A genetic variant in osteoprotegerin is associated with progression of joint destruction in rheumatoid arthritis

Introduction

Progression of joint destruction in rheumatoid arthritis (RA) is partly heritably; 45 to 58% of the variance in joint destruction is estimated to be explained by genetic factors. The binding of RANKL (Receptor Activator for Nuclear Factor κ B Ligand) to RANK results in the activation of TRAF6 (tumor necrosis factor (TNF) receptor associated factor-6), and osteoclast formation ultimately leading to enhanced bone resorption. This bone resorption is inhibited by osteoprotegerin (OPG) which prevents RANKL-RANK interactions. The OPG/RANK/RANKL/TRAF6 pathway plays an important role in bone remodeling. Therefore, we investigated whether genetic variants in OPG, RANK, RANKL and TRAF6 are associated with the rate of joint destruction in RA.

Methods

1,418 patients with 4,885 X-rays of hands and feet derived from four independent data-sets were studied. In each data-set the relative increase of the progression rate per year in the presence of a genotype was assessed. First, explorative analyses were performed on 600 RA-patients from Leiden. 109 SNPs, tagging OPG, RANK, RANKL and TRAF6, were tested. Single nucleotide polymorphisms (SNPs) significantly associated in phase-1 were genotyped in data-sets from Groningen (Netherlands), Sheffield (United Kingdom) and Lund (Switzerland). Data were summarized in an inverse weighted variance meta-analysis. Bonferonni correction for multiple testing was applied.

Results

We found that 33 SNPs were significantly associated with the rate of joint destruction in phase-1. In phase-2, six SNPs in OPG and four SNPs in RANK were associated with progression of joint destruction with P-value <0.05. In the meta-analyses of all four data-sets, RA-patients with the minor allele of OPG-rs1485305 expressed higher rates of joint destruction compared to patients without these risk variants (P = 2.35x10⁻⁴). This variant was also significant after Bonferroni correction.

Conclusions

These results indicate that a genetic variant in OPG is associated with a more severe rate of joint destruction in RA.     

Wild relatives of wheat: <Emphasis Type="Italic">Aegilops</Emphasis>–<Emphasis Type="Italic">Triticum</Emphasis> accessions disclose differential antioxidative and physiological responses to water stress

Wild relatives of wheat are an outstanding source of resistance to both abiotic and biotic stresses. In the present study, we evaluated the activity of four antioxidant enzymes—superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX) and guaiacol peroxidase (GPX)—along with photosynthetic pigments and shoot biomass in 12 Aegilops–Triticum accessions with different genomic constitutions and two tolerant and sensitive control varieties under well-watered (WW; 90% FC), moderate (MS; 50% FC) and severe (SS; 25% FC) water stress treatments. The analysis of variance for measured traits indicated highly significant effects of the water stress treatments, accessions, and their interactions. The 12 domesticated and wild relatives of wheat exhibited more variability and greater activity in the expression of antioxidative enzymes than cultivated wheats. While domesticated forms of wheat, T. aestivum (AABBDD) and T. durum (AABB) seem to have a functionally active antioxidant mechanism, other accessions with alien genomes—Ae. umbellulata (UU), Ae. crassa (MMDD), Ae. caudata (CC), Ae. cylindrica (DDCC) and T. boeoticum (A^bA^b)—respond to water stress by increasing enzymatic antioxidants as the dominant mechanism that contributes to the retention of oxidative balance in the cell. Furthermore, abovementioned accessions with alien genomes had higher photosynthetic pigment contents (chlorophyll a, chlorophyll b, total chlorophyll, and carotenoid) under water stress than well-watered conditions. Hence, these accessions could be used in future breeding programs to combine beneficial stress-adaptive characters of alien genomes into synthetic hexaploid wheat varieties in the field, even at limited water supply.     

Identification and validation of QTL and their associated genes for pre-emergent metribuzin tolerance in hexaploid wheat (<Emphasis Type="Italic">Triticum aestivum</Emphasis> L.)

Background

Herbicide tolerance is an important trait that allows effective weed management in wheat crops. Genetic knowledge of metribuzin tolerance in wheat is needed to develop new cultivars for the industry. Here, we evaluated metribuzin tolerance in a recombinant inbred line (RIL) mapping population derived from Synthetic W7984 and Opata 85 over two consecutive years to identify quantitative trait loci (QTL) contributing to the trait. Herbicide tolerance was measured by two chlorophyll traits, SPAD chlorophyll content index (CCI) and visual senescence score (SNS). The markers associated with major QTL from Synthetic W7984, positively contributing to reduced phytotoxic effects under herbicide treatment were validated in two F_3/4 recombinant inbred populations developed from crosses of Synthetic W7984?×?Westonia and Synthetic W7984?×?Lang.

