MM 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.

Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

The relationship between G1 (c.260 G>A) and G4 (c.721 G>A) polymorphisms in the GDF9 gene and the litter size of sheep: A meta-analysis study.

The results of G1 and G4 polymorphisms as litter-size (LS) markers of ewes remain contradictory. The aim was to evaluate the impact of G1 (c.260 G>A) and G4 (c.721 G>A) polymorphisms on the LS of sheep by synthesizing data from multiple previous studies. Data were extracted from 14 eligible articles. The genotypes of G1 and G4 polymorphisms were homozygous wild-type (WW), heterozygous (WM), and homozygous mutant-type (MM). The standardized mean difference (SMD) method using random effect models was employed to determine the effect size of G1 and G4 polymorphisms on LS under dominant, recessive, additive, and co-dominant genetic models. Heterogeneity was analyzed with the I2 statistic index. Publication bias was depicted with funnel plots and tested by Egger's and Begg's tests. The study showed that the correlation between G1 polymorphism and LS in sheep was not significant (p > 0.05) under all genetic models. The influence of G4 polymorphism on the LS of sheep was found significantly (p < 0.05) under dominant [SMD = 0.28, I2 = 0% (no heterogeneity)] and co-dominant [SMD = -0.14, I2 = 36% (moderate heterogeneity)] genetic models. The WM genotype of G4 polymorphism increased LS, while the MM genotype reduced LS in sheep. Publication bias among G1 and G4 polymorphism studies was absent in all genetic models. Thus, the study revealed that G4 polymorphism could be a potential genetic marker for LS in ewes. On the contrary, G1 polymorphism has no association with the LS of ewes.

Real‐time quaking‐induced conversion assay using a small‐scale substrate production workflow for the diagnosis of Creutzfeldt‐Jakob disease

AbstractBackgroundThe lack of a dedicated surveillance program for prion disease, particularly in low‐ and middle‐income countries (LMICs), has hindered the global effort to address this public health threat. Although CSF Real‐time quaking‐induced conversion (RT‐QuIC) is considered the most reliable test for sporadic Creutzfeldt‐Jakob disease (sCJD), its availability in LMICs is limited due to its cost and technical difficulty in generating the recombinant prion protein substrate (recPrP). This study aimed to evaluate the performance of RT‐QuIC with recPrP produced in‐house through a small‐scale method – i.e. the application of reusable pre‐packed chromatography columns and subsequent dialysis.MethodCSF specimens from patients suspected of having prion disease were consecutively collected and stored between October 2015 and November 2022. Those with available CSF for RT‐QuIC analysis were included in this study. Electronic medical record data were reviewed to clinically classified participants as probable sCJD or non‐sCJD. CSF RT‐QuIC was performed using in‐house recPrP and 2nd generation (improved‐QuIC) protocol (Orrú et al., 2015). Its specificity and sensitivity for diagnosing probable sCJD were reported, along with details of other clinical data and investigations.ResultAmong 38 eligible participants, with a median (interquartile range) age of 64 (56.5‐70) years and 15 (39.5%) female, 12 had probable sCJD and the remaining 26 unequivocally suffered from non‐prion disorders. MRI and EEG were suggestive of sCJD in 100% (12/12) and 50% (6/12) of sCJD participants, respectively. PRNP gene sequencing was performed in all sCJD and 7 non‐sCJD participants, all of whom had MM genotype without mutation. RT‐QuIC was positive in 11/12 sCJD participants (sensitivity 0.92, 95% confidence interval (CI) 0.65‐0.99) and negative in all non‐sCJD participants (specificity 1.00, 95%CI 0.87‐1.00). CSF tau/p‐tau ratio showed sensitivity and specificity of 0.67‐1.0 and 0.85‐1.0, respectively.ConclusionRT‐QuIC using recPrP generated through a small‐scale workflow demonstrated great performance in detecting sCJD. Given its performance results along with its low cost, this technique could feasibly be implemented in LMICs and potentially be the first step towards establishing local prion disease surveillance programs that will strengthen the global efforts.

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 &amp;lt; 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.

The association of paraoxonase I gene polymorphisms Q192R (rs662) and L55M (rs854560) and its activity with metabolic syndrome components in fars ethnic group.

