M235T Genotype Research Articles

Relationship between the AGT M235T genetic variant and the characteristics and prognosis of coronary atherosclerosis in patients with acute myocardial infarction.

Along with environmental components, genetic factors play an essential role in the pathophysiology and progression of acute myocardial infarction (AMI). There is limited and conflicting data on the influence of the AGT M235T genetic variant on coronary atherosclerosis and death in AMI patients. We carried out a prospective cohort study among 504 Vietnamese AMI patients selected between January 2020 and May 2021. All patients underwent invasive coronary angiography, had AGT M235T genetic variant genotyped using the polymerase chain reaction method, and were followed up for 12-month all-cause mortality. The proportions of the MM, MT, and TT genotypes were 0.4%, 20.8%, and 78.8%, respectively. There was no significant difference between the TT genotype and the MM + MT genotype groups regarding the position and number of stenosed coronary artery branches and the Gensini score. The AGT M235T genetic variant did not affect 12-month mortality (hazard ratio of TT vs. MM + MT: 1.185; 95% confidence interval: 0.596-2.354; P = 0.629). Subgroup analyses by age, sex, hypertension, diabetes mellitus, dyslipidemia, obesity, smoking, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy also did not reveal an association between the AGT M235T variant and all-cause mortality. In summary, the AGT M235T genetic variant was not found to be associated with coronary atherosclerosis characteristics and 12-month mortality in Vietnamese patients with AMI. Further multicenter studies with larger sample sizes and extended follow-up periods are needed to investigate this issue.

The HLA-B Leader MM Genotype Has a Negative Impact on Outcomes in HLA-B One Antigen Mismatched and HLA-B Matched Cord Blood Transplantation without Anti-Thymocyte Globulin: Analysis of the Japanese Society for Transplantation and Cellular Therapy

Background: The dimorphism at position -21 of exon 1 in HLA-B gives rise to leader peptides featuring either methionine (M) or threonine (T) as the second residue in the processed leader peptide (HLA-B leader). The cell surface abundance of HLA-E is positively correlated with the copy number of −21M HLA-B. In hematopoietic cell transplantation (HCT), the MM genotype in the recipients is associated with worse outcomes after HLA-matched and mismatched unrelated bone marrow and peripheral blood stem cell transplantation compared with TT (Kanaya M, et al. ASH Annual Meeting 2021, Petersdorf EW et al. Lancet Haematol. 2020 and Blood. 2020). Eurocord/EBMT study revealed HLA-B leader mismatch in HLA-B mismatched combination is associated with relapse and non-relapse mortality (NRM) risks after cord blood transplantation (CBT) (Petersdorf EW et al. Haematologica 2021). Notably, approximately 70% of patients in the literature administrated anti-thymocyte globulin (ATG) for graft-versus-host disease (GVHD) prophylaxis. The impacts of HLA-B leader dimorphism on the outcomes of CBT still needed to be elucidated more. Particularly, we were interested in the significance of HLA-B leaders in CBT without an ATG, then we conducted a retrospective study to elucidate it. Methods: Clinical data of 10,569 patients who underwent single-unit CBT for acute myeloid leukemia (AML, n=5,518), myelodysplastic syndrome (MDS, n=1,483), acute lymphoblastic leukemia (ALL, n=2,020), and lymphoma (n=1,548) between 2008 - 2021 were provided by the Japanese Data Center for Hematopoietic Cell Transplantation. HLA-A, -B, -C, and -DRB1 typing was performed at least at the antigen level. The leader genotype is defined based on the two HLA-B allotypes. All patients were not used ATG for GVHD prophylaxis. Study outcomes were overall survival (OS), cumulative incidences of relapse, NRM, and grade II-IV acute GVHD (aGVHD). Multivariable Cox regression analysis including covariables; disease risk index (DRI), myeloablative/reduced-intensity conditioning, presence of total body irradiation as a conditioning regimen, short-term methotrexate or mycophenolate mofetil for GVHD prophylaxis, recipient cytomegalovirus serostatus. All statistical analyses were performed with EZR. Results: The median patient's age was 53 (range 0-88) years. The numbers of patients with HLA-B leader TT, MT, and MM genotype were 7,639 (72.3 %), 2,707 (25.6 %), and 223 (2.1 %), respectively. To classify HLA-B match/mismatch status, we stratify “HLA-B one locus mismatched (GVH direction)” and HLA-B matched (no GVH direction mismatch)“. First, we focused on HLA-B one antigen mismatched (HLA 5/6 antigen matched, n = 1172) setting as shown in the previous literature. Recipient MM genotype showed significantly worse OS and relapse in the multivariate analysis compared to MT or TT genotype (Tx) (Figure) (OS: hazard ratio [HR] 0.543 [95% CI, 0.311 - 0.947]; p = 0.032, relapse: [HR] 2.863 [95% CI, 1.330 - 6.165]; p = 0.007). Recipient MM didn't relate to relapse and grade II-IV aGVHD. Next, we explored the impacts of HLA-B leaders in HLA-B antigen-matched CBT (3/6 - 6/6 matched, n = 3995). Donor MM genotype demonstrated a negative impact for OS and NRM, not relapse and aGVHD, compared to Tx donor (Figure) (OS: [HR] 0.738 [95% CI, 0.542 - 1.000]; p 0.050, NRM: [HR] 1.695 [95% CI, 1.097 - 2.621]; p = 0.018). Especially, OS and NRM of donor MM genotype were significantly inferior to Tx in HLA 6/6 matched (n = 914) CBT (OS: [HR] 0.311 [95% CI, 0.187 - 0.518]; p < 0.001, NRM: [HR] 3.216 [95% CI, 1.931 - 5.356]; p = 0.034). Conclusions: ATG would affect immune dynamics strongly in CBT via in-vivo T cell depletion, yet the current study demonstrated the HLA-B leader was still a significant risk factor in CBT without ATG for the first time. Recipient MM genotype in HLA-B one locus mismatched (HLA 5/6 matched) and donor MM genotype in HLA-B matched were the risk factors for worse CBT outcomes. We concluded MM genotype donors would be avoided to decrease NRM in HLA-B matched CBT. The precise mechanism of negative impact in CBT outcomes in patients or donor MM genotype remains to be clarified, however, we assume higher level HLA-E expression may be crucial in terms of NKG2A inhibitory signaling to T cells/NK cells and T-cell direct recognition for peptide/HLA-E complex in CBT.

