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Rare disease Background: Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the... more Rare disease Background: Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the CYP24A1 enzyme, which is involved in the catabolism of 1,25-dihydroxyvitamin D3. Patients who are CYP24A1 enzyme deficient are at increased risk of developing hypercalcemia during pregnancy and should avoid additional vitamin D supplementation. This case report provides additional information for managing and diagnosing patients with a CYP24A1 gene mutation. Case Report: A primipara woman with a twin pregnancy was admitted to our hospital for frequent hypertensive crises. She had no history of hypercalcemia-associated signs and symptoms except nephrocalcinosis, and reported no other abnormalities or discomfort at presentation. Laboratory tests revealed that the parathyroid hormone level was suppressed and the serum calcium level was markedly increased. The 25-hydroxyvitamin D level was at the upper limit of the reference range while the 1,25-dihydroxyvitamin D3 level was elevated, suggesting a vitamin D catabolism disorder. A genetic test was performed and a homozygous likely pathogenic variant (based on the American College of Medical Genetics and Genomics guidelines) c.964G>A (p.Glu322Lys) was detected in the CYP24A1 gene (NM_000782.5). A cesarean section delivery was performed due to a single intrauterine demise at 33 weeks of gestation. The preterm newborn was diagnosed with transitional hypercalcemia and hyperphosphatemia; however, he was not treated, as he was asymptomatic. Conclusions: Patients with a CYP24A1 gene mutation are at increased risk of hypercalcemia and fetal demise; therefore, 25-hydroxyvitamin D and calcium levels should be monitored in routine blood tests during pregnancy. Hypercalcemia in a newborn should be carefully evaluated and treated, as hypercalciuria can lead to nephrocalcinosis.
Objective Registers of diagnoses and treatments exist in different forms in the European countrie... more Objective Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design Register-based cross-sectional study. Methods National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. Results Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9,...
Number of patients with diabetes mellitus increases constantly all over the world, and also in La... more Number of patients with diabetes mellitus increases constantly all over the world, and also in Latvia. Treatment of diabetes and care of diabetic patients requires extensive financial sources, which is a growing burden for economy. Quality of care in treatment of diabetes is of crucial importance, as it is associated with development of diabetic complications, which are linked to increased morbidity and mortality. However, long waiting time for endocrinologist or diabetologist visit interferes with efficient diabetes care process. Therefore, e-medicine solutions have been proposed for development of new algorithms in communication between doctors and patients, as well as improvement of patients’ education and quality of diabetes control and self-treatment. The pilot study has been initiated in January 2013 and will last till December 2013. The objective of the project is to develop new practices for virtual consultation in medicine. eMedic pilot study develops new technological appl...
Background: The study aims at solving the problem with the limitations of the homecare CPAP equip... more Background: The study aims at solving the problem with the limitations of the homecare CPAP equipment such as sleep apnea devices in the treatment of COVID-19 pneumonia. By adding an advanced, rapid-to-produce oxygenation module to CPAP device we allow distributing healthcare at all levels, reducing the load on intensive care units, promoting treatment in the early stages at homecare. A significant part of the COVID-19 pneumonia patients requires not only an oxygen supply but also additional air pressure. Existing home care devices are able to create precise positive airway pressure but cannot precisely measure supplied oxygen concentration. Either uses uncertified and potentially unsafe mechanisms.Results: The developed system allows using certified and widely available CPAP (constant positive airway pressure) devices to perform the critical function of delivering pressure and oxygen to airways. CPAP device is connected to the designed add-on module that can provide predefined oxyg...
BACKGROUND AND AIM To study the association between achievement of guideline-defined treatment ta... more BACKGROUND AND AIM To study the association between achievement of guideline-defined treatment targets on HbA1c, low-density lipoproteins (LDL-C), and blood pressure with the progression of diabetic complications in patients with type 1 diabetes (T1D). METHODS The study included 355 patients at baseline and 114 patients with follow-up data after 3-5 years. Outcome variables were the progression of diabetic kidney disease, retinopathy, or cardiovascular disease (CVD). We used logistic regression and other machine learning algorithms (MLA) to model the association of achievement of treatment targets and probability of progression of complications. RESULTS Achievement of the target blood pressure was associated with 96% lower odds of a new CVD event (0.04 (95% CI 0.00, 0.53), p = 0.016), and 72% lower odds of progression of any complication (0.28 (95% CI 0.09, 0.89), p = 0.027. Achievement of HbA1c target was associated with lower odds of composite complication progression by 82% (0.18 (95% CI 0.04, 0.88), p = 0.034.) None of the patients who achieved HbA1c target progressed in CVD. MLA demonstrated good accuracy for the prediction of progression of CVD (AUC 0.824), and lower accuracy for other complications. CONCLUSION The achievement of blood pressure and HbA1c treatment targets is associated with lower odds of vascular complication of T1D in a real life study.
Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases intro... more Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of no...
Journal of thrombosis and haemostasis : JTH, Jan 4, 2016
Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma level... more Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. We sought to replicate the linkage region in an independent sample and to identify the causal locus. Methods We first ran a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study and replicated the linkage peak on chromosome 2q (LOD=3.06). We next defined a follow-up region that included 112603 SNPs under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and MARTHA, a study of 1033 unrelated VTE patients. SNPs with FDR q<0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene study. One SNP, rs62187992, was as...
Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, ... more Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.
The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glyca... more The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glycation end products (AGEs), such as methylglyoxal (MG) and other reactive dicarbonyls, the formation of which is increased in diabetes patients as a result of excessive glycolysis. MG is partly responsible for harmful protein alterations in living cells, notably in neurons, leading to their dysfunction, and recent studies have shown a negative correlation between GLO1 expression and tissue damage. Neuronal dysfunction is a common diabetes complication due to elevated blood sugar levels, leading to high levels of AGEs. The aim of our study was to determine whether single nucleotide polymorphisms (SNPs) in the GLO1 gene influence activity of the enzyme. In total, 125 healthy controls, 101 type 1 diabetes, and 100 type 2 diabetes patients were genotyped for three common SNPs, rs2736654 (A111E), rs1130534 (G124G), and rs1049346 (5′-UTR), in GLO1. GLO1 activity was determined in whole blood lysates for all participants of the study. Our results showed a significant association between the minor alleles rs1130534 and rs1049346 and decreased enzyme activity (P = 0.001 and P = 2.61 × 10 −5 , respectively). Increased allelic counts of the risk alleles were strongly associated with decreased GLO1 activity (standardised β = − 0.24, P = 2.15 × 10 −5), indicating independent actions of these variants on GLO1 activity, as supported by the haplotype analysis. We showed for the first time an association between genetic variants with GLO1 enzyme activity in humans. SNPs in GLO1 can be used to predict enzyme activity and detoxifying capabilities, but further studies are needed to link these SNPs with common complications in diabetes.
Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide... more Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycemic control, necessitating insulin therapy. Fear of hypoglycemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS ® ; glargine) therapy using two treatment algorithms. This subgroup analysis investigated the initiation of once-daily glargine therapy in patients sub-optimally controlled on multiple OADs. Research design and methods: This was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and Algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose ≤100 mg/dL (≤5.5 mmol/L). Algorithms were compared for incidence of severe hypoglycemia (requiring assistance and blood glucose <50 mg/dL [<2.8 mmol/L]) and baseline-to-endpoint change in HbA 1c. Results: Of the 4961 patients enrolled in the study, 865 were included in this subgroup analysis: 340 received glargine plus 1 OAD; 525 received glargine plus >1 OAD. Incidence of severe hypoglycemia was <1%. HbA 1c decreased significantly between baseline and endpoint for patients receiving glargine plus 1 OAD (-1.4%, p<0.001; Algorithm 1-1.3% vs Algorithm 2-1.5%; p=0.03) and glargine plus >1 OAD (-1.7%, p<0.001; Algorithm 1-1.5% vs Algorithm 2-1.8%; p=0.001). Conclusions: This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA 1c with a low risk of hypoglycemia. The greater reduction in HbA 1c was seen in patients randomized to the patient-driven algorithm (Algorithm 2) on one or more than one OAD.
Experimental and Clinical Endocrinology & Diabetes, 2012
Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the... more Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for type 2 diabetes (T2D) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Latvia. We genotyped 4 single nucleotide polymorphisms (SNP) rs7901695, rs7903146, rs11196205 and rs12255372 in 1 093 controls and 1 043 diabetic subjects. Association with T2D was found for 3 SNPs rs7901695, rs7903146 and rs12255372 in the whole sample (under an additive genetic model, the adjusted odds ratios (OR) were 1.26, 95% CI [1.08-1.48], P=0.003; OR=1.32, 95% CI [1.12-1.55], P=0.001 and OR=1.35, 95% CI [1.15-1.60], P=0.0004 respectively). In addition observed effects on T2D susceptibility for analysed SNPs were higher among subjects with BMI under 30 kg/m². The impact of TCF7L2 variation on T2D risk in Latvian population is compatible with that demonstrated by a range of studies conducted in various ethnic groups.
Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.
In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster s... more In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster surveys revealed persisting iodine deficiency among Latvian schoolchildren during the spring season and a noteworthy iodine deficiency in pregnant women in Latvia; these deficiencies warrant intervention. The consequences of mild-to-moderate iodine deficiency during pregnancy and lactation can adversely affect foetal brain development. Data from a Latvian population survey revealed the consumption of approximately 100 μg of iodine per day through foods and iodised salt. Therefore, strategies to increase the consumption of iodine-containing products should be implemented, particularly for children. In addition, to meet the increased iodine requirement during pregnancy, pregnant women should take daily supplements containing 150 μg iodine from the earliest time possible. All women of childbearing age should be advised to increase their dietary iodine intake by using iodised table salt and i...
Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 and type... more Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 and type 2 diabetes. It has been shown to have a heritable component, but prior searches for the genetic determinants of this condition have had limited success. In this study, a new international genomics consortium (the Diabetic Nephropathy Collaborative Research Initiative, funded by the JDRF) has coalesced to assemble nearly 20,000 samples from participants with type 1 diabetes, with and without kidney disease. We report 16 new signals at genome-wide significance and begin to describe the genetic architecture of this globally relevant phenotype. Our top signal centers on a protective missense coding variant at COL4A3, which encodes an integral component of the glomerular basement membrane that when mutated causes Alport syndrome.
Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.
The most common autoimmune disorders with clinically opposite manifestations are hypothyroidism i... more The most common autoimmune disorders with clinically opposite manifestations are hypothyroidism in Hashimoto’s thyroiditis and hyperthyroidism in Graves’ disease. The healthcare burden of thyroid disease is substantial, resulting in substantial health care costs. The aim of the present analysis is to assess the use of thyroid medications in Latvia from 2011 to 2014 by age and gender. Our study used reimbursed medication prescriptions data, collected by the National Health Service of Latvia. The main indicator was the number of prevalent users of thyroid medications each year from 2011 to 2014, stratified by age and gender. From 2011 to 2014, the number of thyroxine users per 100 000 revealed a statistically significant increase in all age and gender groups, except in 0- to 9-year-old girls. The number of Thiamazole users among men increased in the age group from 40 to 89 years and in women age groups above 49 years. Increasing sales of both thyroid hormones and antithyroid medicatio...
Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To i... more Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions based on albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential bio...
Rare disease Background: Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the... more Rare disease Background: Loss-of-function mutations of the CYP24A1 gene cause a deficiency of the CYP24A1 enzyme, which is involved in the catabolism of 1,25-dihydroxyvitamin D3. Patients who are CYP24A1 enzyme deficient are at increased risk of developing hypercalcemia during pregnancy and should avoid additional vitamin D supplementation. This case report provides additional information for managing and diagnosing patients with a CYP24A1 gene mutation. Case Report: A primipara woman with a twin pregnancy was admitted to our hospital for frequent hypertensive crises. She had no history of hypercalcemia-associated signs and symptoms except nephrocalcinosis, and reported no other abnormalities or discomfort at presentation. Laboratory tests revealed that the parathyroid hormone level was suppressed and the serum calcium level was markedly increased. The 25-hydroxyvitamin D level was at the upper limit of the reference range while the 1,25-dihydroxyvitamin D3 level was elevated, suggesting a vitamin D catabolism disorder. A genetic test was performed and a homozygous likely pathogenic variant (based on the American College of Medical Genetics and Genomics guidelines) c.964G>A (p.Glu322Lys) was detected in the CYP24A1 gene (NM_000782.5). A cesarean section delivery was performed due to a single intrauterine demise at 33 weeks of gestation. The preterm newborn was diagnosed with transitional hypercalcemia and hyperphosphatemia; however, he was not treated, as he was asymptomatic. Conclusions: Patients with a CYP24A1 gene mutation are at increased risk of hypercalcemia and fetal demise; therefore, 25-hydroxyvitamin D and calcium levels should be monitored in routine blood tests during pregnancy. Hypercalcemia in a newborn should be carefully evaluated and treated, as hypercalciuria can lead to nephrocalcinosis.
