T-allele Frequency Research Articles

The association between PTPN22 C1858T gene polymorphism and type 1 diabetes mellitus: an Indonesian study

Background Type 1 diabetes mellitus (T1DM) is disease caused by the destruction of β pancreatic cells. The activation of T-lymphocyte and proliferation inhibitor are induced by protein tyrosine phosphatase non-receptor type 22 (PTPN22). However, the link between PTPN22 C1858T gene polymorphism and T1DM is still controversy. This study aimed to analyse the C1858T gene polymorphism in Indonesian children with T1DM. Materials and methods This case-control study was conducted from March 2021 to May 2022 in the Endocrinology Outpatient Clinic at Dr. Soetomo Hospital and Tropical Disease Center Universitas Airlangga. Patients with controlled T1DM during the study period were included. The PTPN22 analysis used polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Results Sixty-two children voluntarily participated in this study, and were equally divided into the T1DM and control groups. Most of the patients (94%, 58/62) are Javanese. This study revealed a more frequent CC genotype (9.4%) and allele-C (54.6%) polymorphism in the T1DM group, while more frequent CT genotype (100%) and allele-T (50%) polymorphism were in the control group. The C- and T-allele frequency was 54.6% and 45.4% in the T1DM group, respectively. The T1DM and control groups did not significantly differ (p= .2381). Conclusions PTPN22 homozygous genotype-CC and allele-C polymorphisms are more frequent in patients with T1DM. However, the PTPN22 C1858T gene polymorphism did not significantly correlate to T1DM children in this study. Key Messages: The PTPN22 C1858T gene polymorphism does not significantly affect the susceptibility of T1DM in Indonesian children. PTPN22 homozygous genotype-CC polymorphism was more observed in the T1DM group; thus, this genotype may play as a risk factor for T1DM children in the Indonesian population.

MiR-146a, miR-196a2, miR-499, and miR-149 linked with susceptibility to acute lymphoblastic leukemia: A case-control study in Tunisia

BackgroundMicroRNAs (miRNAs) are promising biomarkers of hematological malignancies, including acute lymphoblastic leukaemia (ALL). Recent studies revealed that miRNA single nucleotide polymorphisms (miR-SNP) modulate cancer risk by regulating various signaling pathways. However, their association with altered risk of ALL yielded inconsistent results. ObjectiveThis study aims to investigate the association of four miR-SNPs with altered risk of ALL risk in Tunisian, the first on North African population. MethodsA retrospective case-control study exploring the association of miR-146a, miR-196a2, miR-499, and miR-149 SNPs in 126 ALL patients and 126 healthy controls. ResultsOf the tested variants, significantly lower minor allele frequencies (MAF) of miR-146a C-allele and higher MAF frequency of miR-149 T-allele (P = 0.006) were seen in ALL cases. The association of miR-149 rs2292832 (Pc = 0.02), but not miR-146a rs2910164 (Pc = 0.11) persisted after correcting for multiple comparisons. Significantly reduced prevalence of miR-146a G/C genotype and higher frequency of miR-149 C/T genotype were seen in ALL cases vs. control subjects, which translated into negative association of miR-146a (rs2910164) with ALL according to the codominant and dominant models. Similarly, miR-149 (rs2292832) was positively associated with ALL according to the codominant and dominant genetic models. Three combinations comprising miR-146a/miR-196a2 GG vs CT + TT genotype combination, miR-146a/miR-499 GG vs TC + CC genotype combination, and miR-146a/miR-149 GG vs CT + TT genotype combination, were less frequent in ALL patients than in controls, and were negatively associated with the presence of ALL. ConclusionOur study suggests that miR-146a and miR-149 polymorphisms constitute biomarkers for personalized diagnosis of ALL.

The MUC5B Promoter Polymorphism Associates With Severe COVID-19 in the European Population.

