A Systematic Review and Meta-Analysis of Free Triiodothyronine (FT3) Levels in Humans Depending on Seasonal Air Temperature Changes: Is the Variation in FT3 Levels Related to Nonshivering Thermogenesis?

Thyroid hormones play a crucial role in regulating normal development, growth, and metabolic function. However, the controversy surrounding seasonal changes in free triiodothyronine (FT3) levels remains unresolved. Therefore, the aim of this study was to conduct a systematic review and meta-analysis of variations in FT3 levels in relation to seasonal air temperatures in the context of current knowledge about its role in nonshivering thermogenesis. Ten eligible articles with a total of 336,755 participants were included in the meta-analysis. The studies were categorized into two groups based on the air temperature: "Cold winter", where the winter temperature fell below 0 °C, and "Warm winter", where the winter temperature was above 0 °C. The analysis revealed that in cold regions, FT3 levels decreased in winter compared to summer (I2 = 57%, p < 0.001), whereas in warm regions, FT3 levels increased during winter (I2 = 28%, p < 0.001). These findings suggest that seasonal variations in FT3 levels are likely to be influenced by the winter temperature. Considering the important role of the FT3 in the nonshivering thermogenesis process, we assume that this observed pattern is probably related to the differences in use of thyroid hormones in the brown adipose tissue during adaptive thermogenesis, which may depend on intensity of cold exposure.

The GJB2 (Cx26) Gene Variants in Patients with Hearing Impairment in the Baikal Lake Region (Russia).

The GJB2 (Cx26) gene pathogenic variants are associated with autosomal recessive deafness type 1A (DFNB1A, OMIM #220290). Direct sequencing of the GJB2 gene among 165 hearing-impaired individuals living in the Baikal Lake region of Russia identified 14 allelic variants: pathogenic/likely pathogenic-nine variants, benign-three variants, unclassified-one variant, and one novel variant. The contribution of the GJB2 gene variants to the etiology of hearing impairment (HI) in the total sample of patients was 15.8% (26 out of 165) and significantly differed in patients of different ethnicity (5.1% in Buryat patients and 28.9% in Russian patients). In patients with DFNB1A (n = 26), HIs were congenital/early onset (92.3%), symmetric (88.5%), sensorineural (100.0%), and variable in severity (moderate-11.6%, severe-26.9% or profound-61.5%). The reconstruction of the SNP haplotypes with three frequent GJB2 pathogenic variants (c.-23+1G>A, c.35delG or c.235delC), in comparison with previously published data, supports a major role of the founder effect in the expansion of the c.-23+1G>A and c.35delG variants around the world. Comparative analysis of the haplotypes with c.235delC revealed one major haplotype G A C T (97.5%) in Eastern Asians (Chinese, Japanese and Korean patients) and two haplotypes, G A C T (71.4%) and G A C C (28.6%), in Northern Asians (Altaians, Buryats and Mongols). The variable structure of the c.235delC-haplotypes in Northern Asians requires more studies to expand our knowledge about the origin of this pathogenic variant.

Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies

Pathogenic variants in the SLC26A4, FOXI1, and KCNJ10 genes are associated with hearing loss (HL) and specific inner ear abnormalities (DFNB4). In the present study, phenotype analyses, including clinical data collection, computed tomography (CT), and audiometric examination, were performed on deaf individuals from the Sakha Republic of Russia (Eastern Siberia). In cases with cochleovestibular malformations, molecular genetic analysis of the coding regions of the SLC26A4, FOXI1, and KCNJ10 genes associated with DFNB4 was completed. In six of the 165 patients (3.6%), CT scans revealed an incomplete partition of the cochlea (IP-1 and IP-2), in isolation or combined with an enlarged vestibular aqueduct (EVA) anomaly. Sequencing of the SLC26A4, FOXI1, and KCNJ10 genes was performed in these six patients. In the SLC26A4 gene, we identified four variants, namely c.85G>C p.(Glu29Gln), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln), and c.2089+1G>A (IVS18+1G>A), which are known as pathogenic, as well as c.441G>A p.(Met147Ile), reported previously as a variant with uncertain significance. Using the AlphaFold algorithm, we found in silico evidence of the pathogenicity of this variant. We did not find any causative variants in the FOXI1 and KCNJ10 genes, nor did we find any evidence of digenic inheritance associated with double heterozygosity for these genes with monoallelic SLC26A4 variants. The contribution of biallelic SLC26A4 variants in patients with IP-1, IP-2, IP-2+EVA, and isolated EVA was 66.7% (DFNB4 in three patients, Pendred syndrome in one patient). Seventy-five percent of SLC26A4-biallelic patients had severe or profound HL. The morphology of the inner ear anomalies demonstrated that, among SLC26A4-biallelic patients, all types of incomplete partition of the cochlea are possible, from IP-1 and IP-2, to a normal cochlea. However, the dominant type of anomaly was IP-2+EVA (50.0%). This finding is very important for cochlear implantation, since the IP-2 anomaly does not have an increased risk of "gushers" and recurrent meningitis.