Association between angiotensinogen M235T gene polymorphism and risk of ischemic stroke among the Ethiopian population: a case control study

Ischemic stroke (IS) is a multifaceted, complicated illness resulting from a confluence of genetic, environmental and vascular risk factors. Many genes that may contribute to ischemic stroke have been discovered in humans. The genetic contribution appears to be greater in IS patients with hypertension. There is conflicting evidence about a positive correlation between the AGT M235T polymorphism and ischemic stroke. The aim of this study was to examine the possible association of the AGT M235T gene polymorphism with the risk of ischemic stroke. A hospital-based case-control study was carried out in 36 ischemic stroke patient cases and 36 age- and sex-matched healthy controls. Clinical parameters were measured to assess the associated risk factors. DNA was isolated from blood samples, and the AGT M235T genotypes were identified using polymerase chain reaction (PCR) and analyzed by agarose gel electrophoresis. The AGT-TT genotype (OR = 4.64, 95% CL = 1.23–17.4; p = 0.023 and T allele (OR = 2.54, 95% CL = 1.28–5.02; p = 0.003) were significantly more common in patients than in controls, indicating that it may be a major risk factor for the development of ischemic stroke. The results suggest that there may be a significant correlation between the AGT M235T gene polymorphism and the development of ischemic stroke in the studied Ethiopian population.

Angiotensinogen, Angiotensin-Converting Enzyme, and Chymase Gene Polymorphisms as Biomarkers for Basal Cell Carcinoma Susceptibility.

The intake of angiotensin-converting enzyme (ACE) inhibitors and specific antagonists of angiotensin II receptors, widely used as antihypertensive drugs, significantly reduces the risk of developing basal cell carcinoma (BCC), highlighting the possible tumorigenic role of angiotensin II (AngII). We present here the investigated genetic association between the development of BCC and functional DNA polymorphisms M235T, I/D, and A1903G in the genes of angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and chymase (CMA1), which mediate AngII production levels. DNA samples of 203 unrelated Greeks were studied, including 100 patients with BCC and 103 matched healthy controls. The MT genotype of the AGT-M235T polymorphism was significantly more prevalent in the patient group (78.0%) versus the healthy control group (28.3%; p<0.001). The DD genotype of the ACE-I/D polymorphism was also increased in BCC patients (72.8%) compared to controls (46.2%; p=0.001). The heterozygous AG genotype of CMA1-A1903G was significantly more frequent in the BCC group (86%) than in the healthy controls (50.5%; p<0.001). The MT, DD, and AG genotypes of the AGT- M235T, ACE-I/D, and CMA1-A1903G polymorphisms, respectively, were significantly increased in frequency within the group of cancer patients compared to the healthy controls. All three genotypes correspond to increased enzyme levels or activity and result in increased levels of AngII; therefore, they may be potentially utilized as reliable biomarkers associated with an individual's increased risk for BCC development.

