Genetics of T2DM and Its Chronic Complications: Are We Any Closer to the Individual Prediction of Genetic Risk?

Type 2 diabetes mellitus (T2DM) is a complex disease that has risen in global prevalence over recent decades, resulting in concomitant and enormous socio-economic impacts. In addition to the well-documented risk factors of obesity, poor dietary habits and sedentary lifestyles, genetic background plays a key role in the aetiopathogenesis of diabetes and the development of associated micro- and macrovascular complications. Recent advances in genomic research, notably next-generation sequencing and genome- wide association studies, have greatly improved the efficiency with which genetic backgrounds to complex diseases are analysed. To date, several hundred single-nucleotide polymorphisms have been associated with T2DM or its complications. Given the polygenic background to T2DM (and numerous other complex diseases), the degree of genetic predisposition can be treated as a "continuous trait" quantified by a genetic risk score. Focusing mainly on the Central European population, this review summarizes recent state-of-the-art methods that have enabled us to better determine the genetic architecture of T2DM and the utility of genetic risk scores in disease prediction.

[Cognitive functions and modifiable risk factors for chronic non-communicable diseases in ageing in a Russian population sample.]

We aimed to investigate the relationship between the indicators of cognitive functions (CF) and modifiable risk factors for chronic non-communicable diseases (NCD) in a cross-sectional analysis in the urban Russian population sample aged 55-84 years. The study investigated a random sample of 3 153 people (men and women 55-84 years old) from a general population cohort of Novosibirsk residents; a sample was examined within the international project HAPIEE. The study protocol included standardized neuropsychological tests (quantitative assessment of memory, semantic verbal fluency, attention and processing speed) and standardized assessment of risk factors, history and treatment of cardiovascular disease and NCD. In cross-sectional analysis we observed a positive relationship of CF indices with level of education and an inverse relationship with metabolic risk factors and smoking in both sexes. The level of total cholesterol and moderate alcohol consumption had positive relationship with CF indices in women. These associations were independent from age and other factors.

[The frequency and profile of drug treatment in subjects with dyslipidemias and cardimetabolic diseases in an urban russian population older then 55 years].

Aim      To analyze frequency and profile of the lipid-lowering therapy (LLT) in patients with dyslipidemia (DLP) and cardiometabolic diseases (CMD) in a population sample aged 55-84 years at the current time (2015-2017).Material and methods  Despite guidelines on DLP treatment and the availability of effective and safe lipid-lowering drugs, control of DPL in primary and secondary prevention of cardiovascular diseases (CVD) is insufficient. Knowledge of the level of pharmaceutical correction of DLP in the Russian population is limited; it requires an LLT assessment in various regions and in a wide age range, and a regular monitoring taking into account changing approaches to the correction of DLP. A random population of men and women aged 55-84 years (n=3 896) was evaluated in Novosibirsk in 2015-2017 (project HAPIEE). A joint DLP category was established as low-density lipoprotein cholesterol (LDL-C) ≥3.0 mmol/l, or total cholesterol (TC) ≥5.0 mmol/l, or triglycerides (TG) ≥1.7 mmol/l, or LLT. The combined group of DLP and CMD included ischemic heart disease (IHD), type 2 diabetes mellitus (DM2), and DLP. Regular LLD treatment for the recent 12 months, excluding the dosage of medicines, was assessed using the Anatomic Therapeutic Chemical (ATC) classification. The conditional control of serum lipids was taken as the achievement of LDL-C <3.0 mmol/l, TC <5.0 mmol/l, and TG <1.7 mmol/l.Results In the study sample, the total prevalence of DLP and CMD was 88 % (82.8 % for men and 91.3 % for women, p<0.001). 48.3% of patients in the IHD group, 35.0% in the DM2 group, 29.4% in the DLP group, and 32.8% in the CMD group took LLT. Control of serum lipids was achieved in 18.3% (37.9 % of patients on LLT) of patients with IHD; 9 % (25.6 % of patients on LLT) of patients with DM2; 7.3 % (24.8 % of patients on LLT) of patients with DLP; and 9.0 % (27.6 % of patients on LLTсреди) in the DLP and CMD group. Women with DM2 and DLP more frequently achieved lipid control than men (p<0.001). 98.7 % of study participants took statins as LLT.Conclusion      In the sample of urban population aged 55-84 years in 2015-2017, 90 % of patients had DLP or CMD, and at least ¾ of them required blood lipid control. The lipid control was achieved in every fifth IHD patient and in approximately 40% of those who took LLT. For DM2 or DLP patients, the lipid control was achieved in every tenth patient and in approximately 25% of those receiving LLT. Frequency of lipid control in IHD patients was comparable for men and women; in DM2 and DLP, men less frequently achieved the lipid control than women. About 70% of patients in the combined DLP and CMD group and more than 50% of IHD patients did not take LLT, which considerably contributed to the insufficient lipid control in primary and secondary prevention of atherosclerotic CVDs in this population.