Relationships between Uncoupling Protein Genes UCP1, UCP2 and UCP3 and Irisin Levels in Residents of the Coldest Region of Siberia.

Currently, it is known that irisin can participate in the processes of thermoregulation and browning of adipose tissue, and, therefore, it is possible that it is involved in the microevolutionary mechanisms of adaptation to a cold. The aim of this study is to investigate the relationship between the uncoupling protein genes (UCP1, UCP2, UCP3) and the irisin levels in the residents of the coldest region of Siberia. The sample consisted of 279 Yakut people (185 females, 94 males, average age 19.8 ± 2.03 years). The females plasma irisin concentration was 8.33 ± 2.74 mcg/mL and the males was 7.76 ± 1.86 mcg/mL. Comparative analysis of irisin levels with the genotypes of six studied SNP-markers in females revealed a significant association of irisin with rs1800849-UCP3. The TT genotype of rs1800849 was associated with elevated levels of irisin (p = 0.01). It was also found that this TT genotype in females was associated with reduced weight and height (p = 0.03). We searched for natural selection signals for the T-allele rs1800849-UCP3; as a result of which, it was found that this allele has a significantly high frequency of distribution in northern (45%, CI: 0.42-0.484) compared with southern Asian populations (28%, CI: 0.244-0.316) (p = 0.01). The results obtained indicate the probable involvement of irisin and the UCP3 gene in thermoregulation, and the spread of its allelic variants is probably related to adaptation to a cold climate.

Agent-Based Modeling of Autosomal Recessive Deafness 1A (DFNB1A) Prevalence with Regard to Intensity of Selection Pressure in Isolated Human Population.

An increase in the prevalence of autosomal recessive deafness 1A (DFNB1A) in populations of European descent was shown to be promoted by assortative marriages among deaf people. Assortative marriages became possible with the widespread introduction of sign language, resulting in increased genetic fitness of deaf individuals and, thereby, relaxing selection against deafness. However, the effect of this phenomenon was not previously studied in populations with different genetic structures. We developed an agent-based computer model for the analysis of the spread of DFNB1A. Using this model, we tested the impact of different intensities of selection pressure against deafness in an isolated human population over 400 years. Modeling of the "purifying" selection pressure on deafness ("No deaf mating" scenario) resulted in a decrease in the proportion of deaf individuals and the pathogenic allele frequency. Modeling of the "relaxed" selection ("Assortative mating" scenario) resulted in an increase in the proportion of deaf individuals in the first four generations, which then quickly plateaued with a subsequent decline and a decrease in the pathogenic allele frequency. The results of neutral selection pressure modeling ("Random mating" scenario) showed no significant changes in the proportion of deaf individuals or the pathogenic allele frequency after 400 years.

The Role of Nonshivering Thermogenesis Genes on Leptin Levels Regulation in Residents of the Coldest Region of Siberia.