Detection, genotyping and virulence characterization of Fusarium wilt race 4 (VCG0114) causing cotton wilt in three Texas fields

AbstractFusarium wilt of cotton, caused by the soilborne fungus Fusarium oxysporum f.sp. vasinfectum race 4 (Fov4, VCG0114), is a serious disease that has adversely affected cotton production in California since 2001 and in the Upper Rio Grande Region near El Paso in the border areas between Texas and New Mexico since 2017. Fov4 was isolated from cotton stem samples collected from wilted or asymptomatic plants adjacent to the wilting plants from the El Paso area. The MT genotype was the only Fov4 genotype found in two fields in the Lower Valley of El Paso and the T genotype was the only Fov4 genotype found in one field in the Upper Valley Region of El Paso. No N, MiT or mixed genotypes of Fov4 were detected in any of these fields. Furthermore, the F. oxysporum f.sp. vasinfectum isolates were exclusively Fov4. The results support the observation that the MT genotype of Fov4 is mainly distributed in the Lower Valley of El Paso and the T genotype of Fov4 is mainly distributed in the Upper Valley Region of El Paso. Virulence of the MT genotype of Fov4 was higher than that of the T genotype. PCR methods previously developed for Fov4 specific PCR detection and multiplex Fov4 genotyping were validated by VCG analyses of the newly obtained isolates. These PCR methods were adapted for the in planta detection of Fov4, but Fov4 genotyping was limited to the detection of T, MT and MiT genotypes. It is important to continue to monitor dynamic population structure of Fov4 genotypes to prevent the spread of Fov4 and optimize disease control.

Recipient HLA-B Leader Genotype, and Its Relationship to Total KIR Missing Ligand, Informs Relapse and Survival Following Haploidentical Transplantation Using Post-Transplant Cyclophosphamide

