Andre Franke's research while affiliated with University Medical Center Schleswig-Holstein and other places

Restless legs syndrome (RLS) affects up to 10% of older adults. Their healthcare is impeded by delayed diagnosis and insufficient treatment. To advance disease prediction and find new entry points for therapy, we performed meta-analyses of genome-wide association studies in 116,647 individuals with RLS (cases) and 1,546,466 controls of European ancestry. The pooled analysis increased the number of risk loci eightfold to 164, including three on chromosome X. Sex-specific meta-analyses revealed largely overlapping genetic predispositions of the sexes (rg = 0.96). Locus annotation prioritized druggable genes such as glutamate receptors 1 and 4, and Mendelian randomization indicated RLS as a causal risk factor for diabetes. Machine learning approaches combining genetic and nongenetic information performed best in risk prediction (area under the curve (AUC) = 0.82–0.91). In summary, we identified targets for drug development and repurposing, prioritized potential causal relationships between RLS and relevant comorbidities and risk factors for follow-up and provided evidence that nonlinear interactions are likely relevant to RLS risk prediction.

Objective Hard-to-heal (chronic) wounds are common in patients with diabetes and are associated with a decrease in quality of life (QoL). Pathogenic bacteria often colonise hard-to-heal wounds and hinder the healing process which poses a high risk for (systemic) infections. In this study, we aim to prove that probiotics are capable of displacing human pathogenic bacteria, ameliorating inflammation and positively influencing the microenvironment/microbiome of skin and mucosa. Method In this pilot study, patients with diabetes and hard-to-heal wounds with a duration of 2–120 months received an oral multispecies probiotic daily for six months. Changes in oral, stool and wound microbiome were investigated, and the effects of the probiotic intervention on wound healing, periodontitis and wound-specific quality of life (Wound-QOL-17) were analysed throughout the course of this clinical study. Results In total, seven of the 20 patients included were unable to complete the study. After six months of oral probiotic intake supplementation in five out of the remaining 13 patients, the wounds had healed completely. Most patients reported an improvement in wound-specific QoL, with particular positive effects on pain and mobility. Microbiome analysis revealed a reduction in Staphylococcus aureus and Pseudomonas aeruginosa, and Staphylococcus epidermis in healed wounds. Conclusion This findings of this study provide evidence for the beneficial effects of the oral application of a multispecies probiotic over six months in patients with diabetes and hard-to-heal wounds on wound closure, wound microbial pattern, QoL, and on dental health. A randomised, placebo-controlled, double-blinded clinical trial is required to verify the results.

Sudden infant death syndrome (SIDS) is still one of the leading causes of death in infancy. The aim of our study was to assess young mothers’ advance knowledge on SIDS prevention recommendations just prior to discharge from the maternity ward and to evaluate the actual implementation of these recommendations in families during the first year of life. The data were collected as part of the prospective KUNO Kids Health Study. For this purpose, standardized interviews were conducted in the maternity clinic, and questionnaires on the infant’s sleeping place, sleeping environment, and body position, as well as exposure to environmental factors, after 1, 6, and 12 months. Descriptive statistics were used to visualize the knowledge and planned implementation of SIDS prevention measures as relative and absolute frequencies. The majority of mothers were able to actively name the most important recommendations for healthy infant sleep immediately after giving birth. Actual implementation showed that 94% of the 1400 infants slept in their parents’ bedroom at 4 weeks of age. Although the most common sleeping furniture was a bedside-sleeper (48% at 4 weeks), we observed a significant proportion of families who regularly practiced bed-sharing. Thus, for 16% of the children, the parental bed was the default sleeping place. In terms of body position, a total of 12% of infants were still regularly placed in the prone position to sleep. 17% of the children lived in households with one or more smokers. Although most parents in our birth cohort were already implementing many recommendations for the prevention of SIDS, our analysis showed considerable differences between intentions after birth and actual implementation during the first year of life. The most striking deviation from the prevention recommendations was the frequent practice of bed-sharing (sharing the place of sleep with the infant).

