A combination of HLA-DP α and ß chain polymorphisms paired with a SNP in the DPB1 3' UTR region, denoting expression levels, are associated with atopic dermatitis.

Introduction: Components of the immune response have previously been associated with the pathophysiology of atopic dermatitis (AD), specifically the Human Leukocyte Antigen (HLA) Class II region via genome-wide association studies, however the exact elements have not been identified. Methods: This study examines the genetic variation of HLA Class II genes using next generation sequencing (NGS) and evaluates the resultant amino acids, with particular attention on binding site residues, for associations with AD. The Genetics of AD cohort was used to evaluate HLA Class II allelic variation on 464 subjects with AD and 384 controls. Results: Statistically significant associations with HLA-DP α and ß alleles and specific amino acids were found, some conferring susceptibility to AD and others with a protective effect. Evaluation of polymorphic residues in DP binding pockets revealed the critical role of P1 and P6 (P1: α31M + (ß84G or ß84V) [protection]; α31Q + ß84D [susceptibility] and P6: α11A + ß11G [protection]) and were replicated with a national cohort of children consisting of 424 AD subjects. Independently, AD susceptibility-associated residues were associated with the G polymorphism of SNP rs9277534 in the 3' UTR of the HLA-DPB1 gene, denoting higher expression of these HLA-DP alleles, while protection-associated residues were associated with the A polymorphism, denoting lower expression. Discussion: These findings lay the foundation for evaluating non-self-antigens suspected to be associated with AD as they potentially interact with particular HLA Class II subcomponents, forming a complex involved in the pathophysiology of AD. It is possible that a combination of structural HLA-DP components and levels of expression of these components contribute to AD pathophysiology.

Association of KIR2DL5, KIR2DS5, and KIR2DS1 allelic variation and atopic dermatitis.

Natural killer cells (NK) have been associated with the pathophysiology of atopic dermatitis (AD). NK function is regulated by killer cell Ig-like receptor family (KIR) receptors that interact with HLA ligands. The study goal was to focus on allelic variation in genes KIR2DL5, KIR2DS5, and KIR2DS1 with respect to AD. This was a case-control study of individuals with (n = 313) and without (n = 176) AD. Associations were estimated using logistic regression. The prevalence of KIR2DL5 was 52.5% (95% CI 48.0,57.0), KIR2DS5 was 33.0% (28.8,37.3), and KIR2DS1 was 33.6% (29.4,38.0). The presence of the KIR2DL5*001:01 increased the odds of having AD by about 86% (odds ratio (OR): 1.86(1.23,2.82) p = 0.003). The risk for individuals homozygous for KIR2DL5*001:01 was even greater (OR: 2.16 (95% CI 1.31,3.53) p = 0.0023). The odds of having AD with KIR2DL5*001:01 was similar in Whites and Blacks. Allelic variation in KIR2DS5 and KIR2DS1 was not associated with AD. There is no known HLA binding ligand for KIR2DL5. The effect of KIR2DL5*001:01 increased in the presence of HLA-B*-21TT leader sequence (2.46(1.37,4.41) p = 0.0025) and the HLA-C2 ligand (2.07 (1.37,4.41, p = 0.000002). Our study shows an independent association of the KIR2DL5*001:01 with AD and is the first study to associate AD with KIR allelic variation.

Methotrexate Cutaneous Ulceration: A Systematic Review of Cases.