Genetic Markers at ANRIL, FTO and 2q36.3 Locus in Czech Patients Undergoing Coronary Artery Bypass Graft Surgery.

Coronary artery bypass graft (CABG) surgery is one of the most commonly performed operations worldwide. We compared genotype frequencies of three major cardiovascular disease (CVD)-associated genetic markers (ANRIL, FTO and 2q36.3 locus) between 753 patients who underwent CABG at the Institute for Clinical and Experimental Medicine (Prague, Czech Republic) and 2,559 controls from the Czech post-MONICA study. Subjects with at least one major A allele in the rs10757274 polymorphism (ANRIL) were more prevalent in patients after CABG than in the controls (81.7 % vs 72.7 %; OR [95 % CI] 1.67 [1.35-2.05]; P < 0.0001). In contrast, variants within the FTO gene (OR 0.87; 95 % CI, 0.70-1. 09 in a TT vs. GG comparison, P = 0.24) and 2q36.3 locus (OR 1.16; 95% CI, 0.98-1.37 in a +A vs. CC comparison, P = 0.08) were not significantly associated with CVD in our study. Variants were not associated with anthropometric, biochemical, or clinical characteristics within the patient group. Our study suggests that patients with CABG are more commonly carriers of some but not all CVD-associated alleles.

Strong Association between APOA5 Gene Polymorphisms and Hypertriglyceridaemic Episodes.

Plasma triglyceride (TG) levels represent a significant risk factor of cardiovascular and total mortality. Concentrations of TG in the plasma depend, to a large extent, on the genetic background, and the apolipoprotein A5 (APOA5) gene seems to be one of the most powerful players in the plasma TG metabolism regulation. In total, we analysed three tagging APOA5 (rs964184 rs662799, rs3135506) SNPs in 209 patients with plasma TG levels over 10 mmol/l (HTG) on at least one occasion and in 379 treatment-naïve controls (NTG) with plasma TG values within the normal range. Minor alleles of all three analysed APOA5 polymorphisms significantly (all P < 0.0001) increased the risk of hypertriglyceridaemia. The most significant association (P < 0.0000001) was observed for the rs964184 polymorphism, where the minor GG homozygotes had the odds ratio (OR, 95% CI) for hypertriglyceridaemia development 21.30 (8.09-56.07, P < 0.000001) in comparison with the major CC allele homozygotes. Carriers of at least one minor allele at rs3135506 had OR (95% CI) 4.19 (2.75-6.40); (P < 0.000005) for HTG development and similarly, carriers of a minor allele at rs662799 had OR (95% CI) 3.07 (2.00-4.72) (P < 0.0001). The cumulative presence of risk alleles (unweighted gene score) significantly differed between patients with episodes of high TG and controls at P < 0.0000001. There were 73 % of subjects without any of the risk alleles among the controls and 46 % in the patients. In contrast, the controls just included 3 % of subjects with score 3 and more in comparison with 18 % in HTG patients. We conclude that common APOA5 variants are very important genetic determinants of episodic hypertriglyceridaemia in the Czech population with a high potential to be applied in personalized medicine.