Metabolic syndrome (MetS) may cause premature development of some diseases. PON1 genes may be involved in the pathogenesis of MetS. The aim of study was to evaluate the association between Q192R and L55M gene polymorphisms and its enzyme activity with the MetS components in subjects with and without MetS. Polymerase Chain Reaction and Restriction Fragment Length Polymorphism analysis were performed to determine polymorphisms of the paraoxonase1 gene in subjects with and without metabolic syndrome. Biochemical parameters were measured by spectrophotometer. The MM, LM, and LL genotype frequencies of the PON1 L55M polymorphism were 10.5, 43.4, and 46.1%, and 22.4, 46.6, and 31% and; the QQ, QR, and RR genotype frequencies of the PON1 Q192R polymorphism were 55.4, 38.6 and 6%; and 56.5, 34.8 and 8.7% in subjects with and without MetS, respectively. The L and M allele frequencies were 68 and 53%; and 32 and 47% for PON1 L55M in subjects with and without MetS, respectively. The Q and R allele frequencies for PON1 Q192R were 74 and 26% in both groups. There were significant differences in HDL-cholesterol level and PON1 activity in the genotypes QQ, QR, and RR of the PON1 Q192R polymorphism in subjects with MetS. The PON1 Q192R genotypes had only effected on PON1 activity and HDL-cholesterol level in subjects with MetS. Different genotypes of the PON1 Q192R seem to be important candidates to make the subjects susceptible to MetS in the Fars ethnic group.

Correlations of synergistic effect of glucocorticoids on tacrolimus with CYP3A, MDR1 and PXR gene polymorphisms in pediatric patients receiving liver transplantation for malignancy and chronic liver disease

Immune suppression after liver transplant for malignancy, such as hepatocellular carcinoma and end stage liver disease is done using immunosuppressant drugs like tacrolimus. As the immune system in children is not fully developed, combining immunosuppressants like glucocorticoids influence the efficacy and reduce the chances of transplant rejection, particularly in patients with gene polymorphism. However, whether interaction between glucocorticoid and tacrolimus is associated with CYP3A, MDR1, and PXR gene polymorphisms, remains unclear. Here, we explored correlations of synergistic effect of glucocorticoids on tacrolimus with CYP3A, MDR1 and PXR gene polymorphisms in pediatric patients receiving liver transplantation for malignancy and chronic liver disease. A total of 340 eligible children were divided into glucocorticoid (+) (n=148) and glucocorticoid () groups (n=192). They were given tacrolimus + mycophenolate mofetil, based on which glucocorticoid (+) group took prednisone acetate tablets for ≥12 months. The blood trough concentration of tacrolimus was detected by chemiluminescence microparticle immunoassay 1, 3, 6 and 12 months after medication, and blood drug concentration corrected by daily concentration/daily dose (C0/D) was calculated. CYP3A, MDR1 and PXR gene polymorphisms were analyzed using PCR-RFLP. GG, AG and AA genotypes of CYP3A were observed in 130, 166 and 44 cases, respectively. CC, CT and TT genotypes of MDR1 were found in 152, 142 and 46 cases, respectively. There were 252, 74 and 14 cases of WW, WM and MM genotypes of PXR, respectively. The distribution frequencies of GG and AG+AA genotypes had significant differences between the two groups. One month after medication, C0/D of tacrolimus of GG genotype in glucocorticoid (+) group significantly exceeded that of glucocorticoid () group. C0/D was significantly higher in glucocorticoid (+) group with AG+AA genotype1, 3, 6 and 12 months after medication (P &lt;0.05).

Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype

Background & AimsAlpha-1 antitrypsin deficiency is caused by mutations in SERPINA1, most commonly homozygosity for the Pi∗Z variant, and can present as liver disease. While heterozygosity for Pi∗Z (Pi∗MZ) is linked to increased risk of cirrhosis, whether the Pi∗MZ genotype is associated with an increased rate of decompensation among patients who already have compensated cirrhosis is not known.MethodsThis was a retrospective study of Michigan Genomics Initiative participants with baseline compensated cirrhosis. The primary predictors were Pi∗MZ or Pi∗MS genotype (vs. Pi∗MM). The primary outcomes were hepatic decompensation with ascites, hepatic encephalopathy, or variceal bleeding, or the combined endpoint of liver-related death or liver transplant, both modeled with Fine-Gray competing risk models.ResultsWe included 576 patients with baseline compensated cirrhosis who had undergone genotyping, of whom 474 had Pi∗MM, 49 had Pi∗MZ, and 52 had Pi∗MS genotypes. Compared to Pi∗MM genotype, Pi∗MZ was associated with increased rates of hepatic decompensation (hazard ratio 1.81; 95% CI 1.22-2.69; p = 0.003) and liver transplant or liver-related death (hazard ratio 2.07; 95% CI 1.21-3.52; p = 0.078). These associations remained significant after adjustment for severity of underlying liver disease, and were robust across subgroup analyses based on etiology, sex, obesity, and diabetes status. Pi∗MS was not associated with decompensation or death/transplantation.ConclusionsThe SERPINA1 Pi∗MZ genotype is associated with an increased rate of hepatic decompensation and decreased transplant-free survival among patients with baseline compensated cirrhosis.Lay summaryThere is a mutation in the gene SERPINA1 called Pi∗MZ which increases risk of liver scarring (cirrhosis); however, it is not known what effect Pi∗MZ has if someone already has cirrhosis. In this study, we found that people who had cirrhosis and Pi∗MZ developed complications from cirrhosis faster than those who did not have the mutation.