Leptin plays an important role in thermoregulation and is possibly associated with the microevolutionary processes of human adaptation to a cold climate. In this study, based on the Yakut population (n = 281 individuals) living in the coldest region of Siberia (t°minimum -71.2 °C), we analyze the serum leptin levels and data of 14 single nucleotide polymorphisms (SNPs) of 10 genes (UCP1, UCP2, UCP3, FNDC5, PPARGC1A, CIDEA, PTGS2, TRPV1, LEPR, BDNF) that are possibly involved in nonshivering thermogenesis processes. Our results demonstrate that from 14 studied SNPs of 10 genes, 2 SNPs (the TT rs3811787 genotype of the UCP1 gene and the GG rs6265 genotype of the BDNF gene) were associated with the elevated leptin levels in Yakut females (p < 0.05). Furthermore, of these two SNPs, the rs3811787 of the UCP1 gene demonstrated more indications of natural selection for cold climate adaptation. The prevalence gradient of the T-allele (rs3811787) of UCP1 increased from the south to the north across Eurasia, along the shore of the Arctic Ocean. Thereby, our study suggests the potential involvement of the UCP1 gene in the leptin-mediated thermoregulation mechanism, while the distribution of its allelic variants is probably related to human adaptation to a cold climate.

Autosomal recessive cataract (CTRCT18) in the Yakut population isolate of Eastern Siberia: a novel founder variant in the FYCO1 gene.

Congenital autosomal recessive cataract with unknown genetic etiology is one of the most common Mendelian diseases among the Turkic-speaking Yakut population (Eastern Siberia, Russia). To identify the genetic cause of congenital cataract spread in this population, we performed whole-exome sequencing (Illumina NextSeq 500) in one Yakut family with three affected siblings whose parents had preserved vision. We have revealed the novel homozygous c.1621C>T transition leading to premature stop codon p.(Gln541*) in exon 8 of the FYCO1 gene (NM_024513.4). Subsequent screening of c.1621C>T p.(Gln541*) revealed this variant in a homozygous state in 25 out of 29 Yakut families with congenital cataract (86%). Among 424 healthy individuals from seven populations of Eastern Siberia (Russians, Yakuts, Evenks, Evens, Dolgans, Chukchi, and Yukaghirs), the highest carrier frequency of c.1621C>T p.(Gln541*) was found in the Yakut population (7.9%). DNA samples of 25 homozygous for c.1621C>T p.(Gln541*) patients with congenital cataract and 114 unaffected unrelated individuals without this variant were used for a haplotype analysis based on the genotyping of six STR markers (D3S3512, D3S3685, D3S3582, D3S3561, D3S1289, and D3S3698). The structure of the identified haplotypes indicates a common origin for all of the studied mutant chromosomes bearing c.1621C>T p.(Gln541*). The age of the с.1621C>T p.(Gln541*) founder haplotype was estimated to be approximately 260 ± 65 years (10 generations). These findings characterize Eastern Siberia as the region of the world with the most extensive accumulation of the unique variant c.1621C>T p.(Gln541*) in the FYCO1 gene as a result of the founder effect.

A new approach to estimating the prevalence of hereditary hearing loss: An analysis of the distribution of sign language users based on census data in Russia.

The absence of comparable epidemiological data challenges the correct estimation of the prevalence of congenital hearing loss (HL) around the world. Sign language (SL) is known as the main type of communication of deaf people. We suggest that the distribution of SL can be interpreted as an indirect indicator of the prevalence of congenital HL. Since a significant part of congenital HL is due to genetic causes, an assessment of the distribution of SL users can reveal regions with an extensive accumulation of hereditary HL. For the first time, we analyzed the data on the distribution of SL users that became available for the total population of Russia by the 2010 census. Seventy-three out of 85 federal regions of Russia were ranked into three groups by the 25th and 75th percentiles of the proportion of SL users: 14 regions-"low proportion"; 48 regions-"average proportion"; and 11 regions-"high proportion". We consider that the observed uneven prevalence of SL users can reflect underlying hereditary forms of congenital HL accumulated in certain populations by specific genetic background and population structure. At least, the data from this study indicate that the highest proportions of SL users detected in some Siberian regions are consistent with the reported accumulation of specific hereditary HL forms in indigenous Yakut, Tuvinian and Altaian populations.

The Role of Leptin Levels in Adaptation to Cold Climates.