Objective Registers of diagnoses and treatments exist in different forms in the European countrie... more Objective Registers of diagnoses and treatments exist in different forms in the European countries and are potential sources to answer important research questions. Prevalence and incidence of thyroid diseases are highly dependent on iodine intake and, thus, iodine deficiency disease prevention programs. We aimed to collect European register data on thyroid outcomes to compare the rates between countries/regions with different iodine status and prevention programs. Design Register-based cross-sectional study. Methods National register data on thyroid diagnoses and treatments were requested from 23 European countries/regions. The provided data were critically assessed for suitability for comparison between countries/regions. Sex- and age-standardized rates were calculated. Results Register data on ≥1 thyroid diagnoses or treatments were available from 22 countries/regions. After critical assessment, data on medication, surgery, and cancer were found suitable for comparison between 9,...
Number of patients with diabetes mellitus increases constantly all over the world, and also in La... more Number of patients with diabetes mellitus increases constantly all over the world, and also in Latvia. Treatment of diabetes and care of diabetic patients requires extensive financial sources, which is a growing burden for economy. Quality of care in treatment of diabetes is of crucial importance, as it is associated with development of diabetic complications, which are linked to increased morbidity and mortality. However, long waiting time for endocrinologist or diabetologist visit interferes with efficient diabetes care process. Therefore, e-medicine solutions have been proposed for development of new algorithms in communication between doctors and patients, as well as improvement of patients’ education and quality of diabetes control and self-treatment. The pilot study has been initiated in January 2013 and will last till December 2013. The objective of the project is to develop new practices for virtual consultation in medicine. eMedic pilot study develops new technological appl...
Background: The study aims at solving the problem with the limitations of the homecare CPAP equip... more Background: The study aims at solving the problem with the limitations of the homecare CPAP equipment such as sleep apnea devices in the treatment of COVID-19 pneumonia. By adding an advanced, rapid-to-produce oxygenation module to CPAP device we allow distributing healthcare at all levels, reducing the load on intensive care units, promoting treatment in the early stages at homecare. A significant part of the COVID-19 pneumonia patients requires not only an oxygen supply but also additional air pressure. Existing home care devices are able to create precise positive airway pressure but cannot precisely measure supplied oxygen concentration. Either uses uncertified and potentially unsafe mechanisms.Results: The developed system allows using certified and widely available CPAP (constant positive airway pressure) devices to perform the critical function of delivering pressure and oxygen to airways. CPAP device is connected to the designed add-on module that can provide predefined oxyg...
BACKGROUND AND AIM To study the association between achievement of guideline-defined treatment ta... more BACKGROUND AND AIM To study the association between achievement of guideline-defined treatment targets on HbA1c, low-density lipoproteins (LDL-C), and blood pressure with the progression of diabetic complications in patients with type 1 diabetes (T1D). METHODS The study included 355 patients at baseline and 114 patients with follow-up data after 3-5 years. Outcome variables were the progression of diabetic kidney disease, retinopathy, or cardiovascular disease (CVD). We used logistic regression and other machine learning algorithms (MLA) to model the association of achievement of treatment targets and probability of progression of complications. RESULTS Achievement of the target blood pressure was associated with 96% lower odds of a new CVD event (0.04 (95% CI 0.00, 0.53), p = 0.016), and 72% lower odds of progression of any complication (0.28 (95% CI 0.09, 0.89), p = 0.027. Achievement of HbA1c target was associated with lower odds of composite complication progression by 82% (0.18 (95% CI 0.04, 0.88), p = 0.034.) None of the patients who achieved HbA1c target progressed in CVD. MLA demonstrated good accuracy for the prediction of progression of CVD (AUC 0.824), and lower accuracy for other complications. CONCLUSION The achievement of blood pressure and HbA1c treatment targets is associated with lower odds of vascular complication of T1D in a real life study.
Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases intro... more Objective Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of no...
Journal of thrombosis and haemostasis : JTH, Jan 4, 2016
Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma level... more Tissue factor pathway inhibitor (TFPI) regulates fibrin clot formation, and low TFPI plasma levels increase the risk of arterial and venous thromboembolism (VTE). TFPI plasma levels are also heritable, and a previous linkage scan implicated the chromosome 2q region, but no specific genes. We sought to replicate the linkage region in an independent sample and to identify the causal locus. Methods We first ran a linkage analysis of microsatellite markers and TFPI plasma levels in 251 individuals from the F5L Family Study and replicated the linkage peak on chromosome 2q (LOD=3.06). We next defined a follow-up region that included 112603 SNPs under the linkage peak, and meta-analyzed associations between these SNPs and TFPI plasma levels across the F5L Family Study and MARTHA, a study of 1033 unrelated VTE patients. SNPs with FDR q<0.10 were tested for association with TFPI plasma levels in 892 patients with coronary artery disease in the AtheroGene study. One SNP, rs62187992, was as...
Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, ... more Variations in the FTO gene and near the TMEM18 gene are risk factors for common form of obesity, but have also been linked with type 2 diabetes (T2D). Our aim was to investigate the contribution of these variants to risk of T2D in a population in Latvia. Four single nucleotide polymorphisms (SNP) in the first and fourth intronic regions of FTO and one close to TMEM18 were genotyped in 987 patients with T2D and 1080 controls selected from the Latvian Genome Data Base (LGDB). We confirmed association of SNPs in the first intron (rs11642015, rs62048402 and rs9939609) of FTO and rs7561317 representing the TMEM18 locus with T2D. Association between SNP in FTO and T2D remained significant after correction for body mass index (BMI). The rs57103849 located in the fourth intron of FTO and rs7561317 in TMEM18 showed BMI independent association with younger age at diagnosis of T2D. Our results add to the evidence that BMI related variants in and near FTO and TMEM18 may increase the risk for T2D not only through secondary effects of obesity. The influence of variants in the fourth intron of the FTO gene on development of T2D may be mediated by mechanisms other than those manifested by SNPs in the first intron of the same gene.
The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glyca... more The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glycation end products (AGEs), such as methylglyoxal (MG) and other reactive dicarbonyls, the formation of which is increased in diabetes patients as a result of excessive glycolysis. MG is partly responsible for harmful protein alterations in living cells, notably in neurons, leading to their dysfunction, and recent studies have shown a negative correlation between GLO1 expression and tissue damage. Neuronal dysfunction is a common diabetes complication due to elevated blood sugar levels, leading to high levels of AGEs. The aim of our study was to determine whether single nucleotide polymorphisms (SNPs) in the GLO1 gene influence activity of the enzyme. In total, 125 healthy controls, 101 type 1 diabetes, and 100 type 2 diabetes patients were genotyped for three common SNPs, rs2736654 (A111E), rs1130534 (G124G), and rs1049346 (5′-UTR), in GLO1. GLO1 activity was determined in whole blood lysates for all participants of the study. Our results showed a significant association between the minor alleles rs1130534 and rs1049346 and decreased enzyme activity (P = 0.001 and P = 2.61 × 10 −5 , respectively). Increased allelic counts of the risk alleles were strongly associated with decreased GLO1 activity (standardised β = − 0.24, P = 2.15 × 10 −5), indicating independent actions of these variants on GLO1 activity, as supported by the haplotype analysis. We showed for the first time an association between genetic variants with GLO1 enzyme activity in humans. SNPs in GLO1 can be used to predict enzyme activity and detoxifying capabilities, but further studies are needed to link these SNPs with common complications in diabetes.
Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide... more Objective: For many patients with type 2 diabetes, oral antidiabetic agents (OADs) do not provide optimal glycemic control, necessitating insulin therapy. Fear of hypoglycemia is a major barrier to initiating insulin therapy. The AT.LANTUS study investigated optimal methods to initiate and maintain insulin glargine (LANTUS ® ; glargine) therapy using two treatment algorithms. This subgroup analysis investigated the initiation of once-daily glargine therapy in patients sub-optimally controlled on multiple OADs. Research design and methods: This was a 24-week, multinational (59 countries), multicenter (611), randomized study. Algorithm 1 was a clinic-driven titration and Algorithm 2 was a patient-driven titration. Titration was based on target fasting blood glucose ≤100 mg/dL (≤5.5 mmol/L). Algorithms were compared for incidence of severe hypoglycemia (requiring assistance and blood glucose <50 mg/dL [<2.8 mmol/L]) and baseline-to-endpoint change in HbA 1c. Results: Of the 4961 patients enrolled in the study, 865 were included in this subgroup analysis: 340 received glargine plus 1 OAD; 525 received glargine plus >1 OAD. Incidence of severe hypoglycemia was <1%. HbA 1c decreased significantly between baseline and endpoint for patients receiving glargine plus 1 OAD (-1.4%, p<0.001; Algorithm 1-1.3% vs Algorithm 2-1.5%; p=0.03) and glargine plus >1 OAD (-1.7%, p<0.001; Algorithm 1-1.5% vs Algorithm 2-1.8%; p=0.001). Conclusions: This study shows that initiation of once-daily glargine with OADs results in significant reduction of HbA 1c with a low risk of hypoglycemia. The greater reduction in HbA 1c was seen in patients randomized to the patient-driven algorithm (Algorithm 2) on one or more than one OAD.