Background: Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 may be related to the innate immune response in the elderly. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele is a risk allele for the non-infectious aging lung disease idiopathic pulmonary fibrosis (IPF). We investigated if MUC5B rs35705950 associates with severe COVID-19.Methods: In this retrospective candidate gene case-control study we recruited 108 Dutch patients (69% male, median age 66 years, 77% white) requiring hospitalization for COVID-19 (22% ICU stay, 24% died). For validation, genotypes were obtained from the UK-Biobank (n = 436, 57% male, median age 70 years, 27% died), for replication data from the severe COVID-19 GWAS group from Italy (n = 835) and Spain (n = 775) was used, each with a control cohort (n = 356,735, n = 1,255, n = 950, respectively). MUC5B association analysis was performed including adjustment for age and sex.Results: The rs35705950 T-allele frequency was significantly lower in Dutch white patients (n = 83) than in controls (0.04 vs. 0.10; p = 0.02). This was validated in the UK biobank cohort (0.08 vs. 0.11; p = 0.001). While age and sex differed significantly between cases and control, comparable results were obtained with age and sex as confounding variables in a multivariate analysis. The association was replicated in the Italian (p = 0.04), and Spanish (p = 0.03) case-control cohorts. Meta-analysis showed a negative association for the T-allele with COVID-19 (OR = 0.75 (CI: 0.67–0.85); p = 6.63 × 10−6).Conclusions: This study shows that carriage of the T-allele of MUC5B rs35705950 confers protection from development of severe COVID-19. Because the T-allele is a known risk allele for IPF, this study provides further evidence for the existence of trade-offs between optimal mucin expression levels in the aging lung.

Impact on the Risk and Severity of Childhood Onset Schizophrenia of Schizophrenia Risk Genetic Variants at the DRD2 and ZNF804A Loci.

The study explored whether schizophrenia risk alleles of the DRD2 rs2514218 and ZNF804A rs1344706 polymorphisms also influenced the risk and severity of childhood-onset schizophrenia (COS) and differentiated it from autism spectrum disorders (ASD). We compared 75 children with COS to 75 children with ASD, 150 patients with adult-onset schizophrenia and 150 healthy individuals. Frequency of the DRD2 T-allele, assumed to be protective against schizophrenia overall, was higher in COS compared to adult-onset schizophrenia and healthy controls. The risk allele A of ZNF804A was associated with greater severity of negative symptoms in COS. The latter result is consistent with the involvement of ZNF804A in the development of severe forms of schizophrenia. The findings regarding DRD2 suggest that the same genetic variants may play different roles in schizophrenia with childhood and adult onset. This warrants further research, since D2 receptor blockade is a general pharmacodynamic property of antipsychotics.

Genetic Predictors of Type 2 Diabetes in Yakuts

The goal of this study was to investigate the distribution of alleles and genotypes of the KCNJ11 rs5219, PPARG rs1801282, TCF7L2 rs7903146/rs12255372 SNPs in Yakuts with T2D, in comparison with other ethnic populations. Methods and Results: The study cohort consisted of 26 Yakut patients diagnosed with T2D (YKT2D). Genotyping of rs5219 (KCNJ11), rs1801282 (PPARG), rs7903146 and rs12255372 (TCF7L2) SNPs was performed by pyrosequencing using PyroMark Q48 Autoprep sequencer (QIAGEN). The genotyping of the studied group of Yakuts did not reveal statistically significant differences between control groups and YKT2D patients with respect to the polymorphic variants of the KCNJ11, PPARG, and TCF7L2 genes. The allele frequency analysis of the polymorphisms of the KCNJ11, PPARG, and TCF7L2 genes demonstrated a low frequency of the risk T-allele in the TCF7L2 (rs7903146, rs12255372) in Asian populations, compared to other human populations. We identified three haplotypes [CG (90.5%), TT (6.8%), and TG (2.7%)] in the YKT2D cohort. Also, we observed a strong LD between two SNPs (rs7903146 and rs12255372) of the TCF7L2 gene in the majority of groups, including YKT2D (D '= 1, LOD = 4.92), except for African populations, where a very weak LD (D '= 0.001-0.435, LOD = 0.0-0.73) was observed.

