HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

De novo protein design by an energy function based on series expansion in distance and orientation dependence.

MOTIVATION: Despite many successes, de novo protein design is not yet a solved problem as its success rate remains low. The low success rate is largely because we do not yet have an accurate energy function for describing the solvent-mediated interaction between amino acid residues in a protein chain. Previous studies showed that an energy function based on series expansions with its parameters optimized for side-chain and loop conformations can lead to one of the most accurate methods for side chain (OSCAR) and loop prediction (LEAP). Following the same strategy, we developed an energy function based on series expansions with the parameters optimized in four separate stages (recovering single-residue types without and with orientation dependence, selecting loop decoys and maintaining the composition of amino acids). We tested the energy function for de novo design by using Monte Carlo simulated annealing. RESULTS: The method for protein design (OSCAR-Design) is found to be as accurate as OSCAR and LEAP for side-chain and loop prediction, respectively. In de novo design, it can recover native residue types ranging from 38% to 43% depending on test sets, conserve hydrophobic/hydrophilic residues at ∼75%, and yield the overall similarity in amino acid compositions at more than 90%. These performance measures are all statistically significantly better than several protein design programs compared. Moreover, the largest hydrophobic patch areas in designed proteins are near or smaller than those in native proteins. Thus, an energy function based on series expansion can be made useful for protein design. AVAILABILITY AND IMPLEMENTATION: The Linux executable version is freely available for academic users at http://zhouyq-lab.szbl.ac.cn/resources/.

Factors predicting axial spondyloarthritis among first-degree relatives of probands with ankylosing spondylitis: a family study spanning 35 years.

OBJECTIVE: Factors predicting axial spondyloarthritis (axSpA) among first-degree relatives (FDRs) of ankylosing spondylitis (AS) patients need to be defined. We investigated the predictive value of the probands' HLA-B27 and radiographic sacroiliitis status on disease occurrence among their FDR. We also assessed the predictive value of features of the clinical history, including chronic inflammatory back pain (CIBP) and acute anterior uveitis (AAU), among the FDR and how they can be used to improve classification and diagnosis of axSpA. METHODS: In 1985, we studied 363 AS probands and 806 FDR who underwent rheumatologic examination, completed questionnaires, provided blood samples for HLA-typing and underwent radiography of sacroiliac joints. At follow-up in 2018-2019, 125 patients and 360 FDR were available for study, and completed a postal questionnaire about axSpA features. FDRs were asked to report whether after 1985 they had been diagnosed by Swiss rheumatologists as having axSpA. RESULTS: Among HLA-B27(+) FDR, axSpA occurred in 25.4%-26.3%, independent of the radiographic sacroiliitis status of the proband. AAU occurred in 13/34 (38.2%) FDR with axSpA vs 29/251 (11.6%) FDR without axSpA (p=0.00004, OR=4.74 95% CI 2.15 to 10.47). The presence of CIBP at baseline did not predict later occurrence of axSpA but combining CIBP and pain/discomfort at the thoracic spine and at anterior (ventral) chest wall ever, assessed at follow-up in 2018-2019, provided 83.1% sensitivity and 87.2% specificity for current axSpA. CONCLUSION: Occurrence of AAU among FDR of axSpA probands should prompt screening for axSpA. Moreover, co-occurrence of CIBP and pain/discomfort in the thoracic spine and at anterior chest wall as a three-question tool may further enhance clinical suspicion of axSpA among these FDR.

Oligofructose-Enriched Inulin Intake, Gut Microbiome Characteristics, and the V̇O2 Peak Response to High-Intensity Interval Training in Healthy Inactive Adults.