Experimental and Clinical Endocrinology & Diabetes, 2012
Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the... more Polymorphisms in the gene coding for transcription factor 7 like 2 (TCF7L2) are recognized as the strongest common genetic risk factors for type 2 diabetes (T2D) across multiple ethnicities. This study was conducted to evaluate an association between TCF7L2 variants and diabetes susceptibility in the population of Latvia. We genotyped 4 single nucleotide polymorphisms (SNP) rs7901695, rs7903146, rs11196205 and rs12255372 in 1 093 controls and 1 043 diabetic subjects. Association with T2D was found for 3 SNPs rs7901695, rs7903146 and rs12255372 in the whole sample (under an additive genetic model, the adjusted odds ratios (OR) were 1.26, 95% CI [1.08-1.48], P=0.003; OR=1.32, 95% CI [1.12-1.55], P=0.001 and OR=1.35, 95% CI [1.15-1.60], P=0.0004 respectively). In addition observed effects on T2D susceptibility for analysed SNPs were higher among subjects with BMI under 30 kg/m². The impact of TCF7L2 variation on T2D risk in Latvian population is compatible with that demonstrated by a range of studies conducted in various ethnic groups.
Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.
In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster s... more In the absence of a mandatory salt iodisation programme, two nationwide cross-sectional cluster surveys revealed persisting iodine deficiency among Latvian schoolchildren during the spring season and a noteworthy iodine deficiency in pregnant women in Latvia; these deficiencies warrant intervention. The consequences of mild-to-moderate iodine deficiency during pregnancy and lactation can adversely affect foetal brain development. Data from a Latvian population survey revealed the consumption of approximately 100 μg of iodine per day through foods and iodised salt. Therefore, strategies to increase the consumption of iodine-containing products should be implemented, particularly for children. In addition, to meet the increased iodine requirement during pregnancy, pregnant women should take daily supplements containing 150 μg iodine from the earliest time possible. All women of childbearing age should be advised to increase their dietary iodine intake by using iodised table salt and i...
Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 and type... more Diabetic kidney disease (DKD) is a devastating microvascular complication of both type 1 and type 2 diabetes. It has been shown to have a heritable component, but prior searches for the genetic determinants of this condition have had limited success. In this study, a new international genomics consortium (the Diabetic Nephropathy Collaborative Research Initiative, funded by the JDRF) has coalesced to assemble nearly 20,000 samples from participants with type 1 diabetes, with and without kidney disease. We report 16 new signals at genome-wide significance and begin to describe the genetic architecture of this globally relevant phenotype. Our top signal centers on a protective missense coding variant at COL4A3, which encodes an integral component of the glomerular basement membrane that when mutated causes Alport syndrome.
Proceedings of the Latvian Academy of Sciences. Section B. Natural, Exact, and Applied Sciences.
The most common autoimmune disorders with clinically opposite manifestations are hypothyroidism i... more The most common autoimmune disorders with clinically opposite manifestations are hypothyroidism in Hashimoto’s thyroiditis and hyperthyroidism in Graves’ disease. The healthcare burden of thyroid disease is substantial, resulting in substantial health care costs. The aim of the present analysis is to assess the use of thyroid medications in Latvia from 2011 to 2014 by age and gender. Our study used reimbursed medication prescriptions data, collected by the National Health Service of Latvia. The main indicator was the number of prevalent users of thyroid medications each year from 2011 to 2014, stratified by age and gender. From 2011 to 2014, the number of thyroxine users per 100 000 revealed a statistically significant increase in all age and gender groups, except in 0- to 9-year-old girls. The number of Thiamazole users among men increased in the age group from 40 to 89 years and in women age groups above 49 years. Increasing sales of both thyroid hormones and antithyroid medicatio...
Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To i... more Diabetic kidney disease (DKD) is a heritable but poorly understood complication of diabetes. To identify genetic variants predisposing to DKD, we performed genome-wide association analyses in 19,406 individuals with type 1 diabetes (T1D) using a spectrum of DKD definitions based on albuminuria and renal function. We identified 16 genome-wide significant loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM) implicated in heritable nephropathies. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of DKD, including albuminuria and end-stage renal disease. Three other loci are in or near genes with known or suggestive involvement in DKD (BMP7) or renal biology (COLEC11 and DDR1). The 16 DKD-associated loci provide novel insights into the pathogenesis of DKD, identifying potential bio...
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Papers by Valdis Pīrāgs