▪In addition to donor T cells, natural killer (NK) cells are proposed to play a significant role in the graft-versus-leukemia (GVL) effect following haploidentical donor transplantation (HIDT). Following HIDT, donor NK cells express activating (NKG2C) receptors (Ciurea, Leukemia 2021), whose ligand is the non-classical human leukocyte antigen, HLA-E. For surface expression, HLA-E requires binding of leader peptides derived from class I HLA molecules. The rs1050458C/T dimorphism at position -21 of exon 1 of HLA-B gives rise to leader peptides with either methionine (M) or threonine (T) at the second residue of the processed leader peptide. M-containing HLA-B leader peptides promote higher HLA-E expression than T-leaders, potentially favoring more robust natural NK cell recognition of HLA-E-expressing tumor cells. Alternatively, donor NK cells can be activated through inhibitory killer cell immunoglobulin-like receptors (iKIR: 2DL1, 2DL23, 3DL1, 3DL2), if they fail to engage a corresponding class I HLA ligand on recipient leukemia cells (missing ligand (ML) paradigm). We hypothesized that M-containing B-leaders (either MM or MT genotype), and potentially its association with KIR ML, may inform relapse and survival after HIDT using post-transplant cyclophosphamide (PTCy). A total of 322 patients with acute leukemia, MDS, lymphoma, CLL or CML, receiving a HIDT-PTCy from a single institution were evaluated with a median follow-up time of 45 months [range 6, 184]. Baseline characteristics included a median age of 50 years [19, 80], 47% non-white, HCT-CI ≥3 in 50%, PBSC graft in 80%, and myeloablative conditioning in 49%. M-containing B-leader genotype (either MM or MT) was seen in 42% and 44% of recipients and donors, respectively. The B-leader on the unshared donor-recipient haplotypes was matched (either T or M) in 61% of transplants. ML for iKIR 2DL1, 2DL23, 3DL1, and 3DL2 was noted in 29%, 20%, 24% and 72% respectively. Total ML was 0, 1, 2 and 3 in 10%, 43%, 40% and 7% respectively. In univariate analysis, an M-containing recipient B-leader genotype [R(M+)] improved OS and DFS compared to a recipient TT genotype [R(M-)] (75 vs. 53%, p<0.001; 66 vs. 47%, p<0.001), which was primarily due to a lower risk of relapse/progression (24% vs. 38%, p=0.012). In regard to total iKIR ML, the presence of 2-3 ML was associated with better overall (OS) and disease-free (DFS) survival compared with 0-1 (67% vs. 57%, p=0.08; 62% vs. 48%, p=0.019), which was due to lower relapse/progression (25% vs. 38%, p=0.015). There was no association of either recipient B-leader or total iKIR ML with the incidence of NRM, acute or chronic GVHD. When recipient B-leader and ML were combined, the detrimental effect of a R(M-) genotype was seen exclusively in patients with ML 0-1 (see figure). DFS for R(M-)/ML(0-1), R(M+)/ML(0-1), R(M-)/ML(2-3), R(M+)/ML(2-3) was 36%, 68%, 65% and 60%, respectively (p<0.001). Corresponding relapse/progression rates were 49%, 22%, 26% and 25%, respectively (P<0.001). In multivariate analysis, controlling for patient age/sex/race, disease risk index, donor age, HLA-DR mm, HLA-DP npmm and year of transplantation, both recipient B leader and total iKIR ML were independently associated with DFS (HR 0.57, p=0.002 and HR 0.67, p=0.026) and relapse/progression (HR 0.55, p=0.006 and HR 0.55, p=0.007). In summary, a recipient M-containing B-leader genotype (MM or MT) reduces relapse and improves survival following HIDT-PTCy, presumably through HLA-E-mediated effector cell engagement. Furthermore, the negative consequences of low total ML for iKIR, in terms of increased relapse risk and lower DFS, can be mitigated when a R(M+) B-leader is present. In addition to the clinical importance of this novel finding for optimizing HIDT-PTCy, it further supports the role of alloreactive donor NK cells for optimal GVL in this context. [Display omitted] DisclosuresSolh: Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; BMS: Consultancy.

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

Detection and Genotyping of Fov4 (Race 4, VCG0114), the Fusarium Wilt Pathogen of Cotton.

Fusarium wilt, caused by Fusarium oxysporum f. sp. vasinfectum (Fov), is an important disease of cotton. More than 14 different genotypes as determined by VCG and sequence analyses are known to occur in the United States. Fov4 (race 4, VCG0114), originally found in India, was first detected in the United States in 2001 in California and recently in 2017 and 2019 in Texas and New Mexico, respectively. Four sub-genotypes of Fov4 have been identified, with Fov4 N, T, and MiT genotypes occurring in California, and Fov4 T and MT genotypes occurring in Texas. Unlike other genotypes of Fov in the United States, Fov4 does not require the presence of root-knot nematodes (Meloidogyne incognita) to cause severe wilt in cotton and is a major concern to US cotton growers. Fov4 can be spread through a variety of mechanisms including through infected seed. Once a field is infested, the fungus becomes endemic since there are no economically viable means to eradicate the pathogen from infested fields. Therefore, a rapid and accurate detection method is essential for early identification of infested fields and seed lots to prevent further spread of Fov4. This chapter describes multiplex and singleplex PCR diagnostics for detection of Fov4, and for detection and genotyping N, T, MiT, and MT genotypes of Fov4 from wilted cotton plants.

Association of soluble ST2, M235T polymorphism of ATG with insulin resistance in diabetic patients with heart failure with preserved ejection fraction

