[Main methodological approaches to the identification and diagnosis of monogenic hereditary diseases and problems in the organization of medical care and unified preventive programs].

In order to optimize economic and organizational technologies for the provision of medical care to the population and to increase the effectiveness of preventive programs, an analysis of the accumulated morbidity and prevalence of monogenic hereditary diseases (MHDs) has been carried out in 13 federal subjects of the Russian Federation representing 11 ethnic groups: Russians of 6 regions, Tatars, Maris, Chuvashs, Bashkirs, Udmurts, Abazins, Adygeans, Nogays, Circassians and Karachays. The study of the population was carried out according to the developed protocol of complex genetic and epidemiological studies in the Research Center for Medical Genetics, which remains unchanged throughout the study. Here we have studied the structure of the genetic load and diversity of MHDs depending on the prevalence of diseases and in accordance with the classification by organ and system types of disease: neurological, ophthalmological, genodermatosis, skeletal, hereditary syndromes, and other hereditary pathology (metabolic hereditary diseases, disorders of blood, hearing, etc.). It is shown that the maximum number of patients (61.81%) falls in the group of frequent forms of MHDs, which differ by federal subjects / ethnic groups of the Russian Federation. There are frequent forms of MHDs for all populations, and "specific" forms for particular federal subjects of the Russian Federation/ethnic groups. Only for a small group of hereditary diseases there is treatment. Most of the detected diseases-psychiatric, neurological, hematological, and hereditary syndromes-significantly reduce life expectancy. Hereditary diseases of the skeleton, eyes, ears and metabolism affect the quality of life, adaptation in society and public health. On average, 65% of patients are diagnosed with MHDs for the first time. This situation implies changes in medical thinking, changes in education and development of both common for all regions and specific prevention programs. Thus, fundamental research in medicine can improve the quality of medical services and contribute to the improvement of public health.

Spectrum of CFTR mutations in Chechen cystic fibrosis patients: high frequency of c.1545_1546delTA (p.Tyr515X; 1677delTA) and c.274G>A (p.Glu92Lys, E92K) mutations in North Caucasus.

BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.

Expression Profiles of Genes-Potential Therapy Targets-and Their Relationship to Survival in Renal Cell Carcinoma.

The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.

Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations.

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

Risk of statin therapy in elderly.

A meta-analysis of younger patients included in randomized trials found good evidence that statins reduce vascular events and mortality in people with high cholesterol and the risk of coronary heart disease. The use pf statin in the elderly prevents the disease but can exert considerable side effects.

Deficiency of vitamin D and vitamin C in the pathogenesis of bronchial asthma.

Epidemiology of bronchial asthma (BA) indicates a marked paradox: rapid rise in the prevalence.Simultaneous decline in mortality is mostly related to improvement in the diagnosis and therapy. In many economically developed countries the BA affects more than 10 per cent of the population, while mortality related to this respiratory disorder is below 1/100,000. Factors favorably influencing mortality of BA include new more effective medications, decline in smoking and also improved nutrition, based on awareness of protective role of vitamins. Vitamin D deficiency has a number of biological effects that are potentially instrumental in the pathogenesis and severity of BA. Increased number of randomized, controlled, interventional studies is showing positive effects of vitamin D supplementation in pediatric and in adult BA. Oxidative stress is potentially an important pathogenic factor in the progression of BA. Vitamin C (ascorbic acid) belongs to the most effective nutritional antioxidants. By counteracting oxidants, reducing generation of reactive oxygen species, vitamin C may inhibit external attacks in the respiratory tract, thus modulating the development of BA (Fig. 2, Ref. 15).

[Marriage and Migratory Characteristic of Circassians (Late 20th Century)].

This paper analyzes 2052 marriage records for 1990-2000 in the Khabezsky district of Karachay-Cherkessia. The main marriage and migration characteristics of Circassians are studied: index of endogamy, ethnic mar- riage assortativity, intensity of metisation, and Malecot's parameters of isolation by distance.

Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies.

