The Tsunami of COVID-19 Infection Among Kidney Transplant Recipients: A Single-Center Study from Iran

Background Although most evidence supports the fact that kidney transplant (KT) recipients are at significant risk of morbidity and mortality, risk factors of accruing COVID-19 in this population have remained poorly defined. Methods All KT recipients who had been transplanted in Sina Hospital and were actively followed between March 1996 and January 2021 were enrolled in a retrospective manner. The demographic characteristics, immunosuppressive treatment before KT, and death were gathered by calling patients with a designed questionnaire. Results 108 (about 21%) of 523 KT recipients were diagnosed with COVID-19. The mean age of COVID-19 patients was 46.9 ± 13.6, of whom 43% were women. In the multivariate model, body mass index (BMI) ≥ 30 independently increased the risk of COVID-19 incidence with OR 2.00 (95% CI 1.23, 3.26) (P = 0.00), and besides, having diabetes had a marginal association with COVID-19 incidence (OR 1.62 [95% CI 0.98, 2.66]; P = 0.057). The mortality rate of COVID-19 was 15%. In the multivariate model, only pre-transplantation diabetes significantly increased the risk of death by COVID-19 with OR of 3.90 (95% CI 1.00–15.16) (P = 0.04). Conclusion Given the higher incidence rate in KT recipients with obesity and diabetes and higher mortality rate in KT recipients with diabetes as the cause of ESRD, more attention should be paid to KT recipients with these risk factors.

Investigation of the Interaction between Hearing Function and Comorbidities in Adults Living with Human Immunodeficiency Virus

Adults living with the human immunodeficiency virus (HIV) have a high prevalence of co-existing comorbidities. While research indicates that adults living with HIV are at risk of developing hearing impairment, limited research exists on the interaction between hearing function and comorbidities in this population. The objective of this study was to determine and compare the hearing function of a group of adults living with HIV and comorbidities and those without comorbidities. A sample of 132 adults living with HIV underwent a basic audiological test battery to assess their hearing function. Participants with comorbidities were 1.23 times more likely to develop hearing loss, with crude odds of 1.236 (95%CI 0.5467 to 2.795), while those with three comorbidities were 2.52 times more likely to develop hearing loss. Participants with hypertension were 93% more likely to develop hearing loss when compared to nonhypertensive participants (OR = 1.928; 95%CI: 0.7856 to 4.7345). There was only a marginal association between hypercholesterolemia and sensorineural hearing loss (SNHL), with no association between other comorbidities and the type of hearing loss. The current findings raise a need for prioritizing patients with comorbidities in audiological assessment and monitoring in resource-constrained contexts, where capacity versus demand challenges might prevent the provision of audiological services to all adults living with HIV. These findings also highlight the importance of preventive care in this population with regard to the burden of the disease, as it may lead to worse ear and hearing outcomes for affected individuals.

A versatile, fast and unbiased method for estimation of gene-by-environment interaction effects on biobank-scale datasets

Current methods to evaluate gene-by-environment (GxE) interactions on biobank-scale datasets are limited. MonsterLM enables multiple linear regression on genome-wide datasets, does not rely on parameters specification and provides unbiased estimates of variance explained by GxE interaction effects. We applied MonsterLM to the UK Biobank for eight blood biomarkers (N=325,991), identifying significant genome-wide interaction variance with waist-to-hip ratio for five biomarkers, with variance explained by interactions ranging from 0.11 to 0.58. 48% to 94% of GxE interaction variance can be attributed to variants without significant marginal association with the phenotype of interest. Conversely, for most traits, >40% of interaction variance was explained by less than 5% of genetic variants. We observed significant improvements in polygenic score prediction with incorporation of GxE interactions in four biomarkers. Our results imply an important contribution of GxE interaction effects, driven largely by a restricted set of variants distinct from loci with strong marginal effects.