Abstract Background It has been shown that the level of the soluble form of suppression of tumorigenicity 2 (sST2) is associated with an unfavorable course of heart failure (HF). On other hand, has been shown a strong influence of ATG polymorphism on HF development. However, the association of M235T polymorphism of ATG and sST2 level with insulin resistance in diabetic patients with HF with preserved ejection fraction (HFpEF) is still unknown. Purpose To investigate the association between sST2, different types of M235T polymorphism of ATG and insulin resistance in patients with HFpEF and T2DM. Methods A total of eighty-one patients (49 females and 32 males; mean age 62,5±7,3 years) with HFpEF and type 2 diabetes mellitus (T2DM) were examined. Twenty patients had MM genotype, 38 patients had MT genotype and 23 had TT genotype of M235T polymorphism of ATG, which was determined by using of polymerase chain reaction. sST2 was determined by using kits of reagents “PresageST2” (USA). The mean value of sST2 was determined, patients were divided according to the mean. The HOMA-IR was calculated to determine insulin resistance. All statistical tests were 2-tailed and performed in Statistica 10.0, p&amp;lt;0.05 was considered statistically significant. Results In the group of HFpEF and T2DM with sST2&amp;gt;24.4 ng/ml the HOMA-IR was significantly higher than in the group with sST2&amp;lt;24.4 ng/ml and was 16.24±1.22 and 9.30±1.30, respectively (p&amp;lt;0.05). The HOMA-IR was higher in the TT genotype group compared with carriers of M allele. (p&amp;lt;0.05) (Table 1). Conclusion High circulating level of sST2 and TT genotype of the M235T polymorphism of the ATG presence was associated with increased insulin resistance in patients with HFpEF and T2DM. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): government funding Table 1

Characterization of Current Fusarium oxysporum f. sp. vasinfectum Isolates from Cotton in the San Joaquin Valley of California and Lower Valley El Paso, Texas.

Fusarium oxysporum f. sp. vasinfectum race 4 is a causal agent of Fusarium wilt of cotton (Gossypium spp.). This study aimed to characterize the existing distribution and frequency of current field populations of F. oxysporum f. sp. vasinfectum race 4 genotypes in the San Joaquin Valley (SJV) of California and Lower Valley El Paso, TX and examine representative isolates for aggressiveness during different stages of seedling development. A survey was conducted from 2017 to 2019 across 13 locations in the SJV and one location in El Paso, TX during 2018. From the SJV, isolates identified as the F. oxysporum f. sp. vasinfectum race 4 T genotype were dispersed across the SJV, whereas isolates identified as the F. oxysporum f. sp. vasinfectum race 4 N genotype were most frequently isolated from cotton fields in the northern county of Merced. The F. oxysporum f. sp. vasinfectum race 4 isolates from the Texas location were identified as the MT genotype. A selection of representative isolates was evaluated using three inoculation assays (rolled-towel, F. oxysporum f. sp. vasinfectum-infested oat seed, and root-dip inoculation) to test the isolates' abilities to produce symptoms during seedling stages of cotton development. All isolates tested were capable of producing symptoms on cotton; however, isolate aggressiveness varied within and across inoculation assays. In all assays, higher levels of disease development were observed in the moderately susceptible Pima (Gossypium barbadense L.) cultivars (DP-340 or PHY-830) when compared with the moderately tolerant Upland (G. hirsutum L.) cultivar (FM-2334). However, no correlation was found among the different response variables for the rolled-towel assay when compared with the root-dip and infested oat seed assays. These results suggest that different genes are involved in the resistance response during the early seedling development stage measured in the rolled-towel assay compared with the later seedling development stages measured during the root-dip inoculation and infested oat seed assays, revealing the complexity of the Fusarium wilt disease and host-plant resistance mechanisms.

ASSOCIATION OF AGT GENE M235T AND ACE GENE I/D POLYMORPHISMS WITH HYPERTENSION IN MONGOLIAN POPULATION

Objective: In Mongolia, hypertension is major public health problem due to its high prevalence of stroke and mortality rate. The objective of this study was to analyse the relationship between AGT M235T gene variant and ACE I/D gene variant with hypertension in a sample of the Mongolian population of the Ulaanbaatar city. Design and method: Design and Method: A case-control study has been performed in 146 subjects including 96 hypertensives and 50 normo-tensive subjects, aged 18–60 years. Hypertension was defined as systolic BP =&gt;130 mm Hg and/or diastolic BP=&gt;80 mm Hg). After isolation DNA from peripheral blood, the following specific primers were used for polymerize chain reaction (PCR). PCR purification kit and QIAquick Gel extraction kit were used to establish nucleic acid sequence. Results: The mean age of the participants was 39.6 years and 54.7% were men. The M235T variant of AGT gene was identified in 97.9% of all participants (96.8% of hypertensive patients and 100% of normotensive subjects). According to the genotype results, the frequencies of the AGT TT, MT and MM genotypes were 57.3%, 39.6%, and 3.1% in cases and 64.0%, 36.0% and 0.0% in controls respectively. The genotypic distribution of the M235T variant of the AGT gene did not differ in hypertensives and normotensives group (p &gt; 0.328). In this study, we did not observe any significant differences in blood pressure levels with regard to ACE gene I/D polymorphism in both hypertensive and normotensive groups (40% vs 38%, p &gt; 0.543). Conclusions: Conclusion: This is the first report on the frequency of AGT and ACE gene polymorphisms among Mongolian population. About 97.9% of Mongolians carry the M235T variant of the AGT gene that makes them more prone to hypertension when they eat too much sodium.