[Mitochondrial DNA copy number of leucocytes as ageing marker and risk factors for age-related diseases in human.]

We used quantitative real-time PCR method to analyse mtDNA copy number in a random subsample (n=996; 358 men aged 66,31±7,24 years; 468 women aged 67,62±7,1 years) selected from a population cohort (n=9 630) examined at baseline in international project HAPIEE in Novosibirsk, Russia, in 2003-2005. The participants were re-examined after 12 years in 2015-2017. The average relative number of mtDNA copies in peripheral blood leukocytes was greater in women than in men, independently of age and smoking (p=0,001). mtDNA copy number was inversely correlated with age both in men (p=0,005) and women (p<0,001). In age adjusted analysis, mtDNA copy number was inversely associated with waist, hip and heart rate in both sexes. In addition, mtDNA copy number in women was inversely associated with triglycerides and glucose, aterogenity index and positively with HDL cholesterol. In men, mtDNA copy number was positively associated with physical activity. The age-adjusted mean of mtDNA copy number among male never-smokers was greater than in smokers (p=0,003), and the mean mtDNA copy number was lower in women with diabetes than in women without diabetes (p=0,005). In both sexes, subjects with baseline history of hypertension had lower mtDNA copy number after 12-year follow-up than those without hypertension (p=0,05). This broadly supports the hypothesis that mtDNA copy number may act as biomarker of ageing.

Aldehyde dehydrogenase 2 polymorphism affects the outcome of methanol poisoning in exposed humans.

As the susceptibility of humans to xenobiotics often depends on genetic factors, we assumed that ADH1B and ALDH2 genetic variants may affect susceptibility to the acute methanol exposure. To evaluate the role of genetic variants of enzymes involved in methanol catabolism in humans, we analysed ADH1B (rs1229984) and ALDH2 (rs441) polymorphisms in 50 adults who survived acute methanol poisoning, 246 individuals with alcoholic liver cirrhosis, and in 545 healthy controls. GG homozygotes of ADH1B were more common among methanol-poisoned patients (98%) and among patients with alcoholic liver cirrhosis (98%) than among healthy controls (90%) (P = 0.08 and < 0.001, respectively). Minor C allele carriers of the ALDH2 were significantly more common among methanol-poisoned persons (46%) than among patients with alcoholic liver cirrhosis or healthy controls (31% in both groups, P < 0.05 and 0.025, respectively); the odds ratios were 1.89 (95% CI 1.02-3.52) and 1.94 (1.08-3.48), respectively. As there was a substantial amount of subjects with alcohol abuse between both groups of patients, ADH1B is unlikely to affect the susceptibility to methanol poisoning. By contrast, the genetic variant of the ALDH2 enzyme seems to specifically affect the susceptibility to methanol in acutely exposed humans and potentially plays a role in the outcome of methanol poisoning.

Allogeneic stem cell transplantation after fludarabine, melphalan and thymoglobulin followed by early withdrawal of prophylactic immunosuppression in patients with acute lymphoblastic leukemia - update of single center study.

Presented are updated results of allogeneic hematopoietic stem cell transplantations (HSCTs) in 25 adult patients with acute lymphoblastic leukemia (ALL) in complete remission (CR) after a reduced intensity conditioning (RIC) combining fludarabine (150 mg/m2) and melphalan (140 mg/m2) with thymoglobulin (4.5 mg/kg or recently 4.0 mg/kg) followed by early initiation of reduction and withdrawal of prophylactic posttransplant immunosuppression. The median post-transplant follow-up was 32 (range, 4-87) months. Stable engraftment of donor's hematopoiesis was achieved in all patients. Acute graft versus host disease (GVHD) as well as the chronic one were equally observed in four cases (16%). Five patients (20%) relapsed with ALL in the median of 9 (range, 3-15) months after HSCT. During the above post-transplant follow-up, 4 recipients (16%) died. Disease progression and posttransplant complications were the cause of death in three (12%) and one (4%) of them, respectively. The probabilities of 2-year event-free (EFS) and overall survival (OS) were 70.3% (95% CI 51.9-88.7%) and 86.1% (95% CI 71.6-100%), respectively. Presented study confirmed our previously reported promising results and this approach may be considered as an alternative to traditional HSCTs performed in high-risk patients with ALL.