BACKGROUND: The gut microbiome has been associated with cardiorespiratory fitness. OBJECTIVES: To assess the effects of oligofructose (FOS)-enriched inulin supplementation on the gut microbiome and the peak oxygen uptake (V̇O2peak) response to high-intensity interval training (HIIT). METHODS: The study was a randomized controlled trial. Forty sedentary and apparently healthy adults [n = 31 women; aged 31.8 ± 9.8 y, BMI (in kg⋅m-2) 25.9 ± 4.3] were randomly allocated to 1) 6 wk of supervised HIIT (4 × 4-min bouts at 85-95% peak heart rate, interspersed with 3 min of active recovery, 3·wk-1) + 12 g·d-1 of FOS-enriched inulin (HIIT-I) or 2) 6 wk of supervised HIIT (3·wk-1, 4 × 4-min bouts) + 12 g·d-1 of maltodextrin/placebo (HIIT-P). Each participant completed an incremental treadmill test to assess V̇O2peak and ventilatory thresholds (VTs), provided a stool and blood sample, and completed a 24-h diet recall questionnaire and FFQ before and after the intervention. Gut microbiome analyses were performed using metagenomic sequencing. Fecal short-chain fatty acids were measured by mass spectrometry. RESULTS: There were no differences in the mean change in V̇O2peak response between groups (P = 0.58). HIIT-I had a greater improvement in VTs than HIIT-P [VT1 (lactate accumulation): mean difference + 4.3% and VT2 (lactate threshold): +4.2%, P < 0.05]. HIIT-I had a greater increase in the abundance of Bifidobacterium taxa [false discovery rate (FDR) < 0.05] and several metabolic processes related to exercise capacity (FDR < 0.05). Exploratory analysis of merged data found participants with a greater response to HIIT (V̇O2peak ≥3.5 mL⋅kg-1⋅min-1) had a 2.2-fold greater mean abundance of gellan degradation pathways (FDR < 0.05) and a greater, but not significant, abundance of Bifidobacterium uniformis species (P < 0.00023, FDR = 0.08). CONCLUSIONS: FOS-enriched inulin supplementation did not potentiate HIIT-induced improvements in V̇O2peak but led to gut microbiome changes possibly associated with greater ventilatory threshold improvements in healthy inactive adults. Gellan degradation pathways and B. uniformis spp. were associated with greater V̇O2peak responses to HIIT.

Genome-wide association study in Turkish and Iranian populations identify rare familial Mediterranean fever gene (MEFV) polymorphisms associated with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a highly heritable immune-mediated arthritis common in Turkish and Iranian populations. Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease most common in people of Mediterranean origin. MEFV, an FMF-associated gene, is also a candidate gene for AS. We aimed to identify AS susceptibility loci and also examine the association between MEFV and AS in Turkish and Iranian cohorts. We performed genome-wide association studies in 1001 Turkish AS patients and 1011 Turkish controls, and 479 Iranian AS patients and 830 Iranian controls. Serum IL-1ß, IL-17 and IL-23 cytokine levels were quantified in Turkish samples. An association of major effect was observed with a novel rare coding variant in MEFV in the Turkish cohort (rs61752717, M694V, OR = 5.3, P = 7.63×10(-12)), Iranian cohort (OR = 2.9, P = 0.042), and combined dataset (OR = 5.1, P = 1.65×10(-13)). 99.6% of Turkish AS cases, and 96% of those carrying MEFV rs61752717 variants, did not have FMF. In Turkish subjects, the association of rs61752717 was particularly strong in HLA-B27-negative cases (OR = 7.8, P = 8.93×10(-15)), but also positive in HLA-B27-positive cases (OR = 4.3, P = 7.69×10(-8)). Serum IL-1ß, IL-17 and IL-23 levels were higher in AS cases than controls. Among AS cases, serum IL-1ß and IL-23 levels were increased in MEFV 694V carriers compared with non-carriers. Our data suggest that FMF and AS have overlapping aetiopathogenic mechanisms. Functionally important MEFV mutations, such as M694V, lead to dysregulated inflammasome function and excessive IL-1ß function. As IL-1 inhibition is effective in FMF, AS cases carrying FMF-associated MEFV variants may benefit from such therapy.

Polygenic Risk Scores have high diagnostic capacity in ankylosing spondylitis.

