The results suggest that MC is generally progressive in middle age and furthermore is heritable. Since MC is associated with disc degeneration, which is also heritable, further work on potential shared mechanisms is needed.

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Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

Introduction Low back pain (LBP) is a common disorder in the western world and accounts for disability and considerable work absenteeism.1 Lumbar disc degeneration (DD) is associated with LBP.2 It has been suggested that different DD phenotypes should be “split” rather than “lumped” into a single phenotype (DD) so as to allow a more meaningful interrogation of the pathogenic processes underlying the constituent traits.3 One trait of special interest is vertebral endplate or Modic change (MC), which comprises vertebral endplate and bone marrow lesions seen on magnetic resonance imaging (MRI).4 This trait has been found to be associated with LBP in some,5 but not all studies.6 MC is classified into three different types: types I-III. Whether MC is entirely environmental in origin, or whether it is influenced by underlying genetic factors, has not been established. Our purpose was to study (1) the prevalence of MC, (2) the progression of MC over a 10-year follow-up, and (3) the heritability of MC prevalence in a classical twin study. Materials and Methods The study population was recruited from TwinsUK register between 1996 and 2000 when the baseline spine MRI study was performed as previously described7 and at follow-up a decade later.3 MC was evaluated from T2-weighted lumbar MRI. Both rostral and caudal endplates of each lumbar segment were coded using the same method at baseline and follow-up.8 The maximum depth and width of each MC was evaluated and the size index was calculated. Heritability was estimated using variance components analysis. MRI with appropriate data was available for 831 twins at baseline and for 436 twins at follow-up. In total, both baseline and follow-up imaging were available for 347 twins. Results Mean age of the study population at baseline was 54.1 years (range, 45.7-62.5) and females comprised 96%. The prevalence of MC at baseline was 32.1% and at follow-up was 48.4%. The incidence of new MC at any level during the 10-year follow-up was 21.6% and was most frequent at L4-L5 and L5-S1. MC regressed totally in 3.5% of twins. The volume of the MC lesions increased during follow-up: the median MC size index summary score was 10.0 (interquartile range = 5.0-18.0) at baseline and 13.5 (interquartile range = 8.0-21.75) at follow-up (p = 0.012). Twins with prevalent MC at baseline demonstrated a higher incidence of MC at upper lumbar levels compared with twins without baseline MC (p = 0.015). Probandwise concordance rates were higher in monozygotic (0.56) than dizygotic twin pairs (0.39) suggestive of familial influence. Heritability of MC prevalence was estimated using variance components analysis to be 30 (16-43)%. Conclusion This is the first study to assess the heritability of MC. This study suggests that MC is heritable and progressive in middle age. Further work is needed to define the relationship of MC and lumbar DD. That MC shows a degree of heritability suggests that it is reasonable to search for genetic variants. Disclosure of Interest None declared References Murray CJ, Vos ...

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Study Design. Family-based study Objective. To identify rare genetic factors predisposing to Modic changes (MC).Summary of Background Data. Lumbar disc degeneration (LDD) is one of the contributing factors behind low back pain (LBP). Lumbar MC visualized as bone marrow signal intensity changes on magnetic resonance imaging (MRI) represent a specific phenotype of LDD, which has stronger association with LBP than LDD without MC.Methods. The study set consisted of two Finnish families: Family I included seven affected and four unaffected individuals and Family II eight affected and seven unaffected individuals. MC were evaluated in 26 individuals using MRI. Whole exome sequencing was used to identify alleles co-segregating with MC. ANNOVAR was used to carry out functional annotation of alleles and their frequencies were evaluated using 1000Genomes, Sequencing Initiative Suomi (SISu) and the Exome Aggregation Consortium (ExAC) databases.Results. We identified predisposing genetic alleles for MC in two Finnish families. In each family only single allele co-segregated with MC. In Family I the observed allele was an insertion and deletion in the HSPG2 gene, resulting in a premature termination codon. In Family II a single nucleotide polymorphism (rs61753465) in the MAML1 gene was identified in all affected family members.Conclusions. We have identified two novel candidate genes, MAML1 and HSPG2, associating with MC. These genes are important in cartilage structure and joint cartilage maintenance. Our findings are novel among lumbar spine degenerative phenotypes.3

BackgroundLow back pain (LBP) is a common disabling condition. Lumbar disc degeneration (LDD) may be a contributing factor for LBP. Modic change (MC), a distinct phenotype of LDD, is presented as a pathological bone marrow signal change adjacent to vertebral endplate on MRI. It is strongly associated with LBP and has heritability around 30%. Our objective was to identify genetic loci associated with MC using a genome-wide meta-analysis.MethodsPresence of MC was evaluated in lumbar MRI in the Northern Finland Birth Cohort 1966 (n=1182) and TwinsUK (n=647). Genome-wide association analyses were carried out using linear regression model. Inverse-variance weighting approach was used in the meta-analysis.ResultsA locus associated with MC (p<5e-8) was found on chromosome 9 with the lead SNP rs1934268 in an intron of the PTPRD gene. It is located in the binding region of BCL11A, SPI1 and PBX3 transcription factors. The SNP was nominally associated with LBP in TwinsUK (p=0.001) but not associated in the UK Biobank (p=0.914). Suggestive signals (p<1e-5) were identified near XKR4, SCIN, MGMT, DLG2, ZNF184 and OPRK1.Conclusion PTPRD is a novel candidate gene for MC that may act via the development of cartilage or nervous system; further work is needed to define the mechanisms underlying the pathways leading to development of MC. This is the first genome-wide meta-analysis of MC, and the results pave the way for further studies on the genetic factors underlying the various features of spine degeneration and LBP.

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