Rheumatoid arthritis (RA) is a prevalent autoimmune disease, and there is growing evidence suggesting a potential correlation between dietary factors and the pathogenesis of this condition. In order to investigate the causal relationship between diet and RA, we conducted a two-sample Mendelian randomization (MR) analysis to examine the causal associations between 22 dietary factors and RA. Summary data from genome-wide association studies (GWAS) of RA were obtained from large GWAS meta-analyses. GWAS summary data for 22 dietary factors were obtained from UK Biobank (UKB). Random-effects inverse variance weighted (IVW) was used as the primary method for assessing causality, and analyses of heterogeneity and horizontal pleiotropy were performed to ensure the accuracy of the results. Research indicates a negative genetic causal relationship between cereal intake (OR = 0.64, 95% CI: 0.41 - 0.99, P = 0.048) and oily fish intake (OR = 0.70, 95% CI: 0.52 - 0.95, P = 0.020) with the risk of RA. Other dietary factors were not causally related to RA. Sensitivity analysis shows that our results are reliable. This study provides genetic evidence suggesting that cereal intake and oily fish intake are protective factors for RA, indicating that RA patients and individuals at high risk should make appropriate dietary adjustments.

The aim of the present study was to investigate the relationship between leptin and adiponectin gene polymorphisms, circulating levels of leptin and adiponectin, adiposity and clinical markers in patients with myelodysplastic syndrome (MDS). This cross-sectional study was conducted with 102 adults and elderly MDS patients and 102 age- and sex-matched controls. Clinical characteristics, co-morbidities, anthropometric data, laboratory evaluation and genetic analysis (polymorphisms −2548G > A/rs7799039 of the LEP gene and +276G > T/rs1501299 of the ADIPOQ gene) were investigated. Serum leptin was higher and adiponectin lower in MDS when compared with controls. There was a significant positive correlation between serum leptin levels and BMI (r = 0·264, P = 0·025), waist circumference (r = 0·235, P = 0·047), body fat percentage (BF %) (r = 0·373, P = 0·001) and the fat mass index (FMI) (r = 0·371, P < 0·001). A lower mean adiponectin was found among patients with high BF %, higher visceral adiposity index and metabolic syndrome. A significant association was found between the AA genotype (mutant) of the LEP polymorphism rs7799039 and male sex and blast excess (≥ 5 %). In addition, a significant association was observed between the TT genotype (mutant) of the ADIPOQ rs1501299 polymorphism and Fe overload. These results demonstrate the importance of a comprehensive and systematic evaluation in patients with MDS in order to identify and control negative factors not related to the disease at an early stage.

Protoporphyrinogen oxidase (PPO)-inhibiting herbicides remain an important and useful chemistry 60 yr after their first introduction. In this review, based on topics introduced at the Weed Science Society of America 2021 symposium titled “A History, Overview, and Plan of Action on PPO Inhibiting Herbicides,” we discuss the current state of PPO-inhibiting herbicides. Renewed interest in the PPO-inhibiting herbicides in recent years, due to increased use and increased cases of resistance, has led to refinements in knowledge regarding the mechanism of action of PPO inhibitors. Herein we discuss the importance of the two isoforms of PPO in plants, compile a current knowledge of target-site resistance mechanisms, examine non–target site resistance cases, and review crop selectivity mechanisms. Consistent and reproducible greenhouse screening and target-site mutation assays are necessary to effectively study and compare PPO-inhibitor resistance cases. To this end, we cover best practices in screening to accurately identify resistance ratios and properly interpret common screens for point mutations. The future of effective and sustainable PPO-inhibitor use relies on development of new chemistries that maintain activity on resistant biotypes and the promotion of responsible stewardship of PPO inhibitors both new and old. We present the biorational design of the new PPO inhibitor trifludimoxazin to highlight the future of PPO-inhibitor development and discuss the elements of sustainable weed control programs using PPO inhibitors, as well as how responsible stewardship can be incentivized. The sustained use of PPO inhibitors in future agriculture relies on the effective and timely communication from mode of action and resistance research to agronomists, Extension workers, and farmers.