Interactions between cotton genotypes and Fusarium wilt race 4 isolates from Texas and resistance evaluation in cotton

AbstractFusarium wilt, caused by the soil‐borne fungus Fusarium oxysporum f. sp. vasinfectum (FOV) race 4 (FOV4), is one of the most destructive diseases in cotton (Gossypium spp.) in the southwestern and western Cotton Belt. However, the virulence of FOV4 is currently unknown. In this study, 17 FOV isolates collected in the Fabens, TX, area were determined to be FOV4 based on FOV4‐specific polymerase chain reaction (PCR) and sequence analysis of three genes encoding for translation elongation factor, β‐tubulin, and phosphate permease. A further multiplex PCR analysis determined that they all belonged to the Tfo1/MULE MT genotype. Based on disease severity ratings (DSR) on two upland and two pima cotton lines in the greenhouse, virulence of the 17 FOV4 isolates differed but was overall congruent on the four lines, and differences among cotton genotypes accounted for 82% of the total variance. Variance in virulence due to FOV4 isolates and FOV4 isolate × cotton genotype interaction each accounted for only 8–11% of the total variance. A virulent MT FOV4 isolate was used to inoculate 104 entries representing 92 cultivars and elite lines in two tests at 21–23 °C. The combined ANOVA detected a significant genotypic variation in DSR with moderate broad‐sense heritability estimates (.62–.69). About 90–91% of the genotypes were susceptible to FOV4, including 100% mortality in 59–91% of the genotypes. Pima PHY 805 RF and three upland cultivars including FM 2334GLT, Acala 1517‐08, and Acala Daytona RF had similar resistance responses to the resistant check pima PHY 841 RF. This study demonstrated that cotton genotypes played a predominant role in determining FOV4 virulence, reinforcing the validity of using a representative isolate to screen cotton for FOV4 resistance.

Association Between AGT M235T and Left Ventricular Mass in Vietnamese Patients Diagnosed With Essential Hypertension.

Background: Increasing left ventricular mass in hypertensive patients is an independent prognostic marker for adverse cardiovascular outcomes. Genetic factors have been shown to critically affect left ventricular mass. AGT M235T is one of the genetic polymorphisms that may influence left ventricular mass due to its pivotal role in the regulation of plasma angiotensinogen level as well as hypertension pathophysiology in Asian populations. Currently, how M235T affects left ventricular mass is not well-described in Vietnamese hypertensive patients. This study aimed to investigate the association between M235T and left ventricular mass in Vietnamese patients diagnosed with essential hypertension.Materials and Methods: AGT M235T genotyping and 2D echocardiography were performed on 187 Vietnamese subjects with essential hypertension. All the ultrasound parameters were obtained to calculate the left ventricular mass index according to the American Society of Echocardiography and the European Association of Cardiovascular Imaging 2015 guidelines. Other clinical characteristics were also recorded, including age, gender, duration of hypertension, hypertensive treatment, lifestyle, renal function, fasting plasma glucose, and lipid profile.Results: MT and TT genotypes were determined in 30 and 157 subjects, respectively. AGT M235T genotype, duration of hypertension, body mass index, and ejection fraction statistically affected the left ventricular mass index, which was significantly greater in TT compared to MT carriers after adjusting for confounding factors.Conclusion: The TT genotype of AGT M23T was associated with greater left ventricular mass in Vietnamese patients diagnosed with essential hypertension.