Can Leukocyte Telomere Length Predict Survival Time in Heart Transplant Recipients over a Minimal Follow-Up of 20 years?

In humans, leukocyte telomere length (LTL) reduces with age and is reported to be inversely associated with ageing-related diseases. We measured LTL in leukocyte DNA using a quantitative PCR-based method from 127 blood samples of heart recipients (107 males, 20 females, age 44.1 ± 10.5), followed for up to 30 years. Patients with coronary artery disease survived for a shorter time and also had shorter LTL (both P < 0.05 after adjustment for age and sex) than subjects with dilated cardiomyopathy. Patients with non-cardiac causes of death had shorter LTL than patients with cardiac causes (P < 0.05 after adjustment for age). An inverse correlation between LTL and age (P < 0.03) was observed in patients with non-cardiac causes of death only. Most importantly, LTL was not associated with general survival time in patients after heart transplantation. However, shorter LTL was a marker of non-cardiac causes of death. Different LTLs and survival times were determined in association with aetiology of heart failure (HF).

Rs6922269 marker at the MTHFD1L gene predict cardiovascular mortality in males after acute coronary syndrome.

Myocardial infarction (MI) is the leading cause of death in industrialized countries. All the traditional risk factors for MI are responsible for approximately 50% of cases of MI cases. Attention therefore has recently focused on genetic variants that are not associated with conventional risk factors. One of them is the marker rs6922269, which has been suggested as a risk factor for development of MI in Western populations. We analyzed the relationship between rs6922269 variant on MTHFD1L gene and (i) risk of the acute coronary syndrome (ACS) in the Czech population and (ii) mortality in 7 years follow up. Rs6922269 (G>A) variant was analyzed (CR 99.3% for patients and 98.0% for controls) by PCR-RFLP in consecutively examined 1614 men and 503 women with ACS (age below 65 years) and in population-based controls--1191 men and 1368 women (aged up to 65 years). ANOVA and Chi square were used for statistical analysis. The genotype frequencies were almost identical (P=0.87) in the ACS patients and in controls and no differences were observed, if males (P=0.73) and females (P=0.93) were analysed separately. In addition, rs6922269 polymorphism was not associated with the classical risk factors (dyslipidemia, hypertension, obesity, smoking, diabetes) in control population. Cardiovascular mortality was significantly higher in males, carriers of the AA genotype (P<0.001, OR 2.52, 95% CI 1.40-4.55, for AA vs. +G). We conclude, that rs6922269 variant at MTHFD1L gene could be an important prognostic factor for cardiovascular mortality in patients after ACS.

Acute promyelocytic leukemia successfully treated also in elderly patients with significant comorbidities: a 20-year single-center experienc.

UNLABELLED: Acute promyelocytic leukemia is a unique entity among acute leukemias. Introduction of all-trans retinoic acid and, subsequently, arsenic trioxide in its treatment has markedly improved treatment outcomes for this once frequently fatal disease. Improved outcomes have also been observed in elderly patients, including those in whom standard intensive therapy is contraindicated because of comorbidities.In our center, a total of 60 APL patients were treated in 1993-2013, of whom 9 were aged 60 or more years. Although most of them had significant comorbidities at the time of diagnosis, eight achieved complete remission. At the time of the analysis, six patients were alive and in long-term remission; two patients died of causes other than APL. The median follow-up was 59 months.Included is case report of a patient with a high comorbidity score whose treatment was markedly reduced and individualized.Our experience shows that, in APL patients a curative approach is generally tolerated and should always be attempted regardless of age and comorbidities. KEYWORDS: APL - elderly patients - comorbidity.

Allogeneic stem cell transplantation after fludarabine, melphalan and thymoglobulin followed by early withdrawal of prophylactic immunosuppression could be an effective approach to patients with acute lymphoblastic leukemia.