Although previous studies suggested the protective effect of Zn for type 2 diabetes (T2D), the unitary causal effect remains inconclusive. We investigated the causal effect of Zn as a single intervention on glycaemic control for T2D, using a systematic review of randomised controlled trials and two-sample Mendelian randomisation (MR). Four primary outcomes were identified: fasting blood glucose/fasting glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR) and serum insulin/fasting insulin level. In the systematic review, four databases were searched until June 2021. Studies, in which participants had T2D and intervention did not comprise another co-supplement, were included. Results were synthesised through the random-effects meta-analysis. In the two-sample MR, we used single-nucleotide polymorphisms (SNP) from MR-base, strongly related to Zn supplements, to infer the relationship causally, but not specified T2D. In the systematic review and meta-analysis, fourteen trials were included with overall 897 participants initially. The Zn supplement led to a significant reduction in the post-trial mean of fasting blood glucose (mean difference (MD): −26·52 mg/dl, 95 % CI (−35·13, −17·91)), HbA1c (MD: −0·52 %, 95 % CI: (−0·90, −0·13)) and HOMA-IR (MD: −1·65, 95 % CI (−2·62, −0·68)), compared to the control group. In the two-sample MR, Zn supplement with two SNP reduced the fasting glucose (inverse-variance weighted coefficient: −2·04 mmol/l, 95 % CI (−3·26, −0·83)). From the two methods, Zn supplementation alone may causally improve glycaemic control among T2D patients. The findings are limited by power from the small number of studies and SNP included in the systematic review and two-sample MR analysis, respectively.

Using nested case–control data from the Lifelines COVID-19 cohort, we undertook a validation study of a clinical and genetic model to predict the risk of severe COVID-19 in people with confirmed COVID-19 and in people with confirmed or self-reported COVID-19. The model performed well in terms of discrimination of cases and controls for all ages (area under the receiver operating characteristic curve (AUC) = 0.680 for confirmed COVID-19 and AUC = 0.689 for confirmed and self-reported COVID-19) and in the age group in which the model was developed (50 years and older; AUC = 0.658 for confirmed COVID-19 and AUC = 0.651 for confirmed and self-reported COVID-19). There was no evidence of over- or under-dispersion of risk scores but there was evidence of overall over-estimation of risk in all analyses (all P < 0.0001). In the light of large numbers of people worldwide remaining unvaccinated and continuing uncertainty regarding vaccine efficacy over time and against variants of concern, identification of people at high risk of severe COVID-19 may encourage the uptake of vaccinations (including boosters) and the use of non-pharmaceutical inventions.

Clinical and genetic risk factors for severe coronavirus disease 2019 (COVID-19) are often considered independently and without knowledge of the magnitudes of their effects on risk. Using severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) positive participants from the UK Biobank, we developed and validated a clinical and genetic model to predict risk of severe COVID-19. We used multivariable logistic regression on a 70% training dataset and used the remaining 30% for validation. We also validated a previously published prototype model. In the validation dataset, our new model was associated with severe COVID-19 (odds ratio per quintile of risk = 1.77, 95% confidence interval (CI) 1.64–1.90) and had acceptable discrimination (area under the receiver operating characteristic curve = 0.732, 95% CI 0.708–0.756). We assessed calibration using logistic regression of the log odds of the risk score, and the new model showed no evidence of over- or under-estimation of risk (α = −0.08; 95% CI −0.21−0.05) and no evidence or over-or under-dispersion of risk (β = 0.90, 95% CI 0.80–1.00). Accurate prediction of individual risk is possible and will be important in regions where vaccines are not widely available or where people refuse or are disqualified from vaccination, especially given uncertainty about the extent of infection transmission among vaccinated people and the emergence of SARS-CoV-2 variants of concern.