Atlas of epistasis

We performed a genome-wide epistasis search across 502 phenotypes in case control matched cohorts from the UK Biobank. We identified 152,519 genome wide significant interactions in 68 distinct phenotypes, and 3,398 interactions in 19 phenotypes were successfully replicated in independent cohorts from the Finngen consortium. Most interactions (79%) involved variants that did not present significant marginal association and might explain part of the missing heritability for these diseases. In 10 phenotypes we show the presence of epistasis between common variants with intermediate to large effect size (OR > 2) supporting the hypothesis that common diseases are modulated by common variants. Most of the variants in interactions (82%) were more than 1Mb apart and cis-epistasis was hardly found outside the HLA region. Functional annotation of the variants suggests that most mechanisms behind epistasis occurs at the supra pathway level and that intra-gene or intra-pathway epistasis is rare. Surprisingly we find a significant biais toward antagonistic epistasis, representing 60% to 95% of interactions. In type 1 diabetes, hypothyroidism, disorders of mineral absorption, rheumatoid arthritis, asthma, and multiple sclerosis more than 50% of interactions were completely compensating the effect of the marginally associated variant. In psoriasis we identified an interaction between a stop gain variant in CCHCR1 with two missense variants in MUC22 and HSPA1L leading to a 3 fold increase of the effect of CCHCR1 variant on disease risk. Our study shows that there is still much to discover in epistasis and we provide the full summary statistics results to researchers interested in studying epistasis.

Single Nucleotide Polymorphisms of TRAF2 and TRAF5 Gene in Ankylosing Spondylitis: A Case-Control Study

ObjectiveTo investigate the role of eight locus polymorphisms of tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF5 gene and their interaction in the susceptibility to ankylosing spondylitis (AS) in Chinese Han population.MethodsEight single nucleotide polymorphisms (SNPs) (rs3750511, rs10781522, rs17250673, rs59471504, rs6540679, rs12569232, rs4951523, rs7514863) of TRAF2 and TRAF5 gene were genotyped in 673 AS patients and 687 controls.ResultsThe SNPs of TRAF2 and TRAF5 does not indicate a correlation with the susceptibility of AS in Chinese Han population. Genotype frequencies of rs3750511were statistically significant in females between patients and controls. The genotype frequencies of rs12569232 and allele frequencies of rs3750511were statistically significant between groups of different diseases activity. One three-locus model, TRAF2 (rs10781522, rs17250673) and TRAF5 (rs12569232), had a maximum testing accuracy of 52.67% and a maximum cross-validation consistency (10/10) that was significant at the level of P=0.0001, after determined empirically by permutation testing. As to environmental variables, only marginal association was found between sleep quality and AS susceptibility.ConclusionTRAF2 rs3750511 polymorphism may be associated with the susceptibility and severity of AS. Besides, the interaction of TRAF2 and TRAF5 genes may be associated with AS susceptibility, but many open questions remain.

Prognostic Significance of CHIP and RIPK3 in Non-Small Cell Lung Cancer

RIPK3 is a key regulator of necroptosis, which plays a double-edged sword role in tumor progression. CHIP is an E3 ubiquitin ligase that regulates necroptosis by degrading RIPK3. Here, we investigated the prognostic value of RIPK3 and CHIP expression in 404 patients with non-small cell lung cancer (NSCLC). Expressions of CHIP and RIPK3 showed opposite correlations with survival. CHIP expression was associated with the longer overall survival (OS), whereas RIPK3 expression was associated with the shorter OS. RIPK3 positivity showed marginal association with shorter OS and disease-free survival (DFS) in adjuvant radiotherapy recipients but not in non-recipients, suggesting that necroptosis may induce radioresistance. In multivariate analysis, CHIP expression was associated with longer OS. Compared with other patients, CHIP(−)/RIPK3(+) patients had shorter OS and DFS. In summary, in patients with NSCLC, the expression of CHIP was an independent favorable prognostic factor while that of RIPK3 was an adverse prognostic factor.