OBJECTIVE: We sought to test the hypothesis that Polygenic Risk Scores (PRSs) have strong capacity to discriminate cases of ankylosing spondylitis (AS) from healthy controls and individuals in the community with chronic back pain. METHODS: PRSs were developed and validated in individuals of European and East Asian ethnicity, using data from genome-wide association studies in 15 585 AS cases and 20 452 controls. The discriminatory values of PRSs in these populations were compared with other widely used diagnostic tests, including C-reactive protein (CRP), HLA-B27 and sacroiliac MRI. RESULTS: In people of European descent, PRS had high discriminatory capacity with area under the curve (AUC) in receiver operator characteristic analysis of 0.924. This was significantly better than for HLA-B27 testing alone (AUC=0.869), MRI (AUC=0.885) or C-reactive protein (AUC=0.700). PRS developed and validated in individuals of East Asian descent performed similarly (AUC=0.948). Assuming a prior probability of AS of 10% such as in patients with chronic back pain under 45 years of age, compared with HLA-B27 testing alone, PRS provides higher positive values for 35% of patients and negative predictive values for 67.5% of patients. For PRS, in people of European descent, the maximum positive predictive value was 78.2% and negative predictive value was 100%, whereas for HLA-B27, these values were 51.9% and 97.9%, respectively. CONCLUSIONS: PRS have higher discriminatory capacity for AS than CRP, sacroiliac MRI or HLA-B27 status alone. For optimal performance, PRS should be developed for use in the specific ethnic groups to which they are to be applied.

Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.

BACKGROUND: Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. METHODS: Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .

Genetics and the axial spondyloarthritis spectrum.

The axial SpAs (axSpAs) are clearly clinically a heterogeneous set of diseases with markedly varying extra-articular features. These diseases are all highly heritable and have overlapping but differing genetic origins. Shared features include association with HLA class I alleles and genes of the IL-23 pathway, among other things. Significant differences do exist however, both in the genetic loci involved and at specific loci in the individual genetic variants associated with each disease. These similarities and differences are of great interest in regards to disease pathogenesis and treatment development, although individually they are too small in effect to be of prognostic or diagnostic value. Polygenic risk scores, which capture a high proportion of the genetic variation between disorders, have been shown to have clinically useful discriminatory capacity in axSpA. This suggests they have the potential to enable improved disease classification, incorporating basic pathogenic features such as genomics, and ultimately benefitting clinical care. The aim of this article is to review the genetic characteristics of the spectrum of axSpAs and to discuss how this influences our understanding of the disease pathogenesis and the clinical implications of this understanding.

Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.

Bacterial infection is one of the leading causes of death in young, elderly, and immune-compromised patients. The rapid spread of multi-drug-resistant (MDR) bacteria is a global health emergency and there is a lack of new drugs to control MDR pathogens. We describe a heretofore-unexplored discovery pathway for novel antibiotics that is based on self-targeting, structure-disrupting peptides. We show that a helical peptide, KFF- EcH3, derived from the Escherichia coli methionine aminopeptidase can disrupt secondary and tertiary structure of this essential enzyme, thereby killing the bacterium (including MDR strains). Significantly, no detectable resistance developed against this peptide. Based on a computational analysis, our study predicted that peptide KFF- EcH3 has the strongest interaction with the structural core of the methionine aminopeptidase. We further used our approach to identify peptide KFF- NgH1 to target the same enzyme from Neisseria gonorrhoeae. This peptide inhibited bacterial growth and was able to treat a gonococcal infection in a human cervical epithelial cell model. These findings present an exciting new paradigm in antibiotic discovery using self-derived peptides that can be developed to target the structures of any essential bacterial proteins.-Zhan, J., Jia, H., Semchenko, E. A., Bian, Y., Zhou, A. M., Li, Z., Yang, Y., Wang, J., Sarkar, S., Totsika, M., Blanchard, H., Jen, F. E.-C., Ye, Q., Haselhorst, T., Jennings, M. P., Seib, K. L., Zhou, Y. Self-derived structure-disrupting peptides targeting methionine aminopeptidase in pathogenic bacteria: a new strategy to generate antimicrobial peptides.

Residual amplitude modulation and its mitigation in wedged electro-optic modulator.

We theoretically analyze and experimentally investigate the dependence of residual amplitude modulation (RAM) on the beam radius within the electro-optic crystal (EOC), the wedge angle of the EOC and the overlap efficiency between the extraordinary and ordinary beams, and the overlap efficiency is determined by the distance from the wedge facet to the downstream polarizer. The results show that the RAM with the maximum optical path difference Δ at the edge of light spot presents a sinc-like curve,and the magnitude of Δ is directly proportional to the beam radius and the wedge angle. As a scaling factor, with the decrease of the overlap efficiency between the ordinary and extraordinary beams, the RAM can be further reduced.