Presented are results of allogeneic hematopoietic stem cell transplantations (HSCTs) in 13 patients with high-risk acute lymphoblastic leukemia (ALL) in the first complete remission after a reduced intensity conditioning combining fludarabine (150 mg/m2) and melphalan (140 mg/m2) with thymoglobulin (4.5 mg/kg). The immunosuppressive effect of T-cell depletion reducing the risk of graft-versus-host disease (GVHD) and non-relapse mortality was compensated by early initiation of reduction and withdrawal of prophylactic immunosuppression aimed at maintaining effective immunological antileukemic control. The median post-transplant follow-up was 23 (range, 10-65) months. Stable engraftment of donor's hematopoiesis was achieved in all patients. Acute GVHD was observed in two cases (15.4%); the chronic form was not noted. Two patients (15.4%) relapsed with ALL at 3 and 16 months after transplantation. During the above post-transplant follow-up, all 13 recipients were alive, with a probability of 2-year disease-free survival of 76.9% (95% CI 51-100%). Although the results were obtained with a small pilot study group it may be assumed that, given the prognostic risk of most patients and the nearly 2-year median post-transplant follow-up, the approach may be considered as an alternative to HSCTs after traditional myeloablative or reduced conditioning regimens with standard GVHD prophylaxis.

Nobody Is Perfect: Comparison of the Accuracy of PCR-RFLP and KASP™ Method for Genotyping. ADH1B and FTO Polymorphisms as Examples.

DNA genotyping is among the most common analyses currently performed in scientific research. Two high-throughput genotyping techniques are widely used - the "classic" PCR-RFLP and probe-based methods such as TaqMan® PCR assay or KASP™ genotyping. The probe-based techniques are claimed to be more accurate than PCR-RFLP; however, the evidence for this claim is sparse. We have directly compared results of genotyping of two SNPs (rs1229984 and rs17817449) obtained by the PCR-RFLP and KASP™ in 1,502 adult Caucasians. The results were identical in 97.3 % and 95.9 % cases, respectively. Discrepancies (either different results or result obtained with one but not with the other method) were addressed by confirmatory analysis using direct sequencing. The sequencing revealed that both methods can give incorrect results, but the frequency of incorrect genotyping of rs1229984 and rs17817449 was very low for both methods - 0.1 % and 0.5 %, respectively, for PCR-RFLP and 0.1 % and 0.3 %, respectively, for KASP™. These results confirm that the KASP™ technique is slightly more accurate, but it achieves slightly lower call rates than PCR-RFLP. When carefully set up, both PCR-RFLP and KASP™ could have accuracy of 99.5 % or higher.

The association between APOA5 haplotypes and plasma lipids is not modified by energy or fat intake: the Czech HAPIEE study.

BACKGROUND AND AIMS: Several smaller studies reported interactions between dietary factors and apolipoprotein A5 (APOA5) gene polymorphisms in determination of plasma lipids. We tested interactions between APOA5 haplotypes and dietary intake in determination of plasma triglycerides (TG) and other lipids. METHODS AND RESULTS: Participants (5487 males and females aged 45-69) were classified according to the number (0, 1, 2+) of minor APOA5 alleles (using T-1131 > C; rs662799 and Ser19 > Trp; rs3135506 polymorphisms) and into three groups of low (bottom 25%), medium (26th-75th percentile) and high (top 25%) of intake of total energy and total, saturated and polyunsaturated fats, assessed by food frequency questionnaire. The age-sex adjusted geometric means of plasma TG increased with the number of minor alleles, from 1.57 (standard error 0.01), to 1.79 (0.02) to 2.29 (0.10) mmol/L (p < 0.00001) but TG did not differ between groups with low, medium and high total energy intake (p = 0.251). TG concentrations were highest in subjects with the combination of 2+ minor alleles and the highest energy intake (mean 2.59 [0.19], compared with 1.62 [0.03] in subjects with lowest energy intake and no minor allele) but the interaction between energy intake and APOA5 haplotypes was not statistically significant (p = 0.186). Analogous analyses with total, saturated and polyunsaturated fat intake yielded similar nonsignificant results. Effects of APOA5 and dietary intakes on total and HDL cholesterol were weaker and no interactions were significant. CONCLUSION: In this Slavic Caucasian population sample, we did not detect the hypothesized interaction between common SNPs within the APOA5 gene and diet in determination of blood lipids.