Tumors of the jaws may represent different human disorders and frequently associate with pathologic bone fractures. In this report, we analyzed two affected siblings from a family of Russian origin, with a history of dental tumors of the jaws, in correspondence to original clinical diagnosis of cementoma consistent with gigantiform cementoma (GC, OMIM: 137575). Whole exome sequencing revealed the heterozygous missense mutation c.1067G > A (p.Cys356Tyr) in ANO5 gene in these patients. To date, autosomal-dominant mutations have been described in the ANO5 gene for gnathodiaphyseal dysplasia (GDD, OMIM: 166260), and multiple recessive mutations have been described in the gene for muscle dystrophies (OMIM: 613319, 611307); the same amino acid (Cys) at the position 356 is mutated in GDD. These genetic data and similar clinical phenotypes demonstrate that the GC and GDD likely represent the same type of bone pathology. Our data illustrate the significance of mutations in single amino-acid position for particular bone tissue pathology. Modifying role of genetic variations in another gene on the severity of the monogenic trait pathology is also suggested. Finally, we propose the model explaining the tissue-specific manifestation of clinically distant bone and muscle diseases linked to mutations in one gene.

New data on harmful effects of trans-fatty acids.

Various margarines containing trans-fatty acids were marketed as being healthier because of the absence of cholesterol, suggesting to use margarine instead of butter. Fifteen years ago, research documented the grave health risk of trans-fats (T-fat). US FDA in 2015 finalized its decision that T-fat is not safe and set a three-year time limit for complete removal of T-fat from all foods. The greatest danger from T-fat lies in its capacity to distort the cell membranes. The primary health risk identified for T-fat consumption is an elevated risk of coronary heart disease. T-fats have an adverse effect on the brain and nervous system. T-fat from the diet is incorporated into brain cell membranes and alter the ability of neurons to communicate. This can diminish mental performance. Relationship between T-fat intake and depression risk was observed. There is growing evidence for a possible role of T-fat in the development of Alzheimer´s disease and cognitive decline with age.

High prevalence of W1282x mutation in cystic fibrosis patients from Karachay-Cherkessia.

Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease. The spectrum and frequency of CFTR mutations vary significantly in different populations and ethnic groups. A genetic epidemiological study was conducted in the indigenous ethnic group of people known as the Karachais. They live in the Republic of Karachay-Cherkessia, which lies in the northwest of Russia's North Caucasus region. Karachai's are Turkic-speaking and consist of 194 thousand people (approximately 40% of the population of the Republic). Molecular genetic analysis was performed in 10 unrelated Karachai families with CF patients from three districts in the Republic. A high frequency of W1282X mutation was found (18 of 20 mutant alleles): eight patients were homozygous for the W1282X mutation, and two were compound heterozygous (the second alleles were R1066C and R709X). Analysis for 13 common CF mutations in the sample of 142 healthy Karachais identified two 1677delTA and two W1282X mutation carriers. Thus, the most common CFTR mutation, F508del, was not detected among the CF patients or in healthy Karachais. The most frequent mutation among Karachai patients is W1282X (90%). Its frequency in healthy Karachais is approximately 0.007. Haplotype analysis using the CFTR intragene DNA markers IVS1CA, IVS6aGATT, IVS8CA and IVS17bCA showed that the origins of the W1282X mutation in Karachay-Cherkessia and the Eastern European part of Russia are different.

Region-specific differences in colorectal cancer: Slovakia and Hungary have highest incidence in Europe.

Epidemiological data on colorectal cancer (CRC) exhibit high incidence in Central East Europe. Hungary, Slovakia and Croatia represent the lead. For decades it was the Czech Republic but it attained the fourth rank after the mid-2000. Remarkably, the Ashkenazi Jews who imigrated to the USA from Central Europe have the highest incidence of CRC among US minorities. They also have high incidence of inflammatory bowel disease, a risk for CRC. Notably, countries surrounding the Central European focus of CRC, Austria, Germany, Poland, Romania, Ukraine and Russia have substantially lower incidence. CRC in Central Europe has higher incidence than CRC among the highest at-risk cohort in the USA, the elderly blacks. Research and the genome wide screening identified genetic mutations associated with CRC in Ashkenazis from Central Europe. Some risk factors for CRC are non genotypic as evidenced by wide variation in CRC incidence in the course of only a few decades. Recent trends offer hope that identification of the non-innate pathogenic mechanisms would potentially reduce the burden of this third most lethal malignancy (Tab. 1, Fig. 4, Ref. 40).

Novel potential for the management of Alzheimer disease.