SPIN2: Predicting sequence profiles from protein structures using deep neural networks.

Designing protein sequences that can fold into a given structure is a well-known inverse protein-folding problem. One important characteristic to attain for a protein design program is the ability to recover wild-type sequences given their native backbone structures. The highest average sequence identity accuracy achieved by current protein-design programs in this problem is around 30%, achieved by our previous system, SPIN. SPIN is a program that predicts sequences compatible with a provided structure using a neural network with fragment-based local and energy-based nonlocal profiles. Our new model, SPIN2, uses a deep neural network and additional structural features to improve on SPIN. SPIN2 achieves over 34% in sequence recovery in 10-fold cross-validation and independent tests, a 4% improvement over the previous version. The sequence profiles generated from SPIN2 are expected to be useful for improving existing fold recognition and protein design techniques. SPIN2 is available at http://sparks-lab.org.

Investigation of residual amplitude modulation in squeezed state generation system.

We present an analysis on how the optical parametric oscillator (OPO) detuning and the relative phase drift deteriorate the stability of the squeezed states, including the output power and the squeezed degree, and investigate the influence of RAM on the cavity detuning and the relative phase drift under different cases. Subsequently, the RAM is experimentally measured. In term of the measurement results, we perform a comparative study about RAM's influence on the cavity and phase locking in two cases. As a result, with the error signal extracted from the transmission of the OPO, the output power stability of the squeezed light is greatly improved. With the phase modulation imposed on the signal beam, the long-term stability of the squeezed degree is significantly enhanced.

DDIG-in: detecting disease-causing genetic variations due to frameshifting indels and nonsense mutations employing sequence and structural properties at nucleotide and protein levels.

MOTIVATION: Frameshifting (FS) indels and nonsense (NS) variants disrupt the protein-coding sequence downstream of the mutation site by changing the reading frame or introducing a premature termination codon, respectively. Despite such drastic changes to the protein sequence, FS indels and NS variants have been discovered in healthy individuals. How to discriminate disease-causing from neutral FS indels and NS variants is an understudied problem. RESULTS: We have built a machine learning method called DDIG-in (FS) based on real human genetic variations from the Human Gene Mutation Database (inherited disease-causing) and the 1000 Genomes Project (GP) (putatively neutral). The method incorporates both sequence and predicted structural features and yields a robust performance by 10-fold cross-validation and independent tests on both FS indels and NS variants. We showed that human-derived NS variants and FS indels derived from animal orthologs can be effectively employed for independent testing of our method trained on human-derived FS indels. DDIG-in (FS) achieves a Matthews correlation coefficient (MCC) of 0.59, a sensitivity of 86%, and a specificity of 72% for FS indels. Application of DDIG-in (FS) to NS variants yields essentially the same performance (MCC of 0.43) as a method that was specifically trained for NS variants. DDIG-in (FS) was shown to make a significant improvement over existing techniques.

Genetic spectrum of dyschromatosis symmetrica hereditaria in Chinese patients including a novel nonstop mutation in ADAR1 gene.

BACKGROUND: Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant cutaneous disorder caused by the mutations of adenosine deaminase acting on RNA1 (ADAR1) gene. We present a clinical and genetic study of seven unrelated families and two sporadic cases with DSH for mutations in the full coding sequence of ADAR1 gene. METHODS: ADAR1 gene was sequenced in seven unrelated families and two sporadic cases with DSH and 120 controls. Functional significance of the observed ADAR1 mutations was analyzed using PolyPhen 2, SIFT and DDIG-in. RESULTS: We describe six novel mutations of the ADAR1 gene in Chinese patients with DSH including a nonstop mutation p.Stop1227R, which was firstly reported in ADAR1 gene. In silico analysis proves that all the mutations reported here are pathogenic. CONCLUSION: This study is useful for functional studies of the protein and to define a diagnostic strategy for mutation screening of the ADAR1 gene. A three-generation family exhibiting phenotypic variability with a single germline ADAR1 mutation suggests that chilblain might aggravate the clinical phenotypes of DSH.

Reduction of zero baseline drift of the Pound-Drever-Hall error signal with a wedged electro-optical crystal for squeezed state generation.

