also confirmed previous associations of HLA-DRB1*11:04 and –DRB1*01 to susceptibility to develop SSc. Importantly, we mapped the protective role of DQB1*03:01 using three Amerindian blocks. We also found a significant association for the presence of anti-Topoisomerase I antibody with HLA-DQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage. The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients.ConclusionThis is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc. Our findings suggest that HLA class I and class II genes contribute to the protection and susceptibility to develop SSc and its different clinical presentations as well as different autoantibody profiles in Mexicans.
Highlights
Human leukocyte antigen (HLA) polymorphism studies in Systemic Sclerosis (SSc) have yielded variable results
We found a significant association for the presence of anti-Topoisomerase I antibody with HLADQB1*04:02, present in an Amerindian block (DRB1*08:02-DQB1*04:02), and we found several alleles associated to internal organ damage
The admixture estimations revealed a lower proportion of the Amerindian genetic component among SSc patients. This is the first report of the diversity of HLA class I and II alleles and haplotypes Mexican patients with SSc
Summary
We included 159 patients from a cohort of Mexican Mestizo SSc patients. We performed clinical evaluation, obtained SSc-associated antibodies, and determined HLA class I and class II alleles using sequence-based, high-resolution techniques to evaluate the contribution of these genes to SSc susceptibility, their correlation with the clinical and autoantibody profile and the prevalence of Amerindian, Caucasian and African alleles, blocks and haplotypes in this population. Organ involvement attributable to SSc was evaluated using previously published definitions, as follows: (a) peripheral vascular involvement was based on the presence of any of the following: Raynaud phenomenon, digital pitting scars, digital tip ulcerations, or digital gangrene; (b) joints/tendons involvement was defined as any of the following: arthritis, carpal tunnel syndrome, tendon friction rubs, or finger joint contractures (finger to palm distance in full flexion > 1 cm); (c) skeletal muscle involvement required the presence of proximal muscle weakness on physical examination and any of the following: elevated serum creatine kinase, myopathic changes on electromyography, or evidence of myositis on muscle biopsy; (d) gastrointestinal tract involvement required the presence of any of these manifestations: distal esophageal hypomotility or stricture by esophagogram, manometry or endoscopy, small bowel hypomotility by small intestine follow through, wide-mouth colonic sacculations, or malabsorption syndrome; (e) interstitial lung disease (ILD) was defined as forced vital capacity (FVC) < 70% of predicted, and forced expiratory volume in 1 s (FEV1)/FVC >80%, or interstitial fibrosis or ground glass changes on chest radiography or high-resolution computed tomography scan of the lungs; pulmonary arterial hypertension (PAH) was defined as mean PA pressure >25 mmHg by right heart catheterization or PA systolic pressure > 40 mmHg by echocardiogram; (f) cardiac involvement was defined as left-sided congestive heart failure (FEVI
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