C3435T Polymorphism of the ABCB1 gene in the Yakut Population

Background: The ABCB1 gene is responsible for resistance to various cytotoxic drugs. The product of the ABCB1 gene, P-glycoprotein (P-gp), acts as a transmembrane pump and influences the action of many drugs. More than 40 SNPs of the ABCB1 gene that alter the expression of P-gp have been identified. The ABCB1 rs1045642 SNP, designated as C3435T (C-the wild-type allele, T-the variant allele), correlates with the activity of P-gp. The aim of our research was to study the distribution of alleles and genotypes of the ABCB1 C3435T polymorphism in Yakuts, in comparison with other human populations. Methods and Results: The studied cohort included 149 healthy Yakut volunteers (36 men and 113 women). The average age of participants was 30.67±0.06 years. The ABCB1 gene is a highly polymorphic gene; the allele frequency of the C3435T polymorphism differs widely among the studied populations. The frequency of the mutant T-allele among the Yakuts was 51% .In the studied group of Yakuts, we revealed the prevalence of the heterozygous CT genotype (75.8%). The Yakuts have a relatively low frequency of CC (10.7%) and TT (13.4%) genotypes. This preliminary study did not include the objective of proving the relationship between the ABCB1 C3435T polymorphism and addictive disorders in Yakuts. The further search for functional polymorphisms of the ABCB1 gene and associations with addictive behavior using a systematic approach on larger samples is of great practical importance.

Clinical Relevance of VEGFA (rs3025039) +936 C>T Polymorphism in Primary Myelofibrosis: Susceptibility, Clinical Co-Variates, and Outcomes.

We evaluated the association of VEGFA rs3025039 polymorphism with clinical co-variates and outcomes in 849 subjects with primary myelofibrosis (PMF) and 250 healthy controls. Minor T-allele frequency was higher in subjects with JAK2V617F compared with those without JAK2V617F (18% vs. 13%; p = 0.014). In subjects with JAK2V617F, the TT genotype was associated at diagnosis with lower platelet concentrations (p = 0.033), higher plasma LDH concentration (p = 0.005), higher blood CD34-positive cells (p = 0.027), lower plasma cholesterol concentration (p = 0.046), and higher concentration of high-sensitivity C-reactive protein (p = 0.018). These associations were not found in subjects with PMF without JAK2V617F. In subjects with the TT genotype, risk of death was higher compared with subjects with CC/CT genotypes (HR = 2.12 [1.03, 4.35], p = 0.041). Finally, the TT genotype was associated with higher frequency of deep vein thrombosis in typical sites (12.5% vs. 2.5%; OR = 5.46 [1.51, 19.7], p = 0.009). In conclusion, in subjects with PMF, the VEGFA rs3025039 CT or TT genotypes are more common in those with JAK2V617F than in those without JAK2V67F mutation and are associated with disease severity, poor prognosis, and risk of deep vein thrombosis.

Polymorphisms in the Human Aquaporin 4 Gene Are Associated With Schizophrenia in the Southern Chinese Han Population: A Case-Control Study.

BackgroundIn psychiatric illness, pathogenic role of neuroinflammation has been supported by multiple lines of evidence. Astrocytes contribute to the blood-brain barrier (BBB) with formation of the “glymphatic” drainage system of the central nervous system (CNS) through perivascular processes. Found primarily at the end-feet of astrocytes, the aquaporin 4 (AQP4) gene has been suspected to play putative roles in the development of psychiatric disorders as well as the clearance of the glymphatic system. However, there remain many uncertainties because of the limited research on AQP4. The present study is focused on the association between AQP4 gene polymorphisms and schizophrenia (SCZ) in the Southern Chinese Han population.MethodsTwo hundred ninety-two patients and 100 healthy controls were enrolled in this study. To study the relationship of AQP4 gene polymorphisms and SCZ, genetic information was drawn from a cohort of 100 healthy controls and 100 matched patients with SCZ of Southern Han Chinese descent. Comparisons of the allele and genotype distributions between control and case groups were made using the χ2 test. Two-group comparisons were made to assess the linkage equilibrium and haplotype.ResultsThree SNPs were found. In comparison to healthy controls, patients had higher T-allele frequencies at rs1058424 and G-allele frequencies at rs3763043 (p = 0.043 and p = 0.045, respectively). Furthermore, there is an association between the decreased risk of SCZ and the AA genotype at both rs1058424 (p = 0.021, OR = 2.04) and rs3763043 (p = 0.018, OR = 2.25) The TCG haplotype (p = 0.036) was associated with a potential risk of SCZ, while the ACA haplotype (p = 0.0007) was associated with a decreased risk of SCZ and retained statistical significance after Bonferroni correction (p = 0.006).ConclusionsAn etiological reference for SCZ is provided by the association between AQP4 gene polymorphisms and SCZ in Southern Han Chinese population.