Impact of PNPLA3 p.I148M and Hepatic Steatosis on Long-Term Outcomes for Hepatocellular Carcinoma and HBsAg Seroclearance in Chronic Hepatitis B.

BackgroundCoexistence of hepatitis B and nonalcoholic fatty liver disease is common; however, little is known about the impact of hepatic steatosis and its major genetic determinants on the natural history of HBV infection. We aimed to study the effects of hepatic steatosis and PNPLA3 variant p.I148M on the risk of hepatocellular carcinoma (HCC) and the lifetime probability of HBsAg seroclearance, which is associated with functional remission and improved long-term outcome of HBV infection.MethodsWe conducted a cohort study of 2385 male, HBsAg-positive Taiwanese civil servants recruited in 1989–1992, and followed up until 2019. Cox regression with competing-risk models was used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs).ResultsOf 2385 participants, 628 experienced HBsAg seroclearance and 217 developed HCC. Hepatic steatosis, excess body-mass index, and the PNPLA3-148M variant were significantly associated with higher HBsAg seroclearance rate. However, multivariate analyses accounting for HBsAg seroclearance and various HCC risk factors showed that, while steatosis was associated with decreased HCC risk (sHR [95% CI]: 0.49 [0.36–0.66]), carriage of the PNPLA3-148M variant allele (vs II homozygotes: 1.64 [1.20–2.25] for MI heterozygotes; 1.83 [1.20–2.78] for MM homozygotes) and obesity (1.51 [1.07–2.13]) were associated with increased risk. The inverse hepatic steatosis-HCC association persisted after additional adjustment for other viral factors or using different follow-up time cut-offs to account for reverse causality. Moreover, the PNPLA3 MM genotype was positively associated with elevations of ALT and AST and liver cirrhosis, while hepatic steatosis was positively associated with ALT but inversely associated with AST and liver cirrhosis.ConclusionHepatic steatosis and PNPLA3-148M variant appeared to have distinct impacts on the development of HBV-related progressive liver disease and HCC. PNPLA3 p.I148M, but not a diagnosis of hepatic steatosis, can help to identify HBV carriers with high-risk fatty liver disease in the progression to HCC.

Association between CAST and MSTN gene polymorphisms with growth traits in Awassi sheep

This study aims to identify the association between CAST/MspI and MSTN/HaeIII polymorphism with growth traits in Awassi sheep. A total of 129 (male and female) Awassi sheep were used in the study. Growth traits (Body weight BW, body length BL, chest depth CD, heart girth HG and withers height WH) were taken from animals at one year old. PCR-RFLP analysis was used to detect CAST polymorphism (Exon 1C/1D) and MSTN (Exon 3) genes. Three genotypes (MM, MN and NN) were observed for CAST/MspI polymorphism with allele and genotype frequency 0.78(M) and 0.22(N); 0.70(MM), 0.16(MN) and 0.14(NN). Two genotypes (MM and mm) were found for MSTN/HaeIII polymorphism with allele and genotype frequency as 0.10(M) and 0.90(N); 0.10(MM) and 0.90(mm). The genes were in agreement with Hardy-Weinberg equilibrium (p&gt;0.05). The association analysis showed an association between CAST/MspI polymorphism and BW, BL, CD, HG and WH (P&lt;0.05; P&lt;0.10). The MM genotypes had the highest BW compared to MN and NN genotypes. Whereas the MN genotypes had the highest BL, CD, HG and WH compared to MM and NN genotypes. No association was found between MSTN/HaeIII polymorphism and growth traits.