We report an electro-optic modulator (EOM) with a wedged MgO: LiNbO3 as the modulation crystal to reduce the zero baseline drift (ZBD) of the Pound-Drever-Hall (PDH) error signal. When the input linear polarization is not along the modulation direction, the wedged design can separate the two orthogonal polarizations in space after the EOM and eliminate the interference between the carrier and the two orthogonal sidebands. Therefore, the residual amplitude modulation (RAM) of phase modulation process caused by the input polarization misalignment and the etalon effect can be significantly reduced. The noise power spectrum of phase-modulated light with wedged crystal EOM is suppressed from -24 to -69 dBm, which is much lower than that with conventional EOM. The peak-to-peak value of the ZBD of the PDH error signal is reduced effectively to +70/-50 ppm during the 10 h, which meets the requirements for stable squeezed light generation.

Direct prediction of profiles of sequences compatible with a protein structure by neural networks with fragment-based local and energy-based nonlocal profiles.

Locating sequences compatible with a protein structural fold is the well-known inverse protein-folding problem. While significant progress has been made, the success rate of protein design remains low. As a result, a library of designed sequences or profile of sequences is currently employed for guiding experimental screening or directed evolution. Sequence profiles can be computationally predicted by iterative mutations of a random sequence to produce energy-optimized sequences, or by combining sequences of structurally similar fragments in a template library. The latter approach is computationally more efficient but yields less accurate profiles than the former because of lacking tertiary structural information. Here we present a method called SPIN that predicts Sequence Profiles by Integrated Neural network based on fragment-derived sequence profiles and structure-derived energy profiles. SPIN improves over the fragment-derived profile by 6.7% (from 23.6 to 30.3%) in sequence identity between predicted and wild-type sequences. The method also reduces the number of residues in low complex regions by 15.7% and has a significantly better balance of hydrophilic and hydrophobic residues at protein surface. The accuracy of sequence profiles obtained is comparable to those generated from the protein design program RosettaDesign 3.5. This highly efficient method for predicting sequence profiles from structures will be useful as a single-body scoring term for improving scoring functions used in protein design and fold recognition. It also complements protein design programs in guiding experimental design of the sequence library for screening and directed evolution of designed sequences. The SPIN server is available at http://sparks-lab.org.

The role of semidisorder in temperature adaptation of bacterial FlgM proteins.

Probabilities of disorder for FlgM proteins of 39 species whose optimal growth temperature ranges from 273 K (0°C) to 368 K (95°C) were predicted by a newly developed method called Sequence-based Prediction with Integrated NEural networks for Disorder (SPINE-D). We showed that the temperature-dependent behavior of FlgM proteins could be separated into two subgroups according to their sequence lengths. Only shorter sequences evolved to adapt to high temperatures (>318 K or 45°C). Their ability to adapt to high temperatures was achieved through a transition from a fully disordered state with little secondary structure to a semidisordered state with high predicted helical probability at the N-terminal region. The predicted results are consistent with available experimental data. An analysis of all orthologous protein families in 39 species suggests that such a transition from a fully disordered state to semidisordered and/or ordered states is one of the strategies employed by nature for adaptation to high temperatures.

Heterogeneity of axial spondyloarthritis: genetics, sex and structural damage matter.

OBJECTIVE: Axial spondyloarthritis (axSpA) comprises both radiographic and non-radiographic disease. However, the paucity of specific objective measures for the disease and current classification criteria showing suboptimal specificity contribute to disease heterogeneity observed in clinical practice and research. We used a historical cohort of patients with axSpA to assess sources of heterogeneity. METHODS: The study involved 363 axSpA probands recruited from membership of the Swiss Ankylosing Spondylitis Patient Society. Participants underwent examination by a rheumatologist, completed questionnaires and provided blood samples for HLA typing. Patients underwent radiography of sacroiliac joints and were categorised according to the New York (NY) criteria (ankylosing spondylitis (AS) or non-radiographic axSpA (nr-axSpA)) and HLA-B27 status. Genetic characterisation by single nucleotide polymorphism microarray was performed and AS polygenic risk scores (PRS) were calculated. RESULTS: Considerable heterogeneity was observed. The male to female ratio for AS (NY+) was 3:1, but 1:1 for nr-axSpA. For HLA-27(+) AS, the ratio was 2.5:1, but nearly 1:1 for HLA-B27(-) disease. Women with nr-axSpA had strikingly lower mean PRS and lower HLA-B27 prevalence than men with nr-axSpA or NY(+) male and female patients with AS. PRS was able to distinguish male but not female patients with nr-axSpA from related healthy first-degree relatives. Radiographic sacroiliitis was strongly associated with HLA-B27, especially in men. CONCLUSION: Women clinically diagnosed with axSpA but without radiographic sacroiliitis as a group have a disease that is distinct from AS by the modified New York criteria overall and from nr-axSpA in men. Given the high degree of heterogeneity, stratified or adjusted analysis of effectiveness studies is indicated, taking genetics, sex and radiographic damage (sacroiliitis) into account.

