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Associations of HLA alleles with juvenile-onset SSc differed from associations with SSc in women, but were similar to associations with SSc in men. Additionally, a novel association with DRB1*10 was observed in children. The greatest proportion of genetic risk of SSc is contributed by the HLA complex, and the current study reveals the importance of the association of HLA class II genes in juvenile-onset SSc.

Ab initio (coupled-cluster and density-functional) calculations of Gibbs reaction energies in solution, with new entropy-of-solvation damping terms, were performed for the ether-catalyzed hydroboration of alkenes. The goal was to test the accuracy of continuum-solvation models for reactions of neutral species in nonaqueous solvents, and the hope was to achieve an accuracy sufficient to address the mechanism in the "Pasto case": B2H6 + alkene in THF solvent. Brown's SN2/SN1 "dissociative" mechanism, of SN2 formation of borane-ether adducts followed by SN1 alkene attack, was at odds with Pasto's original SN2/SN2 hypothesis, and while Brown could prove his mechanism for a variety of cases, he could not perform the experimental test with THF adducts in THF solvent, where the higher THF concentrations might favor an SN2 second step. Two diboranes were tested: B2H6, used by Pasto, and (9BBN)2 (9BBN = 9-borabicyclo[3.3.1]nonane, C8H15B), used by Brown. The new entropy terms resulted in improved accuracy vs traditional techniques (∼2 kcal mol(-1)), but this accuracy was not sufficient to resolve the mechanism in the Pasto case.

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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