The effect of paraoxonase 1 (PON1) gene polymorphisms T(-107)C and L55M and diet composition on serum PON1 activity in women.

The aim of this study was to evaluate the serum activity of PON1 in women according to SNPs L55M and T-107C and diet composition. Blood and serum samples from 26 women were used. DNA extraction, PCR and digestion with restriction enzymes of the PCR fragment were performed for genotyping the PON1 SNPs T-107C and L55M. Serum PON1 activity was measured in a single time point. Patients completed the semi-quantitative food frequency questionnaire and diet composition was estimated. Genotypic distribution for L55M SNP was 56% for the LL genotype, 32% for LM and 12% for MM; for the PON1 C(-107)T SNP it was 28% for the TT genotype, 41% for CT and 31% for CC. Individuals with C and L alleles had higher serum PON1 activity. Combining the two SNPs, we observed that individuals carrying the LL and CC genotypes had twice the activity of carriers of the TT and MM genotypes. Considering food intake, no significant difference was observed between genotypes and intake levels. PON1 T(-107)C and L55M SNPs exert a strong effect on serum PON1 activity in an additive manner and are more important than diet to predict serum PON1 activity.

Alpha-1 Antitrypsin MZ Heterozygosity Is an Endotype of Chronic Obstructive Pulmonary Disease.

Rationale: Multiple studies have demonstrated an increased risk of chronic obstructive pulmonary disease (COPD) in heterozygous carriers of the AAT (alpha-1 antitrypsin) Z allele. However, it is not known if MZ subjects with COPD are phenotypically different from noncarriers (MM genotype) with COPD. Objectives: To assess if MZ subjects with COPD have different clinical features compared with MM subjects with COPD. Methods: Genotypes of SERPINA1 were ascertained by using whole-genome sequencing data in three independent studies. We compared outcomes between MM subjects with COPD and MZ subjects with COPD in each study and combined the results in a meta-analysis. We performed longitudinal and survival analyses to compare outcomes in MM and MZ subjects with COPD over time. Measurements and Main Results: We included 290 MZ subjects with COPD and 6,184 MM subjects with COPD across the three studies. MZ subjects had a lower FEV1% predicted and greater quantitative emphysema on chest computed tomography scans compared with MM subjects. In a meta-analysis, the FEV1 was 3.9% lower (95% confidence interval [CI], -6.55% to -1.26%) and emphysema (the percentage of lung attenuation areas <-950 HU) was 4.14% greater (95% CI, 1.44% to 6.84%) in MZ subjects. We found one gene, PGF (placental growth factor), to be differentially expressed in lung tissue from one study between MZ subjects and MM subjects. Conclusions: Carriers of the AAT Z allele (those who were MZ heterozygous) with COPD had lower lung function and more emphysema than MM subjects with COPD. Taken with the subtle differences in gene expression between the two groups, our findings suggest that MZ subjects represent an endotype of COPD.

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

Association of the caprine calpastatin MspI polymorphism with growth and reproduction traits in Saanen goats

This study was designed to evaluate the effects of calpastatin (CAST) MspI polymorphism on some growth and reproduction traits, including birth weight, first breeding weight, litter size, and average daily weight gain in Saanen goats. In this sense, blood samples obtained from 73 purebred female Saanen goats were used for genotyping. Genomic DNA was isolated by the phenol-chloroform method and used to determine CAST genotypes, including MM, MN, and NN, by means of the PCR-RFLP method. The population genetic parameters were estimated based on allelic distribution and the data were statistically analysed using analysis of variance (ANOVA) using a general linear model (GLM). Results revealed that N allele frequency was remarkably high (0.64) and the MM genotype was not present. The frequency of the heterozygous genotype was 59.62%. Concerning ANOVA results, significant differences were found between genotypes of the CAST locus concerning birth weight (P&lt;0.05). In this respect, animals with the NN genotype were associated with higher birth weight means (2.85±0.29 kg) compared to heterozygous animals (2.53±0.24 kg). There was no significant association between the CAST marker and any of the remaining phenotypic traits evaluated. The present results suggest that focusing on this genomic region may be particularly useful in improving birth weight in goats which can be considered as an early indicator of post-weaning animal growth and survival.