MTHFR and HFE, but not preproghrelin and LBP, polymorphisms as risk factors for all-cause end-stage renal disease development.

End-stage renal disease (ESRD) is a serious health problem worldwide. The high prevalence of cardiovascular diseases and chronic inflammation remains a major cause of morbidity and mortality in haemodialysed patients. Beside some external factors, genetic predisposition both to renal failure and poor prognosis has been assumed. We have collected a total of 1,014 haemodialysed patients and 2,559 unrelated healthy Caucasians. Single-nucleotide polymorphisms (SNPs) in genes for preproghrelin (GHRL), lipopolysaccharide-binding protein (LBP), HFE and MTHFR were genotyped. In the group of patients, significantly more carriers presented the MTHFR T667T (P = 0.002) and HFE Asp63Asp (P = 0.001) and Cys282Cys (P = 0.01) genotypes. The frequencies of individual SNPs within GHRL and LBP genes did not differ between the patients and controls. The trends in genotype frequencies did not differ between the subgroups of patients with different time on haemodialysis. Common variants in MTHFR and HFE could be a risk factor for all-cause ESRD development, but are not predictors for the survival on haemodialysis.

Tagging rs10811661 variant at CDKN2A/2B locus is not associated with type 2 diabetes mellitus in Czech population.

Genome-wide association studies have resulted in the identification of the CDKN2A/2B locus as an important genetic determinant of type 2 diabetes mellitus development. The aim of this study was to investigate the role of this locus in the development of type 2 diabetes mellitus in Czech Slavonic population. Groups of 1,149 type 2 diabetic patients and a group of 2,312 healthy controls, both of Czech origin, were successfully genotyped for the rs10811661 CDK2A/2B tagging polymorphism. The "risky" TT genotype frequencies were almost identical in both examined groups (69.3 % in patients and 68.9 % in controls, P = 0.52; OR [95% CI] = 1.02 [0.87 - 1.19] for TT versus C allele carriers). Similar negative results were obtained when males (P = 0.93) and females (P = 0.23) were analysed separately. We have not confirmed the association between rs10811661 SNP and susceptibility to the type 2 diabetes mellitus in Czech Slavonic population.

A haemochromatosis-causing HFE mutation is associated with SARS-CoV-2 susceptibility in the Czech population.

BACKGROUND: Coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 virus, has become a global pandemic. While susceptibility to COVID-19 is subject to several external factors, including hypertension, BMI, and the presence of diabetes, it is also genetically determined to a significant extent. Infectious agents require iron (Fe) for proper functioning. Carriers of mutations resulting in increased iron concentrations are understood to be at increased risk of COVID-19. METHODS: We examined HFE genotypes associated with hereditary haemochromatosis (rs1800562 and rs1799945 SNPs) in 617 COVID-19 patients (166 asymptomatic, 246 symptomatic and 205 hospitalised survivors) and 2 559 population-based controls. RESULTS: We found a higher frequency of the minor allele (Tyr282) of the rs1800562 polymorphism (P < 0.002) in patients compared to controls (8.5 % vs 5.5 %). Non-carriers of the minor allele were protected against SARS-Cov-2 infection (OR, 95 %CI; 0.59, 0.42-0.82). The frequency of minor allele carriers was almost identical across asymptomatic, symptomatic, and hospitalised survivors. The rs1799945 variant did not affect disease severity and its occurrence was almost identical in patients and controls (P between 0.58 and 0.84). CONCLUSIONS: In conclusion, our results indicate that presence of the rs1800562 minor allele, which is associated with hereditary haemochromatosis (thus increased levels of plasma Fe), increases susceptibility to SARS-CoV-2.

ABCA3 and LZTFL1 Polymorphisms and Risk of COVID-19 in the Czech Population.