Pathologic characteristics of Alzheimer disease (AD) are ß-amyloid (Aß) plaques, neurofibrillary tangles (NFT) and neurodegeneration. Currently, there is no cure for AD. Cilostazol, a selective inhibitor of type 3 phosphodiesterase, is likely to be a promising agent for AD. In the brain of the experimental animals it significantly reduced the Aß amyloid plaques. Initial clinical reports on the effect of Cilostazol in AD patients are promising. In mice, stem cells favourably influence the pathogenetic process critical in AD, by reducing deposits of Aß plaques. Clinical trials of the drug, called Betablock, are already underway in Britain. Successful management and resolution of AD in man will still require further intensive research (Fig. 4, Ref. 11).

Recent data on Mediterranean diet, cardiovascular disease, cancer, diabetes and life expectancy.

Benefits of dietary moderation when on a Mediterranean diet type (MD) have been known for well over half a century. In the past, there has been a vigorous renewal of interest in preventive potential of MD. This review is unique, by focusing on the very recent confirmatory data on the MD, all published within the first half of 2014. Benefits of MD in preventing and reducing cardiovascular disorders (CVD), known before, have been strongly confirmed. While there is little doubt regarding potential benefit of MD for obesity, diabetes type II, metabolic syndrome and fatty liver, critical evaluation has to be aimed at reported benefits of MD in such widely metabolic diverse disorders as cancer, pulmonary disease and cognition defects, including Alzheimer disease (Ref. 20). Text in PDF www.elis.sk.

Gastric intestinal metaplasia - age, ethnicity and surveillance for gastric cancer.

AIM: Determine the prevalence and distribution of gastric intestinal metaplasia (GIM) in a large cohort of patients subjected to esophagogastroscopy (EGD). Evaluate usefulness of grading the severity of gastritis, GIM and the impact of Helicobacter pylori (HP). Define the population at risk for gastric adenocarcinoma (GC) and assess the value of surveillance. METHODS: In the course of 19 years, we performed 11,600 sequential EGDs in male veterans at Brooklyn, New York. Of all patients, 47 % had EGD only one time while 53 % had EGD repeated, 11 % of these had four or more EGDs. Patients with GIM were matched with equal number of controls with no GI symptoms. All gastric biopsies were processed in one laboratory, using the standardized protocol for histological staining and for grading the severity of epithelial changes. RESULTS: Of all patients subjected to EGD, 354 (3.05 %) were diagnosed with GIM. Compared to controls, GIM patients were older, 80 % were over 71. Regarding ethnicity, GIM was 5.4 % more frequent in 177 African Americans than in 159 Caucasians. Distribution of GIM did not differ with respect to age or ethnicity. As many as 6 %of GIM cases were diagnosed with GC. Grading of GIM severity had a predictive value, the average grade of severity in GC was 50 % higher than in non-cancer patients with GIM. Severity of gastritis was also a useful biomarker: patients with GC had more severe gastritis. Surprisingly, HP positivity had no predictive value: HP positive patients had similar distribution of GIM as the HP negative patients. Use of proton pump inhibitors in the past was unknown. CONCLUSION: Prevalence of GC in patients with GIM was more than 200 times higher than reported in normal population. Age more than 70 years and African Americans appeared to be at higher risk. Routine EGD and histological diagnosis, with simple grading of severity of epithelial changes provides a useful predictive information. Individuals with upper GI symptoms undergoing EGD with gastric biopsy benefited from routine clinical screening for GC. Patients with higher severity of GIM should enter surveillance (Tab. 1, Fig. 10, Ref. 45).

New weapon in fighting atherosclerosis: effective inhibition of circulating low density lipoprotein cholesterol.

Last but not least a warning. Cholesterol is not only a pathogenic metabolite, it is an essential biological component. Indiscriminate cholesterol lowering may be inappropriate and harmful. The more effective is a weapon, the higher is the potential for a collateral damage (Fig. 1, Ref. 10).

Gut microorganisms and cardiovascular disease: carnitine is the answer.

This short paper summarizes the current understanding regarding carnitine and gut bacteria which will provide new clues to uncover the background of multifactorial diseases such as cardiovascular disorders (CVD). Carnitine is a quaternary ammonium compound biosynthesized from phosphatidylcholine and the amino acids lysine and methionine (Fig. 3, Ref. 12).