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

Alpha-1 Antitrypsin and Hepatocellular Carcinoma in Liver Cirrhosis: SERPINA1 MZ or MS Genotype Carriage Decreases the Risk.

Heterozygotes for Z or S alleles of alpha-1-antrypsin (AAT) have low serum AAT levels. Our aim was to compare the risk of hepatocellular carcinoma (HCC) in patients with liver cirrhosis carrying the SERPINA1 MM, MZ and MS genotypes. The study groups consisted of 1119 patients with liver cirrhosis of various aetiologies, and 3240 healthy individuals served as population controls. The MZ genotype was significantly more frequent in the study group (55/1119 vs. 87/3240, p < 0.0001). The MS genotype frequency was comparable in controls (32/119 vs. 101/3240, p = 0.84). MZ and MS heterozygotes had lower serum AAT level than MM homozygotes (medians: 0.90 g/L; 1.40 g/L and 1.67 g/L; p < 0.001 for both). There were significantly fewer patients with HCC in the cirrhosis group among MZ and MS heterozygotes than in MM homozygotes (5/55 and 1/32 respectively, vs. 243/1022, p < 0.01 for both). The risk of HCC was lower in MZ and MS heterozygotes than in MM homozygotes (OR 0.3202; 95% CI 0.1361–0.7719 and OR 0.1522; 95% CI 0.02941–0.7882, respectively). Multivariate analysis of HCC risk factors identified MZ or MS genotype carriage as a protective factor, whereas age, male sex, BMI and viral aetiology of cirrhosis increased HCC risk.

Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients

Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt–Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

Association of M55L and Q192R polymorphisms of paraoxonase 1 gene (PON1) with recurrent pregnancy loss risk: A case-control study.

Background Recurrent pregnancy loss (RPL) refers to the incidence of two or more abortions before the first half of pregnancy. Oxidative stress has been hypothesized to play a central role in RPL.Objective To investigate the relationship between Q192R and L55M polymorphisms of PON1 as antioxidant enzyme and the risk of RPL.Materials and MethodsIn this case–control study, 110 women with RPL (case) and 110 healthy fertile women (control) referred to the Research and Clinical Center for Infertility, Shiraz, Iran were enrolled. Genomic DNA was extracted from the peripheral blood in all participants. Polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism method.ResultsStatistical analysis of Q192R polymorphism showed a significant difference for the RR genotype between the case and control group (OR = 11, CI = 1.39–86.87, p = 0.005) but none for the QR and QQ genotypes. No significant association was observed between the R and Q allelic frequency in the RPL participants compared to the control group (p = 0.53). Also, statistical analysis of the L55M polymorphism for MM genotype in the case group compared with the control group showed a significant difference (OR = 3.59, CI = 0.97–13.30, p = 0.042), but none for the LM and LL genotypes.ConclusionThe findings showed a significant correlation between the Q192R polymorphisms and the L55M PON1 enzyme and RPL in this study population.

ASSOCIATION BETWEEN TUMOR NECROSIS FACTOR, BRAIN NATRIURETIC PEPTIDE AND POLYMORPHISM OF THE M235T OF THE ATG GENE IN HYPERTENSIVE PATIENTS WITH HEART FAILURE

Objective: To investigate the association between tumor necrosis factor alfa (TNFa), N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and polymorphism of the M235T of the ATG gene in hypertensive patients with heart failure with preserved ejection fraction (HFpEF). Design and method: The main group of eighty-four patients (51 females and 33 males; mean age 62,7 ± 8,0 years) with HFpEF and arterial hypertension. Sixty-eight patients and eighteen healthy persons were carriers of 235T allele (MT+TT genotypes), sixteen patients had MM genotype of M235T polymorphism of ATG, determined by using of polymerase chain reaction. Levels of NTproBNP and TNFa were determined by enzyme-linked immunosorbent assay (ELISA) using «NTproBNP-BEST-ELISA» (Russia) and «TNFa-ELISA-BEST» (Russia), respectively. All statistical tests were 2-tailed and p &lt; 0,05 was considered statistically significant and performed in Statistica 10.0. Results: The significant difference in the level of TNFa in hypertensive patients with HFpEF depending on the different genotypes of M235T polymorphism of ATG was not found. Although the serum NTproBNP level increased in patients with MT+TT genotypes compared with patients with MM genotype (Table 1). Conclusions: The presence of T allele of M235T polymorphism of ATG in hypertensive patients with HFpEF was independently associated with increased level of NTproBNP

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.