COLIA1 + 1245 G > T Sp1 Binding Site Polymorphism is Not Associated with ACL Injury Risks Among Indian Athletes.

Type I collagen polypeptides contribute significantly to the structural composition of ligament tissue matrix. Since anterior cruciate ligament (ACL) tears account for roughly 50% of all knee injuries in sports, the objective of the study was to investigate association of Sp1-transcription factor binding site polymorphism COLIA1 Sp1 + 1245 G > T with ACL injury risk among Indian athletes. A total of 166 athletes (90 with ACL tears and 76 as control) were recruited and were genotyped for COLIA1 Sp1 + 1245 G > T polymorphism using allele-specific PCR (AS-PCR) method. Both the groups were matched for nature of sports, training regimen, and other demographic characteristics. We observed no significant difference between ACL cases and control group in GT or TT genotype frequency distribution (p = 0.967) and T-allele frequency distribution (p = 0.861) for COLIA1 Sp1 + 1245 G > T polymorphism. Also, the three models of inheritance of minor allele failed to show any statistical significance in the present study. COLIA1 Sp1 + 1245 G > T polymorphism has been studied in relation to many connective tissue pathologies. This is probably the first study to investigate the association of collagen protein genes with ACL injury risk on Indian athletes. Further studies with more SNPs in genes encoding fibril-forming collagen and large sample sizes are necessary to fully understand the genetic link to ACL injuries among athletes.

The <i>MUC5B</i> Promotor Polymorphism Associates with Severe COVID-19 in the European Population

Diversity in response on exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is common and may be related to the innate immune response in the elderly. The mucin MUC5B is an important component of the innate immune response and expression levels are associated with the MUC5B promoter polymorphism, rs35705950. The high expressing T-allele is a risk allele for the non-infectious aging lung disease idiopathic pulmonary fibrosis (IPF). However, given the theory of trade-offs in aging lung disease and the importance of mucin expression for an adequate immune response, we hypothesized that the T-allele is protective against COVID-19 disease.Methods: MUC5B rs35705950 was genotyped for 108 Dutch patients requiring hospitalisation for COVID-19 at St Antonius Hospital. For replication, genotypes were obtained from the severe COVID-19 GWAS group for Italian (n=835) and Spanish (n=775) patients, and from the UK Biobank (n= 436 patients), each with respective control cohorts.Results: The minor T-allele frequency of rs35705950 was significantly lower in Dutch white patients (n=83) than in controls (0.04 vs 0.10; p=0.02). This finding was replicated in the Italian (0.10 vs 0.13; p=0.04), the Spanish (0.10 vs 0.13; p=0.03), and the UK (0.08 vs 0.11; p=0.001) white case-control cohorts. Meta-analysis showed a significant negative association for the T-allele with COVID-19 disease (0.75 (CI: 0.67–0.85); p=6.63e-06).Conclusions: The MUC5B rs35705950 promoter polymorphism associates with COVID-19. The risk allele (T) for IPF is protective against development of severe COVID-19. This is a further example of a trade-off in aging lung diseases.Funding: This study was funded by ZonMW TopZorg St Antonius Care grant nr 842002001; ZonMW Topspecialistische Zorg en Onderzoek grant nr 10070012010004; Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose COVID-19 grant; GW4 BioMed Medical Research Council Doctoral Training Partnership. Conflict of Interest: All authors declare no competing interests.Ethical Approval: The study was approved by The Medical research Ethics Committees United (MEC-U) of St. Antonius Hospital and all patients provided written informed consent (approval number R05-08A).

KLB gene polymorphism is associated with obesity and non-alcoholic fatty liver disease in the Han Chinese.