Background Inflammatory Bowel Diseases (IBDs), including Crohn’s disease (CD) and Ulcerative colitis (UC) are known to involve shifts in the T cell repertoires of affected individuals. These include a reduction in regulatory T cells in both diseases, increase in TNFα production in CD, expansion of an unconventional T cell population in CD, and clonal expansion of abundant T cell populations in CD mucosal tissue. There are also differential HLA risk and protective alleles between CD and UC, implying CD- and UC-specific repertoire changes that have not yet been identified. Methods We performed ImmunoSequencing on blood samples from 3,853 CD cases, 1,803 UC cases, and 5,596 healthy controls. For each sample we imputed HLA type and cytomegalovirus (CMV) infection status based on public T cell receptor β (TCRB) usage and identified public TCRBs enriched in CD or UC cases. Findings We find that there is a CMV-dependent increase in T cell clonality in CD and UC cases compared to CMV positive controls, and a CMV-independent decrease in low-expansion clonal populations in CD only. Strikingly, from blood we identify public TCRBs specifically expanded in CD or UC. These sequences are more abundant in intestinal mucosal samples, form groups of similar CDR3 sequences, and can be associated to specific HLA alleles. Although the prevalence of these sequences is higher in ileal and ileocolonic CD than colonic CD or UC, the TCRB sequences themselves are shared across CD and not with UC. Interpretation There are peptide antigens that commonly evoke immune reactions in IBD cases and rarely in non-IBD controls. These antigens differ between CD and UC. CD, particularly ileal CD, also seems to involve more substantial changes in clonal population structure than UC, compared to healthy controls.

Aim: The oral microenvironment contributes to microbial composition and immune equilibrium. It is considered to be influenced by dietary habits. Phenylketonuria (PKU) patients, who follow a lifelong low-protein diet, exhibit higher prevalence of oral diseases such as periodontitis, offering a suitable model to explore the interplay between diet, oral microbiota and oral health. Materials and Methods: We conducted 16S rDNA sequencing on saliva and subgin-gival plaque from 109 PKU patients (ages 6-68 years) and 114 age-matched controls and correlated oral microbial composition and dental health. Results: PKU patients exhibited worse dental health, reduced oral microbial diversity and a difference in the abundance of specific taxa, especially Actinobacteriota species, compared to controls. PKU patients with poor periodontal health exhibited higher alpha diversity than the orally healthy ones, marked by high abundance of the genus Tannerella. Notably, the observed taxonomic differences in PKU patients with normal Memduh Bingöl and Alessio Cardilli contributed equally to this study.

Idiopathic Parkinson’s disease is determined by a combination of genetic and environmental factors. Recently, the first genome-wide association study on short-tandem repeats in Parkinson’s disease reported on eight suggestive short-tandem repeat-based risk loci (α = 5.3 × 10−6), of which four were novel, i.e. they had not been implicated in Parkinson’s disease risk by genome-wide association analyses of single-nucleotide polymorphisms before. Here, we tested these eight candidate short-tandem repeats in a large, independent Parkinson’s disease case–control dataset (n = 4757). Furthermore, we combined the results from both studies by meta-analysis resulting in the largest Parkinson’s disease genome-wide association study of short-tandem repeats to date (n = 43 844). Lastly, we investigated whether leading short-tandem repeat risk variants exert functional effects on gene expression regulation based on methylation quantitative trait locus data in human ‘post-mortem’ brain (n = 142). None of the eight previously reported short-tandem repeats were significantly associated with Parkinson’s disease in our independent dataset after multiple testing correction (α = 6.25 × 10−3). However, we observed modest support for short-tandem repeats near CCAR2 and NCOR1 in the updated meta-analyses of all available data. While the genome-wide meta-analysis did not reveal additional study-wide significant (α = 6.3 × 10−7) short-tandem repeat signals, we identified seven novel suggestive Parkinson’s disease short-tandem repeat risk loci (α = 5.3 × 10−6). Of these, especially a short-tandem repeat near MEIOSIN showed consistent evidence for association across datasets. CCAR2, NCOR1 and one novel suggestive locus identified here (LINC01012) emerged from colocalization analyses showing evidence for a shared causal short-tandem repeat variant affecting both Parkinson’s disease risk and cis DNA methylation in brain. Larger studies, ideally using short-tandem repeats called from whole-sequencing data, are needed to more fully investigate their role in Parkinson’s disease.