Evaluation of FGF10 as a candidate gene for high myopia in a Han Chinese population

Background Fibroblast growth factor 10 (FGF10) is implicated in the growth and development of the eye. Four singles nucleotide polymorphisms (SNPs) in the FGF10 gene (including rs1384449, rs339501, rs12517396 and rs10462070) were found to be associated with extreme myopia (EM, refractive error ≤ − 10.0 diopters) in Japanese and Chinese Taiwan population. This case-control association study was conducted to explore the relationship between these four SNPs and high myopia in a western Chinese population. Methods A total of 869 high myopia patients (HM, including 485 EM patients) and 899 healthy controls were recruited. These four SNPs were genotyped using the ABI SNaPshot method. Five genetic models (allelic, homozygous, heterozygous, dominant, and recessive) were applied to further evaluate the possible correlation between the SNPs and high myopia. The linkage-disequilibrium block (LD) structure was tested by Haploview Software. Results In our study, no statistically significant differences were found between HM/EM patients and controls after Bonferroni multiple-correction (P > 0.05) in the allele frequencies of these four SNPs in the FGF10 gene. We further found that rs12517396AA and rs10462070GG carriers showed a decreased risk of HM/EM compared with rs12517396AC + CC and rs10462070GA + AA carriers (P = 0.045, OR = 0.366; P = 0.021, OR = 0.131; P = 0.03, OR = 0.341; P = 0.015, OR = 0.122; respectively). Additionally, rs12517396AA and rs10462070GG carriers showed the same decreased risk of HM/EM compared with rs12517396CC and rs10462070AA carriers (P = 0.048, OR = 0.370; P = 0.023, OR = 0.133; P = 0.032, OR = 0.346; P = 0.017, OR = 0.126). However, these significant associations between rs12517396/rs10462070 and HM/EM disappeared after Bonferroni multiple-correction (P > 0.05). Conclusion Our findings indicate that rs12517396 and rs10462070 had marginal association with HM and EM. The other two common polymorphisms in FGF10 unlikely have significant effects in the genetic predisposition to HM/EM in western Chinese population. Further replication studies are needed to validate our findings in both animal models and human genetic epidemiologic studies.

Association of Kiss1 and GPR54 Gene Polymorphisms with Polycystic Ovary Syndrome among Sri Lankan Women

Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder affecting women of reproductive age. Its aetiology, though yet unclear, is presumed to have an oligogenic basis interacting with environmental factors. Kisspeptins are peptide products of Kiss1 gene that control the hypothalamic pituitary (HPG) axis by acting via G protein-coupled receptor known as GPR54. There is paucity of data on the role of Kiss1 and GPR54 gene in PCOS. We aimed to identify the polymorphisms in Kiss1 and GPR54 genes and explore their association with serum kisspeptin levels among Sri Lankan women with well-characterized PCOS. Consecutive women with PCOS manifesting from adolescence (n=55) and adult controls (n=110) were recruited. Serum kisspeptin and testosterone levels were determined by ELISA method. Whole gene sequencing was performed to identify the polymorphisms in Kiss1 and GPR54 genes. Serum kisspeptin and testosterone concentrations were significantly higher in women with PCOS than controls: kisspeptin 4.873nmol/L versus 4.127nmol/L; testosterone 4.713nmol/L versus 3.415 nmol/L, p<0.05. Sequencing the GPR54 gene revealed 5 single nucleotide polymorphisms (SNPs), rs10407968, rs1250729403, rs350131, chr19:918686, and chr19:918735, with two novel SNPs (chr19:918686 and chr19:918735), while sequencing the Kiss1 gene revealed 2 SNPs, rs5780218 and rs4889. All identified SNPs showed no significant difference in frequency between patients and controls. GPR54 gene rs350131 polymorphism (G/T) was detected more frequently in our study population. The heterozygous allele (AG) of GPR54 gene novel polymorphism chr19:918686 showed a marginal association with serum kisspeptin levels (p=0.053). Genetic variations in GPR54 and Kiss1 genes are unlikely to be associated with PCOS among Sri Lankan women manifesting from adolescence. Meanwhile the heterozygous allele of chr19:918686 is probably associated with serum kisspeptin concentrations, which suggests a potential role in the aetiology of PCOS.