Single-nucleotide polymorphisms in miRNA-machinery genes may alter the biogenesis of miRNAs affecting disease susceptibility. In this case–control study, we aimed to evaluate the impact of three single-nucleotide polymorphisms (DICER rs1057035, DROSHA rs10719, and XPO5 rs11077) and their combined effect in a genetic risk score model on congenital heart disease (CHD) risk. A total of 639 participants was recruited, including 125 patients with CHD (65 males; age 9.2 ± 10 years) and 514 healthy controls (289 males; age 15.8 ± 18 years). Genotyping of polymorphisms in miRNA-machinery genes was performed using a TaqMan®SNP genotyping assay. A genetic risk score was calculated by summing the number of risk alleles of selected single-nucleotide polymorphisms. There was a significantly increased risk of CHD in patients with XPO5 rs11077 CC genotype as compared to AC heterozygote and AA homozygote patients (ORadjusted = 1.7; 95% CI: 1.1–2.8; p = 0.018). A clear tendency to significance was also found for DROSHA rs10719 AA genotype and CHD risk for both codominant and recessive models (ORadjusted = 1.8; 95% CI: 0.91–3.8; p = 0.09 and ORadjusted = 1.9; 95% CI: 0.92–4; p = 0.08, respectively). The resulting genetic risk score predicted a 1.73 risk for CHD per risk allele (95% CI: 1.2–2.5; p = 0.002). Subjects in the top tertile of genetic risk score were estimated to have more than three-fold increased risk of CHD compared with those in the bottom tertile (ORadjusted = 3.52; 95% CI: 1.4–9; p = 0.009). Our findings show that the genetic variants in miRNA-machinery genes might participate in the development of CHD.

Leg weakness (LW) issues are a great concern for pig breeding industry. And it also has a serious impact on animal welfare. To dissect the genetic architecture of limb-and-hoof firmness in commercial pigs, a genome-wide association study was conducted on bone mineral density (BMD) in three sow populations, including Duroc, Landrace and Yorkshire. The BMD data were obtained by ultrasound technology from 812 pigs (including Duroc 115, Landrace 243 and Yorkshire 454). In addition, all pigs were genotyped using genome-by-sequencing and a total of 224 162 single-nucleotide polymorphisms (SNPs) were obtained. After quality control, 218 141 SNPs were used for subsequent genome-wide association analysis. Nine significant associations were identified on chromosomes 3, 5, 6, 7, 9, 10, 12 and 18 that passed Bonferroni correction threshold of 0.05/(total SNP numbers). The most significant locus that associated with BMD (P value = 1.92e−14) was detected at approximately 41.7 Mb on SSC6 (SSC stands for Sus scrofa chromosome). CUL7, PTK7, SRF, VEGFA, RHEB, PRKAR1A and TPO that are located near the lead SNP of significant loci were highlighted as functionally plausible candidate genes for sow limb-and-hoof firmness. Moreover, we also applied a new method to measure the BMD data of pigs by ultrasound technology. The results provide an insight into the genetic architecture of LW and can also help to improve animal welfare in pigs.

To identify genetic risk loci for major depressive disorder (MDD), two broad study design approaches have been applied: (1) to maximize sample size by combining data from different phenotype assessment modalities (e.g. clinical interview, self-report questionnaires) and (2) to reduce phenotypic heterogeneity through selecting more homogenous MDD subtypes. The value of these strategies has been debated. In this review, we summarize the most recent findings of large genomic studies that applied these approaches, and we highlight the merits and pitfalls of both approaches with particular attention to methodological and psychometric issues. We also discuss the results of analyses that investigated the heterogeneity of MDD. We conclude that both study designs are essential for further research. So far, increasing sample size has led to the identification of a relatively high number of genomic loci linked to depression. However, part of the identified variants may be related to a phenotype common to internalizing disorders and related traits. As such, samples containing detailed clinical information are needed to dissect depression heterogeneity and enable the potential identification of variants specific to a more restricted MDD phenotype. A balanced portfolio reconciling both study design approaches is the optimal approach to progress further in unraveling the genetic architecture of depression.