Impact of HLA-B27 and Disease Status on the Gut Microbiome of the Offspring of Ankylosing Spondylitis Patients.

Multiple studies have shown the microbiota to be abnormal in patients with spondyloarthritis (SpA). The purpose of this study was to explore the genetic contributions of these microbiota abnormalities. We analyzed the impact of HLA-B27 on the microbiota of children at risk for SpA and compared the microbiota of HLA-B27+ pediatric offspring of ankylosing spondylitis (AS) patients with that of HLA-B27+ children with SpA. Human DNA was obtained from the offspring for determination of HLA-B27 status and polygenic risk score (PRS). Fecal specimens were collected from both groups for sequencing of the V4 region of the 16S ribosomal RNA gene. Among the offspring of AS patients, there was slight clustering by HLA-B27 status. After adjusting for multiple comparisons, five operational taxonomic units (OTUs) representing three unique taxa distinguished the HLA-B27+ from negative children: Blautia and Coprococcus were lower in the HLA-B27+ offspring, while Faecalibacterium prausnitzii was higher. HLA-B27+ offspring without arthritis were compared to children with treatment-naïve HLA-B27+ SpA. After adjustments, clustering by diagnosis was present. A total of 21 OTUs were significantly associated with diagnosis state, including Bacteroides (higher in SpA patients) and F. prausnitzii (higher in controls). Thus, our data confirmed associations with B. fragilis and F. prausnitzii with juvenile SpA, and also suggest that the mechanism by which HLA-B27 is associated with SpA may not involve alterations of the microbiota.

Recurrence of axial spondyloarthritis among first-degree relatives in a prospective 35-year-follow-up family study.

OBJECTIVE: The lifetime recurrence rate (RR) of axial spondyloarthritis (axSpA) among first-degree relatives (FDR) and the effect of proband's gender, HLA-B27 and radiographic status is unclear. Our 35-year-follow-up family study has enabled these issues to be addressed. METHODS: In 1985, 363 ankylosing spondylitis (AS) probands (members of the Swiss AS Patient Society) and 806 FDR recruited into the study, completed questionnaires regarding axSpA manifestations, underwent a physical examination and most also underwent pelvic radiography and HLA-B27 typing. At follow-up in 2018-2019, of the former participants whose current addresses could be retrieved, 162 had died and 485 (125 patients with AS plus 360 FDR) completed a postal questionnaire. RESULTS: At follow-up, 48 of 177 HLA-B27(+) FDR had developed axSpA, an RR of 27.1% (95% CI 20.6% to 33.7%). 27/148 (18.2%) children of AS probands (modified New York (mNY) criteria) were affected versus 2/50 (4.0%) children of non-radiographic axSpA probands (p=0.0138, OR=5.36; 95% CI 1.23 to 23.40). Children of female probands were more often affected (12/22; 54.5%) than of male probands (15/78; 19.2%) (p=0.0003; OR=4.89; 95% CI 1.96 to 12.23). This increased risk applies equally to sons and daughters. CONCLUSION: The lifetime RR of axSpA for HLA-B27(+) FDR is substantial (27.1%), and disease severity (as defined by radiographic sacroiliitis by the mNY criteria) is an additional risk factor. Affected mothers pass on the disease significantly more often to their offspring than do affected fathers. These findings may lead to better assessment of lifetime risk for axSpA in the offspring. Moreover, investigation of this gender effect may uncover additional putative disease susceptibility factors.