👤 Ekaterina A Semenova

Obesity and weight regulation disorders are determined by the combined effects of genetics and environment. Polygenic obesity results from the combination of common variants in several genes which predisposes the individual to obesity and its related complications. In contrast, monogenic obesity results from changes in single genes, especially those in leptin-melanocortin pathway, and presents with early onset severe obesity, with or without other syndromic features. Rare variants in melanocortin 4 receptor are the commonest form of monogenic obesity. In addition, structural variation in small or large segments of chromosomes may also present with syndromic forms of obesity. Prader-Willi Syndrome, caused by imprinting errors in chromosome 15q11-13, is the most prevalent genetic cause of severe hyperphagia and obesity. With the advances in technologies, the past decade has witnessed a revolution in the identification of novel genetic causes of obesity, primarily in genes related to the leptin melanocortin pathway. The availability of safe melanocortin analogs holds the potential for targeted therapies for some of these disorders. This review summarizes known and novel rare genetic forms of obesity, along with approaches for the clinical investigation of copy number and sequence variants. The goal is to provide a reference for practicing clinicians to encourage genetic testing in obesity. IMPACT: What does this article add to the existing literature? Genetic obesity is an expanding frontier with potential to change management. Here, we summarize current information on the genetic causes of obesity and provide guidance for genetic testing. Emerging treatments may provide targeted precise treatment and change management practices. Show less

This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the Show less

Gene fusion events result in chimeric proteins that are frequently found in human cancers. Specific targeted therapies are available for several types of cancer fusions including receptor tyrosine kinase gene moieties. RNA sequencing (RNAseq) can directly be used for detection of gene rearrangements in a single test, along with multiple additional biomarkers. However, tumor biosamples are usually formalin-fixed paraffin-embedded (FFPE) tissue blocks where RNA is heavily degraded, which in theory may result in decreased efficiency of fusion detection. Here, for the first time, we compared the efficacy of gene fusion detection by RNAseq for matched pairs of freshly frozen in RNA stabilizing solution (FF) and FFPE tumor tissue samples obtained from 29 human colorectal cancer patients. We detected no statistically significant difference in the number of chimeric transcripts in FFPE and FF RNAseq profiles. The known fusion Show less

Phenotypes of athletic performance and exercise capacity are complex traits influenced by both genetic and environmental factors. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status summarises recent advances in sports genomics research, including findings from candidate gene and genome-wide association (GWAS) studies, meta-analyses, and findings involving larger-scale initiatives such as the UK Biobank. As of the end of May 2023, a total of 251 DNA polymorphisms have been associated with athlete status, of which 128 genetic markers were positively associated with athlete status in at least two studies (41 endurance-related, 45 power-related, and 42 strength-related). The most promising genetic markers include the Show less

Moreland, E, Borisov, OV, Semenova, EA, Larin, AK, Andryushchenko, ON, Andryushchenko, LB, Generozov, EV, Williams, AG, and Ahmetov, II. Polygenic profile of elite strength athletes. J Strength Cond Res 36(9): 2509-2514, 2022-Strength is a heritable trait with unknown polygenic nature. So far, more than 200 DNA polymorphisms associated with strength/power phenotypes have been identified majorly involving nonathletic populations. The aim of the present study was to investigate individually and in combination the association of 217 DNA polymorphisms previously identified as markers for strength/power phenotypes with elite strength athlete status. A case-control study involved 83 Russian professional strength athletes (53 weightlifters, 30 powerlifters), 209 Russian and 503 European controls. Genotyping was conducted using micro-array analysis. Twenty-eight DNA polymorphisms (located near or in ABHD17C , ACTG1 , ADCY3 , ADPGK , ANGPT2 , ARPP21 , BCDIN3D , CRTAC1 , DHODH , GBE1 , IGF1 , IL6 , ITPR1 , KIF1B , LRPPRC , MMS22L , MTHFR , NPIPB6 , PHACTR1 , PLEKHB1 , PPARG , PPARGC1A , R3HDM1 , RASGRF1 , RMC1 , SLC39A8 , TFAP2D , ZKSCAN5 genes) were identified to have an association with strength athlete status. Next, to assess the combined impact of all 28 DNA polymorphisms, all athletes were classified according to the number of "strength" alleles they possessed. All highly elite strength athletes were carriers of at least 22 (up to 34) "strength" alleles, whereas 27.8% of Russian controls had less than 22 "strength" alleles ( p < 0.0001). The proportion of subjects with a high (≥26) number of "strength" alleles was significantly greater in highly elite strength athletes (84.8%) compared with less successful strength athletes (64.9%; odd ratio [OR] = 3.0, p = 0.042), Russian (26.3%; OR = 15.6, p < 0.0001) or European (37.8%; OR = 6.4, p < 0.0001) controls. This is the first study to demonstrate that the likelihood of becoming an elite strength athlete depends on the carriage of a high number of strength-related alleles. Show less