BACKGROUND: Methotrexate cutaneous ulceration is a rare methotrexate complication, and has only been described in case reports and case series. OBJECTIVE: To document patient characteristics, morphologic features, and mortality risk factors for methotrexate cutaneous ulceration. METHODS: A systematic literature review of PubMed and Embase (last date 1 November 2021) was performed with data collected from case reports and case series. This study was limited to cases of cutaneous ulceration; presence of oral ulceration was collected from within these cases. RESULTS: 114 cases (men = 57.9%, mean age = 61 years) of methotrexate cutaneous ulceration met inclusion criteria. Psoriasis (69.3%), rheumatoid arthritis (18.4%), and mycosis fungoides (6.1%) were the most common indications for methotrexate use. Morphologies included erosions localized to psoriatic plaques (33.3%), epidermal necrosis/necrolysis (35.1%), localized ulceration (16.7%), and skin-fold erosions (5.3%). Methotrexate dose preceding toxicity varied greatly; median 20 mg/week, interquartile range 15-40 mg/week, range 5-150 mg/week. Most patients had risk factors for serum toxicity (baseline renal dysfunction = 37.8%, concurrent NSAID use = 28.1%, inadequate folic acid use = 89.1%). Thirty percent of cases involved mistakenly high methotrexate doses. Fourteen patients (12%) died. Absence of folic acid use (69% vs. 100%, p value < 0.001), pancytopenia (33% vs. 86%, p value < 0.001), and renal dysfunction at presentation (47% vs. 92%, p value < 0.001) were associated with increased mortality. LIMITATIONS: Selection bias present due to abstraction from case reports and case series. CONCLUSION: Methotrexate cutaneous ulceration is commonly preceded by dosage mistakes, absence of folic acid supplementation, and concurrent use of nephrotoxic medications. Renal impairment, pancytopenia, and absence of folic acid supplementation are key risk factors for mortality from this adverse medication reaction. Providers should regularly monitor methotrexate dosing adherence, drug-drug interactions, and perform routine laboratory evaluation. Index of suspicion for this toxicity should remain high given the varied clinical presentation and high mortality.

Uncommon variants in FLG2 and TCHHL1 are associated with remission of atopic dermatitis in a large longitudinal US cohort.

Atopic dermatitis (AD) is a relapsing inflammatory skin disease; filaggrin (FLG) variation has been consistently associated with its pathogenesis. Filaggrin-2 (FLG2) and trichohyalin-like-1 (TCHHL1) are members of the same protein family (S100 fused-type proteins), are similar in structure to FLG, and may be involved in AD pathogenesis. We sought to evaluate the association between variation in FLG2, TCHHL1 and AD remission. We sequenced FLG2 and TCHHL1 in a longitudinal AD cohort using targeted capture-based massively parallel sequencing. Association between individual alleles and AD remission was evaluated with generalized estimating equations for binary outcomes. Association between groups of alleles and AD remission was evaluated using a genetic algorithm to group alleles. We identified two loss-of-function (LoF) mutations in FLG2 (Ser2377Ter, Arg2207Ter) and 2 LoF mutations in TCHHL1 (Gln656Ter, Gln294Ter), none of which were associated with AD remission. Common (MAF > 5%) alleles in FLG2 were similarly unassociated with AD. No common alleles in TCHHL1 were associated with AD remission after multiple testing correction. Among self-described whites, a group of 34 uncommon alleles in FLG2 were associated with increased AD remission (OR 7.64e17; 95% CI 4.41e17-1.32e18; adjusted p < 1.0e-16). Twelve uncommon alleles in TCHHL1 trended toward association with increased AD remission (OR 23.46; 95% CI 7.07-77.89; adjusted p = 0.064). Among self-described African Americans, 13 uncommon FLG2 alleles were associated with increased AD remission (OR 21.01; 95% CI 11.90-37.09; adjusted p < 1.0e-16). No TCHHL1 uncommon allele groups were associated with AD remission among African Americans. Our study supports the role of uncommon alleles in FLG2 and TCHHL1 in AD pathogenesis.

Using a Machine Learning Approach to Identify Low-Frequency and Rare FLG Alleles Associated with Remission of Atopic Dermatitis.

Atopic dermatitis (AD) is a common relapsing inflammatory skin disease. FLG is the gene most consistently associated with AD. Loss-of-function variants in FLG have been previously associated with AD. Low-frequency and rare alleles (minor allele frequency < 5%) in this gene have been given less attention than loss-of-function variants. We fine sequenced the FLG gene in a cohort of individuals with AD. We developed a machine learning‒based algorithm to associate low-frequency and rare alleles with the disease. We then applied this algorithm to the FLG data, searching for associations between groups of low-frequency and rare FLG alleles and AD remission. A group of 46 rare and low-frequency FLG alleles was associated with increased AD remission (P = 2.76e-11). Overall, 16 of these 46 FLG variants were identified in an independent cohort and were associated with decreased AD incidence (P = 0.0007). This study presents an application of statistical methods in AD genetics and suggests that low-frequency and rare alleles may play a larger role in AD pathogenesis than previously appreciated.