Currently, adipose tissue is considered an endocrine organ that produces hormone-active substances, including leptin, which can play a key role in thermoregulation processes. Therefore, we performed a meta-analysis to investigate the influence of the climatic environment on leptin levels. A systematic literature search in the databases was carried out on 10 January 2020. Finally, 22 eligible articles were included in the current meta-analysis and a total of 13,320 participants were covered in the final analysis. It was shown that males of the "North" subgroup demonstrated significantly higher levels of leptin (10.02 ng/mL; CI: 7.92-12.13) than males of the "South" subgroup (4.9 ng/mL; CI: 3.71-6.25) (p = 0.0001). On the contrary, in the female group, a similar pattern was not detected (p = 0.91). Apparently, in order to maintain body temperature, higher leptin levels are required. The results of the study indicate that such effects are most pronounced in males and to a smaller extent in females, apparently due to a relatively high initial concentration of leptin in females. The correlation between leptin levels and climatic environment data support the hypothesis of leptin-mediated thermoregulation as an adaptive mechanism to cold climates.

A rare case of Waardenburg syndrome with unilateral hearing loss caused by nonsense variant c.772C>T (p.Arg259*) in the MITF gene in Yakut patient from the Eastern Siberia (Sakha Republic, Russia).

Waardenburg syndrome (WS) is an orphan genetic disease with autosomal dominant pattern of inheritance characterised by varying degrees of hearing loss accompanied by skin, hair and iris pigmentation abnormalities. Four types of WS differing in phenotypic characteristics are now described. We performed a Sanger sequencing of coding regions of genes PAX3, MITF, SOX10 and SNAI2 in the patient with WS from a Yakut family living in the Sakha Republic. No changes were found in the PAX3, SOX10 and SNAI2 coding regions while a previously reported heterozygous transition c.772C>T (p.Arg259*) in exon 8 of the MITF gene was found in this patient. This patient presents rare phenotype of WS type 2: congenital unilateral hearing loss, unilateral heterochromia of irises, and absence of skin/hair depigmentation and dystopia canthorum. Audiological variability in WS type 2, caused by the c.772C>T (p.Arg259*) variant in the MITF gene, outlines the importance of molecular analysis and careful genotype-phenotype comparisons in order to optimally inform patients about the risk of hearing loss. The results of this study confirm the association of pathogenic variants in the MITF gene with WS type 2 and expanded data on the variability of audiological features of the WS.

Comparison of Predictive In Silico Tools on Missense Variants in GJB2, GJB6, and GJB3 Genes Associated with Autosomal Recessive Deafness 1A (DFNB1A).

In silico predictive software allows assessing the effect of amino acid substitutions on the structure or function of a protein without conducting functional studies. The accuracy of in silico pathogenicity prediction tools has not been previously assessed for variants associated with autosomal recessive deafness 1A (DFNB1A). Here, we identify in silico tools with the most accurate clinical significance predictions for missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes associated with DFNB1A. To evaluate accuracy of selected in silico tools (SIFT, FATHMM, MutationAssessor, PolyPhen-2, CONDEL, MutationTaster, MutPred, Align GVGD, and PROVEAN), we tested nine missense variants with previously confirmed clinical significance in a large cohort of deaf patients and control groups from the Sakha Republic (Eastern Siberia, Russia): Сх26: p.Val27Ile, p.Met34Thr, p.Val37Ile, p.Leu90Pro, p.Glu114Gly, p.Thr123Asn, and p.Val153Ile; Cx30: p.Glu101Lys; Cx31: p.Ala194Thr. We compared the performance of the in silico tools (accuracy, sensitivity, and specificity) by using the missense variants in GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) genes associated with DFNB1A. The correlation coefficient (r) and coefficient of the area under the Receiver Operating Characteristic (ROC) curve as alternative quality indicators of the tested programs were used. The resulting ROC curves demonstrated that the largest coefficient of the area under the curve was provided by three programs: SIFT (AUC = 0.833, p = 0.046), PROVEAN (AUC = 0.833, p = 0.046), and MutationAssessor (AUC = 0.833, p = 0.002). The most accurate predictions were given by two tested programs: SIFT and PROVEAN (Ac = 89%, Se = 67%, Sp = 100%, r = 0.75, AUC = 0.833). The results of this study may be applicable for analysis of novel missense variants of the GJB2 (Cx26), GJB6 (Cx30), and GJB3 (Cx31) connexin genes.

A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2).