Klotho beta (KLB) mediates binding of fibroblast growth factor (FGF) 21 to the FGF receptor (FGFR). FGF21-KLB-FGFR signaling regulates multiple metabolic systems in the liver, and we hypothesized that FGF21, KLB and FGFR single-nucleotide polymorphisms (SNPs) are involved in hepatic lipid accumulation. The SNPs were detected in 1688 individuals divided into four groups: non-obese without non-alcoholic fatty liver disease (NAFLD), obese without NAFLD, non-obese with NAFLD, and obese with NAFLD. The A-allele of KLB SNP rs7670903 correlated with higher body mass index (P = 0.0005), and the A-allele frequency was higher in the obese than non-obese group (P = 0.003). The G-allele frequency of KLB rs7674434 and T-allele frequency of rs12152703 were higher in the obese with NAFLD than obese without NAFLD group (P = 0.004 and P = 0.006), but the genotype distribution between two non-obese groups did not differ. KLB rs7674434 and rs12152703 had associations with alanine aminotransferase (ALT) (P = 0.03 and P = 0.04, respectively) and gamma-glutamyltransferase (P = 0.03 and P = 0.02, respectively) levels in all subjects, but the associations were especially strong with ALT in the NAFLD group (P = 0.005 and P = 0.008, respectively). These findings suggest that KLB SNPs are related to obesity and hepatic inflammation and that they may be involved in the pathogenesis of NAFLD.

FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women.

FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women.

Low maternal folate concentrations and maternal MTHFR C677T polymorphism are associated with an increased risk for neural tube defects in offspring: a case-control study among Pakistani case and control mothers.

There is considerable evidence that periconceptional maternal folate deficiency and coding variants in maternal genes coding for critical enzymes in the folate pathway are associated with neural tube defects (NTDs) in offspring. In a case-control study we investigated C677T polymorphism in the 5,10- methylenetetrahydrofolate reductase (MTHFR) gene in case and control mothers of Pakistani origin, and compared these with the respective maternal folate concentrations measured at the time of delivery. A case-control study was conducted among 109 case and 100 control mothers identified through the Holy Family Hospital Rawalpindi, Quaid-i-Azam University, Islamabad, Pakistan. Red blood cell (RBC) and serum folate concentrations and MTHFRC677T polymorphism were compared between case and control mothers. Mean RBC folate and serum folate concentrations were significantly lower in cases compared with control mothers (p<0.0001). Maternal MTHFR 677CT and 677TT genotypes were more common among cases compared with control mothers (CC vs TT p<0.0393 and CC/CT vs TT p<0.021). T-allele frequency was higher in cases compared with control mothers (C vs T p<0.017). Case mothers with 677CT or 677TT genotypes had significantly lower serum (p<0.0001) and RBC folate concentrations (p<0.0001) compared with control mothers. The present study provides further evidence that maternal folate deficiency and MTHFRC677T polymorphism might be associated with an increased risk for NTDs in offspring. Our results are limited by the fact that maternal folate concentrations were not obtained during the periconceptional period, but at delivery. Further analyses, including maternal folate levels during the periconceptional period, are warranted.

PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity.

Single nucleotide polymorphisms (SNPs) of various genes increase susceptibility to monoglandular autoimmunity. Data on autoimmune polyglandular syndromes (APSs) are scarce. Evaluate potential associations of eight SNPs with APSs. Academic referral endocrine clinic. A total of 543 patients with APS and monoglandular autoimmunity and controls. The SNP protein tyrosine phosphatase nonreceptor type 22 (PTPN22) rs2476601 (+1858); cytotoxic T-lymphocyte‒associated antigen 4 (CTLA-4) rs3087243 (CT60) and rs231775 (AG49); vitamin D receptor (VDR) rs1544410 (Bsm I), rs7975232 (Apa I), rs731236 (Taq I); tumor necrosis factor α rs1800630 (-863); and interleukin-2 receptor alpha rs10795791 were tested by single-base extension in all subjects. The PTPN22 +1858 allele and genotype distribution were markedly different between APS, type 1 diabetes [T1D; odds ratio (OR): 2.67; 95% confidence interval (CI): 1.52 to 4.68; P = 0.001], Graves disease (GD; OR: 1.94; 95% CI: 1.16 to 3.25; P = 0.011), and controls (OR: 3.31, 95% CI: 1.82 to 6.02; P < 0.001). T-allele carriers' risk for APS was increased (OR: 3.76; 95% CI: 1.97 to 7.14; P < 0.001). T-allele frequency was higher among APS than controls (OR: 3.25; 95% CI: 1.82 to 5.82; P < 0.001), T1D (OR: 2.54; 95% CI: 1.48 to 4.36; P = 0.001), or GD (OR: 1.89; 95% CI: 1.15 to 3.11; P = 0.012). The SNP CTLA-4 CT60 G-allele carriers were more frequent in APS (85%) than controls (78%) (OR: 1.55; 95% CI: 0.81 to 2.99). Combined analysis of CTLA-4 AG49 and CT60 revealed OR 4.89; 95% CI: 1.86 to13.59; P = 0.00018 of the genotype combination AG/GG for APS vs controls. VDR polymorphisms Bsm I, Apa I, and Taq I did not, but the haplotypes differed between APS and controls (P = 0.0011). PTPN22 and CTLA-4 polymorphisms are associated with APS and differentiate between polyglandular and monoglandular autoimmunity.