Local zebu cattle breeds in Indian villages are crossbred with exotic breeds at an unprecedented rate without utilising the full potential of genomic technologies. In addition to agriculture produce, livestock, particularly cattle, constitute a vital source of livelihood for farmers in India. Age-old agricultural practices, errant monsoon, and frequent crop failures have resulted in Maharashtra having the highest number of farmer suicides in the country. Local cattle breeds are considered low-yield breeds and thus are primarily used as beasts of burden. Information on functional gene variants in Indian cattle breeds is scant and limited to PCR-RFLP study in few breeds. In this study, 32 samples from 8 cattle breeds were obtained from remote villages of Maharashtra state. By using the re-sequencing technology, we sequenced 403 bp of the exon IV CSN3 allele and inferred its haplotypes. From 32 samples, 14 genotypes (G1–G14) defined by 7 single-nucleotide polymorphisms (SNP's) were identified. From these 14 genotypes, we reconstructed 3 haplotypes (H01, H02, and H03) and estimated their frequencies. Of the 3 haplotypes, two (H01 and H03) corresponded to CSN3*B4 and CSN3*B and CSN3*H and CSN3*G alleles, respectively. The third haplotype H02 was identified as a new allele and differed from CSN3*B4 and CSN3*B and CSN3*H and CSN3*G alleles by one nonsynonymous mutation at the position C5306T-Ile100Thr. The neighbour-joining tree reconstruction revealed haplotype sharing or hybridisation between B. t. indicus and B. t. taurus because the 3 haplotypes originated in this study clustered with A1, B2, B4, B, G, and H alleles, which were reported previously in both the subspecies of B. taurus. The occurrence of one new allele in a small sample size highlights the urgency to screen local zebu cattle breeds by using genomic tools for circumventing genetic erosion that is widespread in Indian villages in India.

Dongxiang wild rice (Oryza rufipogon, DXWR) exhibits valuable agronomic traits and represents a precious germplasm resource for rice breeding. The use of genetic markers can greatly speed up the breeding process and facilitate research on genetics and genomics. In our previous study, we identified insertion–deletion polymorphisms between DXWR and cultivated rice Nipponbare (Oryza sativa ssp. japonica), using whole-genome sequencing in DXWR. In this study, to further explore the genetic variations and enrich the available genetic markers of DXWR, we identified 1,089,478 single-nucleotide polymorphisms (SNPs) (corresponding to one SNP per 0.33 kb of the genome) by genomic comparison between DXWR and Nipponbare, using the genome sequencing data and bioinformatics approaches. Furthermore, the accuracy of the identified SNPs was also validated by polymerase chain reaction amplification and Sanger sequencing. This genome-wide SNPs identification greatly increases the number of genetic markers available for DXWR and provides new opportunities to exploit this valuable and endangered germplasm resource.

Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.

Alternative oxidase (AOX) has been proposed as a promising functional marker candidate for multiple plant stress behaviour. The present paper describes natural polymorphism in AOX2b of Daucus carota L. (DcAOX2b). Exon-primed intron crossing-PCR (EPIC-PCR) revealed length variation (intron length polymorphisms, ILPs) in intron 1. Six fragment patterns were identified in 40 genotypes. However, no more than two fragments were found per genotype, suggesting the presence of two alleles. The ILPs were able to discriminate between single plant genotypes in cv. Rotin and to distinguish individual wild carrot plants. The repetitive pattern of intron 1 length variation allows the grouping of genotypes for functional analysis in future studies. Sequence analysis in intron 1 of polymorphic but also of obviously identical PCR-fragments revealed underlying high levels of sequence polymorphisms between alleles and genotypes. Variation was due to repetitive insertion/deletion (InDel) events and single-nucleotide polymorphisms (SNPs). The results suggest that high AOX2b gene diversity in D. carota may be a source of functional markers for agronomic traits related to environmental stress responses.