Here, we report a novel hemizygous transition c.975G>A (p.Trp325*) in POU3F4 gene (Xq21) found in two deaf half-brothers from one Yakut family (Eastern Siberia, Russia) with identical inner ear abnormalities ("corkscrew" cochlea with an absence of modiolus) specific to X-linked deafness-2 (DFNX2). Comprehensive clinical evaluation (CT and MR-imaging, audiological and stabilometric examinations) of available members of this family revealed both already known (mixed progressive hearing loss) and additional (enlargement of semicircular canals and postural disorders) clinical DFNX2 features in affected males with c.975G>A (p.Trp325*). Moreover, mild enlargement of semicircular canals, postural abnormalities and different types of hearing thresholds were found in female carrier of this POU3F4-variant.

Opinions of hearing parents about the causes of hearing impairment of their children with biallelic GJB2 mutations.

Hereditary hearing impairment (HI) caused by recessive GJB2 mutations is a frequent sensory disorder. The results of the molecular-based studies of HI are widely used in various genetic test systems. However, the ethical aspects are less described than the genetic aspects. The concerns expressed by individuals from groups with genetic risks must be included in the counseling of patients and their families. For evaluation of subjective opinions of hearing parents about the presumed causes of HI of their children, we analyze the cohort of parents having children with confirmed hereditary HI caused by biallelic recessive GJB2 mutations (in a homozygous or a compound heterozygous state). This study included 70 deaf children with HI due to mutations in the GJB2 gene and 91 questionnaires about the presumed causes of their deafness filled by their parents. Most of the parents at 78% (CI 68.4-85.4%) attributed their children's HI to "non-hereditary" causes and 22% (CI 14.7-31.6%) to "hereditary" causes (p < 0.05). Therefore, the prior opinions of the parents did not correspond to positive GJB2 genetic testing results. The subjective opinions of parents are probably partly based on family history, since respondents with deaf relatives in their pedigree more likely supposed hereditary causes for HI in their children than the respondents without deaf relatives (p < 0.001).

Spectrum and Frequency of the GJB2 Gene Pathogenic Variants in a Large Cohort of Patients with Hearing Impairment Living in a Subarctic Region of Russia (the Sakha Republic).

Pathogenic variants in the GJB2 gene, encoding connexin 26, are known to be a major cause of hearing impairment (HI). More than 300 allelic variants have been identified in the GJB2 gene. Spectrum and allelic frequencies of the GJB2 gene vary significantly among different ethnic groups worldwide. Until now, the spectrum and frequency of the pathogenic variants in exon 1, exon 2 and the flanking intronic regions of the GJB2 gene have not been described thoroughly in the Sakha Republic (Yakutia), which is located in a subarctic region in Russia. The complete sequencing of the non-coding and coding regions of the GJB2 gene was performed in 393 patients with HI (Yakuts-296, Russians-51, mixed and other ethnicities-46) and in 187 normal hearing individuals of Yakut (n = 107) and Russian (n = 80) populations. In the total sample (n = 580), we revealed 12 allelic variants of the GJB2 gene, 8 of which were recessive pathogenic variants. Ten genotypes with biallelic recessive pathogenic variants in the GJB2 gene (in a homozygous or a compound heterozygous state) were found in 192 out of 393 patients (48.85%). We found that the most frequent GJB2 pathogenic variant in the Yakut patients was c.-23+1G>A (51.82%) and that the second most frequent was c.109G>A (2.37%), followed by c.35delG (1.64%). Pathogenic variants с.35delG (22.34%), c.-23+1G>A (5.31%), and c.313_326del14 (2.12%) were found to be the most frequent among the Russian patients. The carrier frequencies of the c.-23+1G>A and с.109G>A pathogenic variants in the Yakut control group were 10.20% and 2.80%, respectively. The carrier frequencies of с.35delG and c.101T>C were identical (2.5%) in the Russian control group. We found that the contribution of the GJB2 gene pathogenic variants in HI in the population of the Sakha Republic (48.85%) was the highest among all of the previously studied regions of Asia. We suggest that extensive accumulation of the c.-23+1G>A pathogenic variant in the indigenous Yakut population (92.20% of all mutant chromosomes in patients) and an extremely high (10.20%) carrier frequency in the control group may indicate a possible selective advantage for the c.-23+1G>A carriers living in subarctic climate.