Genetic variations of complement factor H and C3 in patients with thrombotic thrombocytopenic purpura (TTP) in northwest of Iran

Background: Thrombotic thrombocytopenic purpura (TTP) is a common form of thrombotic microangiopathy. These patients have renal insufficiency as well as thrombocytopenia and microangiopathic hemolysis. Objectives: The present study was aimed to assess if TTP patients with renal failure have prompting polymorphisms in the complement system genes as seen in patients with the atypical hemolytic uremic syndrome (aHUS). Patients and Methods: Twenty TTP patients and 30 healthy individuals were included. Two single-nucleotide polymorphisms rs3753394 and rs2230199 respectively in the complement factor H (CFH) and complement component 3 (C3) genes were determined using the PCRrestriction fragment length polymorphism (RFLP) method. To evaluate the power of the associations between the polymorphisms and TTP development, odds ratios (ORs) and 95% confidence intervals (CIs) were employed. Results: In rs2230199 polymorphism, the frequency of the C and G alleles and genotype were not significantly different in case and control groups. Moreover, the frequency of T allele and CC, CT, and TT genotypes of the rs3753394 polymorphism in TTP patients were not significantly different from those in the controls, the OR of 0.77 [CI: 0.33 to 1.79] and 0.76 [CI: 0.24 to 2.38], respectively (P > 0.05). Conclusions: Based on our results, there was no significant association between the incidence of TTP and polymorphisms of the CFH and C3 genes, neither at the allele nor at the genotypic levels (P > 0.05). This finding can be affected by the limited sample size or the genetic context of the studied population.

Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: A transethnic genome-wide meta-analysis.

BackgroundGlycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findingsUsing genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04–1.06, per HbA1c-raising allele, p = 3 × 10−29); whereas GS-E was not (OR = 1.00, 95% CI 0.99–1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66–0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38–0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI 0.55–0.74) of African American adults with T2D to remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.ConclusionsAs G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.

A modified response of NAFLD patients with non-significant fibrosis in nutritional counseling according to GCKR rs1260326.

To investigate the association between GCKR gene and nutritional treatment in NAFLD-related biomarkers. This was an open-label and single-arm clinical trial in 44 overweight or obese adults with NAFLD receiving nutritional counseling for 6months. Nutritional data, MedDietScore, clinical, biochemical, inflammatory and oxidative stress biomarkers were evaluated before and after intervention. Further, we genotyped GCKR rs1260326 and in T-allele carriers and non-Τ-carriers we assessed associations between the GCKR variant and nutritional counseling related to change in all biomarkers evaluated. Anthropometric measurements were significantly reduced after the end of the intervention in patients assigned to nutritional counseling. Liver imaging and fibrosis were significantly improved. GCKR rs1260326 T-allele frequency was 46.7%. T-carriers responded better to nutritional counseling regarding fasting blood glucose levels (mean6-0 change=-4.94mg/dL (±9.33), p=0.005), whereas non-T-carriers did not benefit from the intervention regarding glucose. On the other hand, levels of oxLDL decreased in the non-T-carriers group after the intervention, but not in T-carriers. Our results show that GCKR rs1260326 T-allele is associated with better response of NAFLD patients to nutritional treatment regarding fasting blood glucose, but not oxLDL levels. Despite this important finding in the field of nutrigenetics, it is tricky to generalize this effect unless larger studies are conducted.

TTN genotype is associated with fascicle length and marathon running performance.