Results

Composite interval mapping (CIM) identified four QTL, two on chromosome 4A and one each on chromosomes 2D and 1A. The chromosomal position of the two QTL mapped on 4A within 10 cM intervals was refined and validated by multiple interval mapping (MIM). The major QTL affecting both measures of tolerance jointly explained 42 and 45% of the phenotypic variation by percentage CCI reduction and SNS, respectively. The identified QTL have a pure additive effect. The metribuzin tolerant allele of markers, Xgwm33 and Xbarc343, conferred lower phytotoxicity and explained the maximum phenotypic variation of 28.8 and 24.5%, respectively. The approximate physical localization of the QTL revealed the presence of five candidate genes (ribulose-bisphosphate carboxylase, oxidoreductase (rbcS), glycosyltransferase, serine/threonine-specific protein kinase and phosphotransferase) with a direct role in photosynthesis and/or metabolic detoxification pathways.

Conclusion

Metribuzin causes photo-inhibition by interrupting electron flow in PSII. Consequently, chlorophyll traits enabled the measure of high proportion of genetic variability in the mapping population. The validated molecular markers associated with metribuzin tolerance mediating QTL may be used in marker-assisted breeding to select metribuzin tolerant lines. Alternatively, validated favourable alleles could be introgressed into elite wheat cultivars to enhance metribuzin tolerance and improve grain yield in dryland farming for sustainable wheat production.

     

Salt tolerance of Beta macrocarpa is associated with efficient osmotic adjustment and increased apoplastic water content

The chenopod Beta macrocarpa Guss (wild Swiss chard) is known for its salt tolerance, but the mechanisms involved are still debated. In order to elucidate the processes involved, we grew wild Swiss chard exposed to three salinity levels (0, 100 and 200 mm NaCl) for 45 days, and determined several physiological parameters at the end of this time. All plants survived despite reductions in growth, photosynthesis and stomatal conductance in plants exposed to salinity (100 and 200 mm NaCl). As expected, the negative effects of salinity were more pronounced at 200 mm than at 100 mm NaCl: (i) leaf apoplastic water content was maintained or increased despite a significant reduction in leaf water potential, revealing the halophytic character of B. macrocarpa; (ii) osmotic adjustment occurred, which presumably enhanced the driving force for water extraction from soil, and avoided toxic build up of Na⁺ and Cl^– in the mesophyll apoplast of leaves. Osmotic adjustment mainly occurred through accumulation of inorganic ions and to a lesser extent soluble sugars; proline was not implicated in osmotic adjustment. Overall, two important mechanisms of salt tolerance in B. macrocarpa were identified: osmotic and apoplastic water adjustment.     

Efficacy and deficiencies of rapid biomonitoring in biodiversity conservation: a case study in South Africa

Rapid biomonitoring protocols, using biotic indices based on macroinvertebrate diversity to assess river ecosystem health, are widely used globally. Such quick assessment techniques are lauded for the rapid results obtained and the relatively easy protocol used to achieve an answer. However, do such quick assessments of water quality give enough information about ecosystems? Are important details being overlooked? When should a full faunal survey be used in preference? Important research programmes, including environmental impact studies, often misuse biomonitoring techniques, making influential management decisions using superficial, low-level data obtained using biomonitoring tools, inappropriate to address those management objectives. The value of using biomonitoring as a quick tool, versus a more detailed faunal assessment, is considered here. The assessment of teloganodid mayfly fauna occurring in South African rivers provides an example of the value of detailed studies versus superficial family level investigations, showing that a rapid biomonitoring approach should not be used as a shortcut when a more detailed survey is needed. Each situation should be assessed for its own merit in a given set of project circumstances. A checklist of criteria is presented, giving guidance on when rapid biomonitoring alone is valuable and when more detailed assessments would give a more relevant result.     

A single base deletion from the C1-inhibitor gene causes type I hereditary angio-oedema.

RFLP analysis, the polymerase chain reaction and nucleotide sequencing have been used to characterise a C1-inhibitor gene mutation responsible for type I hereditary angio-oedema (HAE). A single base deletion (C-16698) from the eighth exon of the C1-inhibitor gene alters the reading frame of the exon and generates a premature translation termination codon. This represents the first report of this form of C1-inhibitor gene mutation in type I HAE.     

The poliovirus sensitivity (PVS) gene is on chromosome 19q12----q13.2

Sensitivity to nonmodified poliovirus infection is an autosomal dominant trait, specific to primates. The gene for poliovirus sensitivity (PVS) is encoded on human chromosome 19. In order to sublocalize the PVS gene, we infected rodent-human hybrid cell lines that divide human chromosome 19 into four regions with poliovirus 1 and/or 3. When infected, these hybrid cell lines showed the typical cytopathic effect of poliovirus infection only if they contained 19q12----q13.2 as the smallest region of overlap. Appropriate negative and positive controls were used. PVS may be of relevance to myotonic dystrophy (DM) and the inherited motor neuron diseases: to DM because it localizes to the same region of chromosome 19 and to the inherited motor neuron diseases because it encodes a cell-surface receptor expressed on motor neurons.