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OBJECTIVE: Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)-specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD-4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti-PAD-4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti-PAD-4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD-4 polymorphisms influence the anti-PAD-4 autoantibody response. METHODS: Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti-PAD-4 autoantibodies by immunoprecipitation of in vitro-translated PAD-4. The epitope(s) recognized by PAD-4 autoantibodies were mapped using various PAD-4 truncations. PAD-4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. RESULTS: PAD-4 autoantibodies were found in 36-42% of RA patients, and were very infrequent in controls. Recognition by anti-PAD-4 autoantibodies required the 119 N-terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti-PAD-4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti-PAD-4 antibodies were associated with more severe joint destruction in RA. CONCLUSION: Our findings indicate that anti-PAD-4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti-PAD-4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD-4 protein, potentially contributing to disease propagation. [ABSTRACT FROM AUTHOR]

Background: Eczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+)., Methods: Whole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation., Results: Eight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR)., Conclusion: SIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR., (© 2021 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Background: Prenatal care provider weight gain advice consistent with the Institute of Medicine recommendations is related to guideline-adherent gestational weight gain (GWG), yet many women may not receive guideline-congruent advice. We examined pregnant women's recall of prenatal care provider GWG advice in relation to prepregnancy body mass index (BMI)., Methods: We conducted a prospective cohort study of women (n = 149) receiving prenatal care for a singleton pregnancy at a large academic medical center in 2010. Data were collected via a survey during late pregnancy and medical record abstraction., Results: Thirty-three percent of women did not recall receiving the provider GWG advice; 33 percent recalled advice consistent with 2009 Institute of Medicine recommendations. Recalled advice differed by prepregnancy BMI; 29 percent of normal weight, 26 percent of overweight, and 45 percent of obese women reported not receiving advice, and 6, 37, and 39 percent, respectively, recalled advice exceeding Institute of Medicine recommendations. Among the 62 percent who recalled that their provider had labeled their prepregnancy BMI, 100 percent of normal weight, 32 percent of overweight, and 23 percent of obese women recalled the labels "normal weight," "overweight," and "obese," respectively., Conclusions: Helping providers give their patients memorable and guideline-consistent GWG advice is an actionable step toward preventing excessive GWG and associated maternal and child health consequences., (© 2014 Wiley Periodicals, Inc.)

Background: Helicobacter pylori infection is a strong risk factor for gastric cancer, likely due to the extensive inflammation in the stomach mucosa caused by these bacteria. Many studies have reported an association between IL10 polymorphisms, the risk of gastric cancer, and IL-10 production. The aim of the study was to evaluate the association between IL10 genetic variants, Helicobacter pylori infection, and IL-10 production by peripheral blood leukocytes in children., Materials and Methods: We genotyped a total of 12 single nucleotide polymorphisms in IL10 in 1259 children aged 4-11 years living in a poor urban area in Salvador, Brazil, using TaqMan probe based, 5' nuclease assay minor groove binder chemistry. Association tests were performed by logistic regression for Helicobacter pylori infection and linear regression for IL-10 spontaneous production (whole-blood cultures) including sex, age, and principal components for informative ancestry markers as covariates, using PLINK., Results: Our results shown that IL10 single nucleotide polymorphisms rs1800896 (OR = 1.63; 95% CI = 1.11-2.39), rs3024491 (OR = 1.71; 95% CI = 1.14-2.57), rs1878672 (OR = 1.79; 95% CI = 1.19-2.68), and rs3024496 (OR = 1.48; 95% CI = 1.05-2.08) were positively associated with Helicobacter pylori infection. Eight single nucleotide polymorphisms were associated with spontaneous production of IL-10 in culture, of which three (rs1800896 and rs1878672, p = .04; rs3024491, p = .01) were strongly associated with infection by Helicobacter pylori., Conclusions: Our results indicate that IL10 variants rs1800896, rs3024491, rs1878672, and rs3024496 are more consistently associated with the presence of anti-H. pylori IgG by inducing increased production of IL-10. Further studies are underway to elucidate the role of additional genetic variants and to investigate their impact on the occurrence of gastric cancer., (© 2014 John Wiley & Sons Ltd.)

Background: Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion., Methods: We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS)., Main Results: Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS., Conclusions: TSLP variants are associated with asthma in a sex-specific fashion., (© 2010 John Wiley & Sons A/S.)