Titin provides a molecular blueprint for muscle sarcomere assembly, and sarcomere length can vary according to titin isoform expression. If variations in sarcomere length influence muscle fascicle length, this may provide an advantage for running performance. Thus, the aim of this study was to investigate whether the titin (TTN) rs10497520 polymorphism was associated with muscle fascicle length in recreationally active men (RA; n=137) and marathon personal best time in male marathon runners (MR; n=141). Fascicle length of the vastus lateralis was assessed in vivo using B-mode ultrasonography at 50% of muscle length in RA. All participants provided either a whole blood, saliva or buccal cell sample, from which DNA was isolated and genotyped using real-time polymerase chain reaction. Vastus lateralis fascicle length was 10.4% longer in CC homozygotes, those carrying two copies of the C-allele, than CT heterozygotes (P=.003) in RA. In the absence of any TT homozygotes, reflective of the low T-allele frequency within Caucasian populations, it is unclear whether fascicle length for this group would have been smaller still. No differences in genotype frequency between the RA and MR groups were observed (P=.500), although within the MR group, the T-allele carriers demonstrated marathon personal best times 2minutes 25seconds faster than CC homozygotes (P=.020). These results suggest that the T-allele at rs10497520 in the TTN gene is associated with shorter skeletal muscle fascicle length and conveys an advantage for marathon running performance in habitually trained men.

ГЕН ФОЛАТНОГО ЦИКЛА MTHFR И ПИТАНИЕ

Climatic and geographical features always influenced on adaptation to the environment as well as the development level of economy and culture. The formation of certain food behavior in population determined fixation of specific gene alleles and mutation. They were responsible for digestion a typical food for the population. At the moment there is information about such genetic features as metabolism of proteins, carbohydrates and fats for many races and nations. But a few studies are about causes of prevalence differences of gene polymorphisms of folate cycle in the world's populations. The main objective was to explore 677C>T mutation MTHFR gene among Russian and Buryat to compare it with ones in other populations. The total of399 children and adolescents (200 Russians and 199 Buryats) were involved in this study. Genotyping of MTHFR 677C>T was performed by PCR-RT We used soft STATISTICA 8.0 to compare results. As a result, T-allele frequency was 30 % in Russians and 21,1 % in Buryats. We found significant differences of prevalence of polymorphism 677C>T between studied groups (p = 0.011). Also we found significant difference between Russian and British (p = 0.054), French (p = 0.0263), Spanish (p < 0.0001), Italian (p < 0.0001) and Greek samples (p = 0.0454). The Buryat group had significant differences with Chinese (p < 0.0001), Korean (p < 0.0001), Mongolian (p < 0.004), Japanese (p < 0.0001), Kazakh (p = 0.0198) samples and two samples of Hans (p < 0.0001; p = 0.0390).

Multiple sclerosis: Association of gelatinase B/matrix metalloproteinase-9 with risk and clinical course the disease

BackgroundMultiple sclerosis (MS) is an autoimmune disease characterized by inflammation and axonal degeneration of the central nervous system and a leading cause of disability in young adults. The matrix metalloproteinases in general and specially gelatinase B/metalloproteinase-9 (MMP-9) plays a role in the pathogenesis of multiple sclerosis. ObjectiveTo investigate the presence of the MMP-9 −1562C/T polymorphism in a Portuguese population of MS patients and assess its impact in susceptibility and course of the disease. The relation of MMP-9 serum levels with the polymorphism and with clinical and therapeutic factors will also be assessed. MethodsOur study included 355 Caucasian individuals distributed as MS patients (n=169) and controls (n=186). Samples were genotyped for −1562C/T polymorphism by PCR-RFLP analysis. MMP-9 concentration in serum was analyzed using a commercially available enzyme-linked immunosorbent assay. ResultsA significant increase in T-allele frequency was found in female MS patients, but not in the total patient population. No association between the presence of the polymorphism and disease progression was found. MMP-9 serum concentrations were increased in patients, and although not influenced by the −1562C/T polymorphism, were modified by INF-beta therapy. ConclusionAlthough we did not find an association of this polymorphism with disease susceptibility or prognosis, MMP-9 appears to be a good therapeutic response marker for multiple sclerosis.