Brisk walkers are physically more active, taller, have reduced body fat and greater physical fitness and muscle strength. The aim of our study was to determine whether genetic variants associated with increased walking pace were overrepresented in elite sprinters compared to controls. A total of 70 single-nucleotide polymorphisms (SNPs) previously identified in a genome-wide association study (GWAS) of self-reported walking pace in 450,967 European individuals were explored in relation to sprinter status. Genotyping of 137 Russian elite sprinters and 126 controls was performed using microarray technology. Favorable (i.e., high-speed-walking) alleles of 15 SNPs (FHL2 rs55680124 C, SLC39A8 rs13107325 C, E2F3 rs4134943 T, ZNF568 rs1667369 A, GDF5 rs143384 G, PPARG rs2920503 T, AUTS2 rs10452738 A, IGSF3 rs699785 A, CCT3 rs11548200 T, CRTAC1 rs2439823 A, ADAM15 rs11264302 G, C6orf106 rs205262 A, AKAP6 rs12883788 C, CRTC1 rs11881338 A, NRXN3 rs8011870 G) were identified as having positive associations with sprinter status (p < 0.05), of which IGSF3 rs699785 survived correction for multiple testing (p = 0.00004) and was linked (p = 0.042) with increased proportions of fast-twitch muscle fibers of m. vastus lateralis in physically active men (n = 67). Polygenic analysis revealed that individuals with ≥18 favorable alleles of the 15 SNPs have an increased odds ratio of being an elite sprinter when compared to those with ≤17 alleles (OR: 7.89; p < 0.0001). Using UK Biobank data, we also established the association of 14 favorable alleles with low BMI and fat percentage, 8 alleles with increased handgrip strength, and 7 alleles with increased height and fat-free mass. In conclusion, we have identified 15 new genetic markers associated with sprinter status. Show less

Background: Hypertriglyceridemia (HTG) is one of the most common forms of lipid metabolism disorders. The leading clinical manifestations are pancreatitis, atherosclerotic vascular lesions, and the formation of eruptive xanthomas. The most severe type of HTG is primary (or hereditary) hypertriglyceridemia, linked to pathogenic genetic variants in LPL, APOC2, LMF1, and APOA5 genes. Case: We present a clinical case of severe primary hypertriglyceridemia (TG level > 55 mmol/L in a 4-year-old boy) in a consanguineous family. The disease developed due to a previously undescribed homozygous deletion in the APOA5 gene (NM₀₅₂₉₆₈: c.579₅₉₂delATACGCCGAGAGCC p.Tyr194Gly*68). We also evaluate the clinical significance of a genetic variant in the LPL gene (NM₀₀₀₂₃₇.2: c.106G>A (rs1801177) p.Asp36Asn), which was previously described as a polymorphism. In one family, we also present a different clinical significance even in heterozygous carriers: from hypertriglyceridemia to normotriglyceridemia. We provide evidence that this heterogeneity has developed due to polymorphism in the LPL gene, which plays the role of an additional trigger. Conclusions: The homozygous deletion of the APOA5 gene is responsible for the severe hypertriglyceridemia, and another SNP in the LPL gene worsens the course of the disease. Show less

Branched-chain amino acid (BCAA) levels are associated with skeletal muscle cross-sectional area (CSA). Serum BCAA levels are enhanced by whey protein supplementation (WPS), and evidence in clinical populations suggests an association of single nucleotide polymorphisms (SNPs) with BCAA metabolite levels. It is not known whether the same SNPs are associated with the ability to catabolise BCAAs from exogenous sources, such as WPS. The present study investigated whether possessing a higher number of alleles associated with increased BCAA metabolites correlates with muscle fiber CSA of m. vastus lateralis in physically active participants, and whether any relationship is enhanced by WPS. Endurance-trained participants (n = 75) were grouped by self-reported habitual WPS consumption and genotyped for five SNPs (PPM1K rs1440580, APOA5 rs2072560, CBLN1 rs1420601, DDX19B rs12325419, and TRMT61A rs58101275). Body mass, BMI, and fat percentage were significantly lower and muscle mass higher in the WPS group compared to Non-WPS. The number of BCAA-increasing alleles was correlated with fiber CSA in the WPS group (r = 0.75, p < 0.0001) and was stronger for fast-twitch fibers (p = 0.001) than slow-twitch fibers (p = 0.048). Similar results remained when corrected for multiple covariates (age, physical activity, and meat and dairy intake). No correlation was found in the Non-WPS group. This study presents novel evidence of a positive relationship between BCAA-increasing alleles and muscle fiber CSA in athletes habitually consuming WPS. We suggest that a high number of BCAA-increasing alleles improves the efficiency of WPS by stimulation of muscle protein synthesis, and contributes to greater fiber CSA. Show less