A study of the association between angiotensinogen (AGT) gene polymorphism (M235T) and preeclampsia in Thai pregnant women

AGT M235T gene polymorphism may cause increased blood pressure in preeclampsia in pregnancy; however, the evidence remains controversial. This study investigated the association between AGT M235T and preeclampsia in Thai pregnant women. A case-control study was conducted to compare the distributions of AGT M235T genotypes and alleles between 142 normotensive pregnancies as controls and 61 preeclampsia pregnancies as cases in a tertiary-care university hospital in Chiang Mai, Thailand. The results show that the distribution of AGT M235T genotypes (MM, MT and TT) of both groups were not significantly different (preeclampsia: 0.0, 16.4, 83.6%; control: 2.1, 22.5, 75.4%, respectively; p = .30). Additionally, there was no statistical difference in the distribution of AGT M235T alleles (M and T alleles) (preeclampsia: 8.2 and 91.8% versus control: 13.4 and 86.6%, respectively; p = .14). In this study, the distributions of AGT M235T were not different in both groups. Therefore, AGT M235T polymorphism may not play a significant role in preeclampsia pathophysiology in Thai population. Impact statement What is already known on this subject? Preeclampsia is one of the major complications during pregnancy; it significantly affects maternal and perinatal morbidity and mortality. Effort has been made to find markers and predictors that are associated with the pathophysiology of preeclampsia. AGT M235T gene polymorphism may cause increased blood pressure in preeclampsia pregnancy; however, evidences are still controversial. What do the results of this study add? We conducted a case-control study to compare the distributions of AGT M235T genotypes and alleles between 142 normotensive pregnancies as controls and 61 preeclampsia pregnancies as cases. The results show that preeclamptic women are more likely to deliver at an earlier gestational age and have a smaller baby in comparison with the normotensive group. In addition, women with preeclampsia had a higher chance of having an operative delivery and caesarean section. However, the distribution of AGT M235T polymorphism of preeclampsia women and the control group were not significantly different. What are the implications of these findings for clinical practice and/or further research? AGT M235T polymorphism may not play a significant role in preeclampsia pathophysiology in Thai population.

HLA-B leader and survivorship after HLA-mismatched unrelated donor transplantation

AbstractHematopoietic cell transplantation (HCT) from HLA-mismatched unrelated donors can cure life-threatening blood disorders, but its success is limited by graft-versus-host disease (GVHD). HLA-B leaders encode methionine (M) or threonine (T) at position 2 and give rise to TT, MT, or MM genotypes. The dimorphic HLA-B leader informs GVHD risk in HLA-B–mismatched HCT. If the leader influences outcome in other HLA-mismatched transplant settings, the success of HCT could be improved for future patients. We determined leader genotypes for 10 415 patients receiving a transplant between 1988 and 2016 from unrelated donors with one HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatch. Multivariate regression methods were used to evaluate risks associated with patient leader genotype according to the mismatched HLA locus and with HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1 mismatching according to patient leader genotype. The impact of the patient leader genotype on acute GVHD and mortality varied across different mismatched HLA loci. Nonrelapse mortality was higher among HLA-DQB1–mismatched MM patients compared with HLA-DQB1–mismatched TT patients (hazard ratio, 1.35; P = .01). Grades III to IV GVHD risk was higher among HLA-DRB1–mismatched MM or MT patients compared with HLA-DRB1–mismatched TT patients (odds ratio, 2.52 and 1.51, respectively). Patients tolerated a single HLA-DQB1 mismatch better than mismatches at other loci. Outcome after HLA-mismatched transplantation depends on the HLA-B leader dimorphism and the mismatched HLA locus. The patient's leader variant provides new information on the limits of HLA mismatching. The success of HLA-mismatched unrelated transplantation might be enhanced through the judicious selection of mismatched donors for a patient's leader genotype.

Mutation density changes in SARS-CoV-2 are related to the pandemic stage but to a lesser extent in the dominant strain with mutations in spike and RdRp

Since its emergence in Wuhan, China in late 2019, the origin and evolution of SARS-CoV-2 have been among the most debated issues related to COVID-19. Throughout its spread around the world, the viral genome continued acquiring new mutations and some of them became widespread. Among them, 14408 C>T and 23403 A>G mutations in RdRp and S, respectively, became dominant in Europe and the US, which led to debates regarding their effects on the mutability and transmissibility of the virus. In this study, we aimed to investigate possible differences between time-dependent variation of mutation densities (MDe) of viral strains that carry these two mutations and those that do not. Our analyses at the genome and gene level led to two important findings: First, time-dependent changes in the average MDe of circulating SARS-CoV-2 genomes showed different characteristics before and after the beginning of April, when daily new case numbers started levelling off. Second, this pattern was much delayed or even non-existent for the “mutant” (MT) strain that harbored both 14408 C>T and 23403 A>G mutations. Although these differences were not limited to a few hotspots, it is intriguing that the MDe increase is most evident in two critical genes, S and Orf1ab, which are also the genes that harbor the defining mutations of the MT genotype. The nature of these unexpected relationships warrants further research.