SARS-CoV-2 infection, which causes the respiratory disease COVID-19, has spread rapidly from Wuhan, China, since 2019, causing nearly 7 million deaths worldwide in three years. In addition to clinical risk factors such as diabetes, hypertension, and obesity, genetic variability is an important predictor of disease severity and susceptibility. We analyzed common polymorphisms within the LZTFL1 (rs11385942) and ABCA3 (rs13332514) genes in 519 SARS-CoV-2-positive subjects (164 asymptomatic, 246 symptomatic, and 109 hospitalized COVID-19 survivors) and a population-based control group (N?=?2,592; COVID-19 status unknown). Rare ABCA3 AA homozygotes (but not A allele carriers) may be at a significantly increased risk of SARS-CoV-2 infection [P?=?0.003; OR (95 % CI); 3.66 (1.47-9.15)]. We also observed a borderline significant difference in the genotype distribution of the LZTFL1 rs11385942 polymorphism (P?=?0.04) between the population sample and SARS-CoV-2-positive subjects. In agreement with previous studies, a nonsignificantly higher frequency of minor allele carriers was detected among hospitalized COVID-19 subjects. We conclude that a common polymorphism in the ABCA3 gene may be a significant predictor of susceptibility to SARS-CoV-2 infection.

Association between a marker on chromosome 9 and acute coronary syndrome. confirmatory study on Czech population.

Myocardial infarction (MI) is the leading cause of death in industrialized countries. All the classical risk factors for MI are responsible for approximately 50 % of MI cases. Attention has therefore recently been attracted to those genetic variants that are not associated with conventional risk factors. One of them is the marker rs10757274 in the "genefree" zone on chromosome 9, which has been repeatedly recognized as a risk factor for development of MI in Western populations. We analysed the relationship between the rs10757274 variant on chromosome 9 and risk of the acute coronary syndrome (ACS) in Czech population. The rs10757274 (A > G) variant was successfully analysed (CR = 99.4 % for patients and 98.4 % for controls) by PCR-RFLP in consecutively examined 1,046 men and 281 women with ACS (age below 65 years) and in population-based controls - 1,162 men and 1,355 women (aged up to 65 years). ANOVA and χ2 were used for statistical analysis. We confirmed that GG homozygotes are more frequent (codominant model of analysis) among patients with myocardial infarction than in the control group both in men (28.5 % vs. 22.0 %, P = 0.0001, OR 1.73, 95 % CI 1.36-2.19) and women (32.0 % vs. 24.6 %, P = 0.02, OR 1.62, 95 % CI 1.13-2.34). However, rs10757274 polymorphism was not associated with the classical risk factors either in control population or in ACS patients. We conclude that the rs10757274 variant at 9p23.1 is an important genetic risk factor for ACS development in the Czech population.

[FTO gene and his role in genetic determination of obesity]. / Gen pro FTO a jeho role v genetické determinaci obezity.

Obesity is a risk factor for development of cardiovascular disease, type 2 diabetes and some cancers. Substantial proportions of obese people die from diseases caused by complications of overweight. The incidence of obesity in different populations exceeds 15%. The emergence of obesity is influenced by external factors (especially excessive energy intake and reduced physical activity). Body Mass Index (BMI) is also influenced by genetic factors, estimates of the degree of inheritance of obesity, according to the type of study range from 30 to 70%. Newly detected genetic risk factor for body weight is the FTO gene ("fat mass and obesity associated"). Variants in the first (and in some populations also in the third) intron of this gene are associated with BMI values and the presence of one risk allele is associated with an increase of body weight by about 1.5-2 kg. Studies on the possible causality (impact on energy intake, basal metabolism, physical activity) did not show consistent results. Variants in the first intron are also associated with higher risk of type 2 diabetes, polycystic ovary syndrome, and cardiovascular disease and seem to play a role in the determination of certain types of cancer and are associated with higher mortality. The exact mechanism of the effect of FTO on BMI determination is not yet known, however, the FTO exhibit a DNA demethylase activity and its role is designed as a transcription coactivator.