Identifying genetic variants regulating MGMT gene expression - A study in monozygotic Danish twins.

Identifying genetic factors affecting the regulation of the O-6-Methylguanine-DNA Methyltransferase (MGMT) gene and estimating the genetic contribution of the MGMT gene through within-pair correlation in monozygotic twin pairs is of particular importance in various types of cancer such as glioblastoma. We used gene expression data in whole blood from 448 monozygotic twins from the Middle Age Danish Twins (MADT) study to investigate genetic regulation of the MGMT gene by performing a genome-wide association study (GWAS) of the variation in MGMT expression. Additionally, we estimated within-pair dependence measures of the expression values looking for the genetic influence of significant identified genes. We identified 243 single nucleotide polymorphisms (SNPs) significantly (p < 5e-8) associated with expression of MGMT, all located on chromosome 10 near the MGMT gene. Of the 243 SNPs, 7 are novel cis-eQTLs. By further looking into the suggestively significant SNPs (increasing cutoff to p = 1e-6), we identified 11 suggestive trans-eQTLs located on chromosome 17. These variants were in or proximal to a total of seven genes, which may regulate MGMT expression. The within-pair correlation of the expression of MGMT, TRIM37, and SEPT4 provided the upper bound genetic influence of these genes. Overall, identifying cis- or trans-acting genetic variations regulating the MGMT gene can pave the way for a better understanding of the MGMT gene function and ultimately in understanding the patient's sensitivity to therapeutic alkylating agents.

Clonal hematopoiesis in elderly twins: concordance, discordance, and mortality.

Clonal hematopoiesis (CH) of indeterminate potential (CHIP) is defined by mutations in myeloid cancer-associated genes with a variant allele frequency of at least 2%. Recent studies have suggested a possible genetic predisposition to CH. To further explore this phenomenon, we conducted a population-based study of 594 twins from 299 pairs aged 73 to 94 years, all with >20 years' follow-up. We sequenced DNA from peripheral blood with a customized 21-gene panel at a median coverage of 6179X. The casewise concordance rates for mutations were calculated to assess genetic predisposition. Mutations were identified in 214 (36%) of the twins. Whereas 20 twin pairs had mutations within the same genes, the exact same mutation was only observed in 2 twin pairs. No significant difference in casewise concordance between monozygotic and dizygotic twins was found for any specific gene, subgroup, or CHIP mutations overall, and no significant heritability could be detected. In pairs discordant for CHIP mutations, we tested if the affected twin died before the unaffected twin, as a direct measurement of the association of having CH when controlling for familial factors. A total of 127 twin pairs were discordant for carrying a mutation, and in 61 (48%) cases, the affected twin died first (P = .72). Overall, we did not find a genetic predisposition to CHIP mutations in this twin study. The previously described negative association of CHIP mutations on survival could not be confirmed in a direct comparison among twin pairs that were discordant for CHIP mutations.

Twin studies on cancer.

Studies on cancer loci by use of twin data reveal sources of variation in risk. The Nordic twin and cancer registries contain the largest cohort of population representative twins ever studied with more than median 40 years of follow-up. This article considers findings that show influences on familial risk and demonstrates the strengths of the matched case co-twin design for unraveling important risk factors of cancers. Studies using twin data will expectedly continue to provide insights into cancer epidemiology and genetics for the benefit of prevention and treatment.

Circulating microRNAs related to lipid metabolism and solid tissue maintenance and morphology associate with mortality in elderly twins.

The lifespan of humans varies greatly between individuals. Here, we aimed to explore what biological roles miRNAs may have on old age mortality-variation. Circulating miRNAs were measured in plasma from 43 monozygotic twin pairs (73-95 years of age) and mortality analyses were applied using Cox regression survival analyses and linear regression analyses of lifespan. In general, nominally significant miRNAs were mainly upregulated with shorter lifespan, both in Cox analysis (72 % upregulated) and in linear regression analysis (81 % upregulated). A total of 29 miRNAs were associated to mortality at a nominal significance level (p < 0.05) in the survival analysis, but no miRNAs passed the FDR adjusted level of significance. Seven of the 29 miRNAs; hsa-miR-140-3p, hsa-miR-16-5p, hsa-miR-487b-3p, hsa-miR-19a-3p, hsa-let-7d-5p, hsa-miR-320a, hsa-miR-375, were nominally significant across two linear twin-paired analyses and the cox analysis. Pathway analyses of the 29 nominally significant miRNAs from the individual level analyses resulted in two nominally significant associated Reactome pathways (unadjusted p < 0.05); 'Negative regulation of FGFR signaling' and 'Neurotransmitter receptor binding and downstream transmission in the postsynaptic cell', and two significantly associated KEGG pathways; 'Linoleic acid metabolism' and 'Toxoplasmosis'. Additional pathway analyses and results of previous studies support that miRNAs linked to mortality at age 70 years or older play a role in lipid metabolism, tissues maintenance and morphology.

Is tranexamic acid use in patients with a hip fracture safe?

AIMS: To assess the safety of tranexamic acid (TXA) in a large cohort of patients aged over 65 years who have sustained a hip fracture, with a focus on transfusion rates, mortality, and thromboembolic events. METHODS: This is a consecutive cohort study with prospectively collected registry data. Patients with a hip fracture in the Region of Southern Denmark were included over a two-year time period (2015 to 2017) with the first year constituting a control group. In the second year, perioperative TXA was introduced as an intervention. Outcome was transfusion frequency, 30-day and 90-day mortality, and thromboembolic events. The latter was defined as any diagnosis or death due to arterial or venous thrombosis. The results are presented as relative risk (RR) and hazard ratio (HR) with 95% confidence intervals (CIs). RESULTS: A total of 3,097 patients were included: 1,558 in the control group and 1,539 in the TXA group.31% (n = 477) of patients had transfusions in the control group compared to 27% (n = 405) in the TXA group yielding an adjusted RR of 0.83 (95% CI 0.75 to 0.91). TXA was not associated with increased 30-day mortality with an adjusted HR of 1.10 (95% CI 0.88 to 1.39) compared to the control group as well as no association with increased risk of 90-day mortality with a per protocol adjusted HR of 1.24 (95% CI 0.93 to 1.66). TXA was associated with a lower risk of thromboembolic events after 30 days (RR 0.63 (95% CI 0.42 to 0.93)) and 90 days (RR 0.72 (95% CI 0.52 to 0.99)). A subanalysis on haemoglobin demonstrated a median 17.7 g/L (interquartile range (IQR) 11.3 to 27.3) decrease in the control group compared to 17.7 g/L (IQR 9.7 to 25.8) in the per protocol TXA group (p = 0.060 on group level difference). CONCLUSION: TXA use in patients with a hip fracture, was not associated with an increased risk of mortality but was associated with lower transfusion rate and reduced thromboembolic events. Thus, we conclude that it is safe to use TXA in this patient group. Cite this article: Bone Joint J 2021;103-B(3):449-455.