Association of angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen (AGT M235T) polymorphisms with the risk of obesity in a Tunisian population.

Objective:This study aims to determine whether genetic variants in ACE I/D and AGT M235T are associated with overweight-obesity and body mass index (BMI) in a Tunisian population.Methods:We designed an age- and sex-matched case-control study. The height and weight were measured and BMI was calculated. A total of 259 overweight-obese patients and 369 healthy controls were genotyped for the ACE I/D and AGT M235T genes using polymerase chain reaction and restriction fragment length polymorphism.Results:ACE I/D and AGT M235T genes were associated with BMI, waist circumference and overweight-obesity (p⩽0.001). In an additive model, the I and the M alleles in ACE and AGT variants, respectively, were associated with a lower BMI: –1.45 and −2.29 units, respectively. ACE I/D genotypes were associated with dyslipidemia; AGT M235T genotypes with dyslipidemia and total cholesterol.Conclusion:These data suggest that variations in ACE I/D and AGT M235T affect the risk of overweight-obesity, BMI and dyslipidemia, and could point to a key molecular pathway of metabolic syndrome and its related comorbidities.

Role of HLA-B exon 1 in graft-versus-host disease after unrelated haemopoietic cell transplantation: a retrospective cohort study

The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. The National Institutes of Health, USA.

Selenium restricts cadmium uptake and improve micronutrients and proline concentration in tomato fruits

Abstract In order to identify the beneficial effects of Selenium (Se) in tomato (Solanum lycopersicum), genotypes MT and hp1, under Cadmium (Cd) toxicity, the following analyses were performed: Cd and Se concentration and translocation index in roots, leaves and fruits as well as the macro and micronutrients quantification, proline concentration, fruits dry weight, chlorophyll and carotenoids concentration in fruits. Se reduced the Cd concentration in roots of both genotypes. The Cd translocation to above ground parts were restricted by Se only in the MT genotype. Fruit proline concentration increased either in genotype hp1 when Se was applied alone or in the MT genotype, by the mixture of Se and Cd. When Se was applied alone the concentration of Mn and Zn in hp1 fruits and Fe in MT fruits were enhanced. The beneficial mechanisms of Se to tomato plants under Cd stress could be partially related to the restriction of Cd uptake and translocation, enhancing proline concentration and micronutrient improvements in fruits.

Gene polymorphisms of angiotensin-converting enzyme and angiotensinogen and risk of idiopathic ischemic stroke

ObjectiveThe renin-angiotensin system (RAS) is a hormonal signaling mechanism implicated in the atherosclerosis and regulation of blood pressure. Angiotensin-converting enzyme (ACE) a key enzyme in the RAS, plays important roles in vascular remodeling atherosclerosis, and ischemic stroke. The aim of this study was to examine the possible contribution of the I/D in the ACE gene, M235T and T174M in the angiotensinogen (AGT) gene polymorphisms with ischemic stroke in young Mexican population. Materials and methodsA total of 224 patients with diagnosis of idiopathic ischemic stroke ≤45 years of age, and 224 controls matched by age and gender, were recruited from 2006 and 2016. The I/D, M235T and T174M polymorphisms were determined in all participants by PCR-RFLP. ResultsThere was a significant difference in the M235T genotype distribution (p = 0.01) and allele frequency between two groups (p = 0.01). Also, we found a significant difference in the T174M genotype distribution (p = 0.01) and the allele frequency between groups; (p = 0.02). In contrast, in I/D polymorphism, there was a similar genotype distribution; (p = 0.20) and allele distribution (p = 0.20). There were independent factors for ischemic stroke: M235T and T174M polymorphisms, smoking, hypertension, and familial history of atherothrombotic disease. The AGT levels were increased in the group of patients with stroke compared with the control group, but the AGT levels were not influenced by the allele or genotype in each polymorphism. ConclusionsThe M235T and T174M polymorphisms represented an increased risk for stroke in young Mexican individuals. In contrast, the I/D was not associated with in the same group of patients. The AGT levels were higher in the acute phase of stroke, but it was not determined by the polymorphisms.