Objective: Wegener's granulomatosis (WG) is a systemic inflammatory disease that is associated with substantial morbidity. The aim of this study was to understand the biology underlying WG and to discover markers of disease activity that would be useful for prognosis and treatment guidance., Methods: Gene expression profiling was performed using total RNA from peripheral blood mononuclear cells (PBMCs) and granulocyte fractions from 41 patients with WG and 23 healthy control subjects. Gene set enrichment analysis (GSEA) was performed to search for candidate WG-associated molecular pathways and disease activity biomarkers. Principal components analysis was used to visualize relationships between subgroups of WG patients and controls. Longitudinal changes in proteinase 3 (PR3) gene expression were evaluated using reverse transcription-polymerase chain reaction, and clinical outcomes, including remission status and disease activity, were determined using the Birmingham Vasculitis Activity Score for WG (BVAS-WG)., Results: Eighty-six genes in WG PBMCs and 40 in WG polymorphonuclear neutrophils (PMNs) were significantly up-regulated relative to controls. Genes up-regulated in WG PBMCs were involved in myeloid differentiation, and these included the WG autoantigen PR3. The coordinated regulation of myeloid differentiation genes was confirmed by GSEA. The median expression values of the 86 up-regulated genes in WG PBMCs were associated with disease activity (P = 1.3 x 10(-4)), and WG patients with low-level expression of the WG signature genes showed expression profiles that were only modestly different from that in healthy controls (P = 0.07). PR3 transcription was significantly up-regulated in WG PBMCs (P = 1.3 x 10(-5), false discovery rate [FDR] 0.002), but not in WG PMNs (P = 0.03, FDR 0.28), and a preliminary longitudinal analysis showed that the fold change in PR3 RNA levels in WG PBMCs corresponded to changes in the BVAS-WG score over time., Conclusion: Transcription of PR3 and related myeloid differentiation genes in PBMCs may represent novel markers of disease activity in WG.

Background: Allergic diseases are thought to involve dysregulated activation of T cells including CD4+ lymphocytes. T-cell activation results in changes in gene expression, but the optimal method to study gene expression profiles in T cells, and how this changes over time, are not known., Methods: Circulating CD4+ T cells were obtained from subjects with atopic asthma, nonatopic asthma or nonallergic controls, and total mRNA was rapidly isolated. Atopy was defined as positive skin prick test to one of nine allergens. Gene expression was analyzed using hybridization and Affymetrix oligonucleotide arrays (Hu133A and Hu133B chips, n = 84), or by reverse transcription-polymerase chain reaction (RT-PCR) with a pathway-targeted array (Human Th1-Th2-Th3 RT(2) Profiler PCR Array, Superarray, n = 16)., Results: Using Affymetrix arrays, it was difficult to discern a dominant allergy-associated profile because of heterogeneity in gene expression profiles. In contrast, a Th2-like signature was evident using RT-PCR arrays with increased expression of expected genes (e.g. IL-4, 5, 9, and 13, all P < 0.05) as well as unexpected gene transcripts (e.g. osteopontin). Gene expression profiles were relatively stable over time in circulating CD4+ T cells from two subjects using both platforms., Conclusions: Unstimulated CD4+ T cells isolated from allergic subjects express a characteristic profile of genes when analyzed using RT-PCR based microarrays.

In this study we describe inbreeding in a large pedigree from Tangier Island, Virginia, in which we compare two commonly used methods to estimate inbreeding in humans: pedigree and isonymy (identical surnames of spouses). Genealogical data on 3,512 individuals dating back to 1722 were used. Using the pedigree method, we determined an average inbreeding coefficient (F) of 0.00873 for the community as a whole, and 0.018 for inbred individuals. Analysis of temporal trends showed that inbreeding began around 1800 and peaked at 0.0109 in 1824-1849 and 1875-1899. Thereafter, inbreeding steadily declined to 0.00565 in 1975-1997. Analysis of pedigree structure complexity over time showed that close consanguinity contributes to inbreeding in the earlier cohorts, and remote consanguinity accounts for much of the inbreeding in the later cohorts. The number of common ancestors increases over time, as does the number of paths connecting inbred individuals to these common ancestors. Inbreeding estimates based on the isonymy approach yielded a 2.2-fold higher value of F (0.01945) compared to the pedigree method. Total isonymy estimates over 25-year cohorts overestimated inbreeding values from pedigree data between 1. 5-8-fold. We speculate that the overestimation is probably due to the inability of our data to satisfy the method's assumption of monophyletic origin of each surname. In conclusion, inbreeding in the Tangier Island population is consistent with the isolated nature of its population, and temporal trends reflect patterns in emigration and a breakdown in isolation over time., (Copyright 2000 Wiley-Liss, Inc.)