Sports genomics is the scientific discipline that focuses on the organization and function of the genome in elite athletes, and aims to develop molecular methods for talent identification, personalized exercise training, nutritional need and prevention of exercise-related diseases. It postulates that both genetic and environmental factors play a key role in athletic performance and related phenotypes. This update on the panel of genetic markers (DNA polymorphisms) associated with athlete status and soft-tissue injuries covers advances in research reported in recent years, including one whole genome sequencing (WGS) and four genome-wide association (GWAS) studies, as well as findings from collaborative projects and meta-analyses. At end of 2020, the total number of DNA polymorphisms associated with athlete status was 220, of which 97 markers have been found significant in at least two studies (35 endurance-related, 24 power-related, and 38 strength-related). Furthermore, 29 genetic markers have been linked to soft-tissue injuries in at least two studies. The most promising genetic markers include HFE rs1799945, MYBPC3 rs1052373, NFIA-AS2 rs1572312, PPARA rs4253778, and PPARGC1A rs8192678 for endurance; ACTN3 rs1815739, AMPD1 rs17602729, CPNE5 rs3213537, CKM rs8111989, and NOS3 rs2070744 for power; LRPPRC rs10186876, MMS22L rs9320823, PHACTR1 rs6905419, and PPARG rs1801282 for strength; and COL1A1 rs1800012, COL5A1 rs12722, COL12A1 rs970547, MMP1 rs1799750, MMP3 rs679620, and TIMP2 rs4789932 for soft-tissue injuries. It should be appreciated, however, that hundreds and even thousands of DNA polymorphisms are needed for the prediction of athletic performance and injury risk. Show less

The genetic predisposition to elite athletic performance has been a controversial subject due to the underpowered studies and the small effect size of identified genetic variants. The aims of this study were to investigate the association of common single-nucleotide polymorphisms (SNPs) with endurance athlete status in a large cohort of elite European athletes using GWAS approach, followed by replication studies in Russian and Japanese elite athletes and functional validation using metabolomics analysis. The association of 476,728 SNPs of Illumina DrugCore Gene chip and endurance athlete status was investigated in 796 European international-level athletes (645 males, 151 females) by comparing allelic frequencies between athletes specialized in sports with high ( This is the first report of genome-wide significant SNP and related metabolites associated with elite athlete status. Further investigations of the functional relevance of the identified SNPs and metabolites in relation to enhanced athletic performance are warranted. Show less

Astrocyte activation is one of the earliest findings in the brain of methamphetamine (Meth) abusers. Our goal in this study was to identify the characteristics of the astrocytic acute response to the drug, which may be critical in pathogenic outcomes secondary to the use. We developed an integrated analysis of gene expression data to study the acute gene changes caused by the direct exposure to Meth treatment of astrocytes in vitro, and to better understand how astrocytes respond, what are the early molecular markers associated with this response. We examined the literature in search of similar changes in gene signatures that are found in central nervous system disorders. We identified overexpressed gene networks represented by genes of an inflammatory and immune nature and that are implicated in neuroactive ligand-receptor interactions. The overexpressed networks are linked to molecules that were highly upregulated in astrocytes by all doses of methamphetamine tested and that could play a role in the central nervous system. The strongest overexpressed signatures were the upregulation of MAP2K5, GPR65, and CXCL5, and the gene networks individually associated with these molecules. Pathway analysis revealed that these networks are involved both in neuroprotection and in neuropathology. We have validated several targets associated to these genes. Gene signatures for the astrocytic response to Meth were identified among the upregulated gene pool, using an in vitro system. The identified markers may participate in dysfunctions of the central nervous system but could also provide acute protection to the drug exposure. Further in vivo studies are necessary to establish the role of these gene networks in drug abuse pathogenesis. Show less