Geographical distribution of MTHFR C677T gene polymorphisms among the reproductive-age women in Chinese Han populations: based on migration.

BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is essential for the metabolism of folic acid and homocysteine. The MTHFR C677T polymorphism is associated with several disorders. Our study aims to explore the geographical distributions of the MTHFR C677T polymorphism of women in China and how migration affected the polymorphism in Suzhou. METHODS: A total of 7188 women of reproductive age were recruited in Suzhou of the study. Subjects were classified according to their native places after data extraction. MTHFR C677T gene polymorphisms were detected by quantitative PCR with genomic DNA isolated from blood samples. RESULTS: The frequencies of the 677T allele and 677TT genotype were higher in northern China than that in southern China and decreased in geographical gradients from north to south. The frequencies were considerably higher in the migrant population than that in the indigenous population of Suzhou. The migrant population have gradually changed the prevalence in Suzhou. CONCLUSIONS: Our study suggested that the prevalence of MTHFR C677T polymorphisms among women varied across different geographical regions in Chinese Han populations. The 677T allele frequencies of the northern populations were significantly higher than those of the southern populations. The migrant population gradually changed the prevalence of the MTHFR C677T polymorphism in Suzhou.

Age and Sex-related Chromogranin A Gene Polymorphisms and its Association with Metabolic Syndrome Components.

Introduction: The purpose of this study was to determine the possible differences in genetic polymorphisms and serum levels of chromogranin A (CgA), according to age and sex, in subjects with and without metabolic syndrome (MetS). Methodology: The genotyping and serum level of CgA and biochemical parameters were measured by the T-ARMS-PCR and PCR-RFLP and ELISA and spectrophotometer methods, respectively. Results: A comparison of males with and without MetS showed significantly lower high-density lipoprotein-cholesterol (HDL-C) levels than those of females.At ages 30-70 years, both sexes showed significant differences in triglycerides (TG), fasting blood sugar (FBS), CgA levels and waist circumference (WC) when compared to the two groups. Both sexes with MetS indicated significant differences in systolic blood pressure (SBP) at ages 40-70 years, while at ages 40-59 years, there was a significant difference in HDL-C level in males.There was a significant correlation between serum levels of FBS, TG, SBP and WC (in both sexes), and CgA in subjects with MetS. Significant correlation was found between HDL-C level and diastolic blood pressure (DBP), and CgA level in males and females, respectively. CgA genotype frequency (T-415C and C+87T polymorphisms) showed no significant differences between males and females with and without MetS, while there was only a significant difference in frequency of the genotypes T-415C when compared to males with and without MetS. Conclusion: The CgA appears to be strongly associated with MetS components in both sexes. Variation in CgA gene expression may affect the T-415C polymorphism in males. This may mean that the structure of CgA genetics differs in different ethnic groups. Differences in the serum level and expression of CgA gene may show valuable study results that it may be expected a relationship between these variables and the MetS.

ACE gene polymorphisms (rs4340) II and DI are more responsive to the ergogenic effect of caffeine than DD on aerobic power, heart rate, and perceived exertion in a homogeneous Brazilian group of adolescent athletes.

The purpose of this study was to verify the association between angiotensin-converting enzyme (ACE) genotypes DD, DI, and II and caffeine (CAF) ingestion on endurance performance, heart rate, ratio of perceived exertion (RPE), and habitual caffeine intake (HCI) of adolescent athletes. Seventy-four male adolescent athletes (age: DD=16±1.7; DI=16±2.0; II=15±1.7 years) ingested CAF (6 mg/kg) or placebo (PLA) one hour before performing the Yo-Yo Intermittent Recovery level 1 (Yo-Yo IR1) test. No difference was found among groups for HCI. However, CAF increased the maximal distance covered and VO2max in DI and II genotype carriers compared to PLA (DD: Δ=31 m and 0.3 mL·kg-1·min-1; DI: Δ=286 m and 1.1 mL·kg-1·min-1; II: Δ=160 m and 1.4 mL·kg-1·min-1). Heart rate of DI and II genotype carriers increased with CAF compared to PLA, while RPE was higher in the II and lower in the DD genotypes. The correlations between HCI and maximal distance covered or VO2max were significant in the II genotype carriers with CAF. CAF increased endurance capacity, heart rate, and RPE in adolescent athletes with allele I, while endurance performance and aerobic power had a positive correlation to HCI in the II genotype group. These findings suggested that DD genotype were less responsive to CAF and that genetic variations should be taken into account when using CAF supplementation to enhance exercise performance.

Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn's disease patients.

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

Gene detection of VDR BsmI locus and its approteins, genes and growthplication in rational drug use in patients with osteoporosis.

Aim: This paper determines the polymorphism distribution of the VDR BsmI gene in 350 patients and provides medication recommendations for osteoporosis based on detection results. Materials & methods: Chi-square tests compared genotype and allele frequencies with other populations. Results: Genotype frequencies were 91.66 bb, 8.72 Bb and 0.21% BB, with allelic frequencies of 95.43 b and 4.57% B, adhering to Hardy-Weinberg equilibrium. These findings suggest that VDR gene polymorphisms, particularly at the BsmIlocus, play an essential role in bone health and osteoporosis treatment. Genotype-based drug selection reduced adverse reactions from 14 to two cases. Conclusion: These findings improve clinical treatment efficacy and guide rational drug use for osteoporosis patients.

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Polymorphism of Transforming Growth Factor TGFB and Its Receptors TGFBRI, TGFBRII, TGFBRIIII Genes in Western Siberia Patients with Open-Angle Glaucoma.

Polymorphism of genes of transforming growth factor TGFB and its receptors (TGFBRI, TGFBRII, and TGFBRIIII) in patients with primary open-angle glaucoma was analyzed. The frequency of the TGFBRII CC genotype in patients is increased relative to the control group (OR=6.10, p=0.0028). Heterozygosity in this polymorphic position is reduced (OR=0.18, p=0.0052). As the effects of TGF-ß is mediated through its receptors, we analyzed complex of polymorphic variants of the studied loci in the genome of patients. Two protective complexes consisting only of receptor genes were identified: TGFBRI TT:TGFBRII CG (OR=0.10, p=0.02) and TGFBRII CG:TGFBRIII CG (OR=0.09, p=0.01). The study showed an association of TGFBRII polymorphism with primary open-angle glaucoma and the need to study functionally related genes in the development of the disease, which should contribute to its early diagnosis and prevention.

The influence of hippocampal dopamine D2 receptor losses on episodic-memory decline across 5 years is moderated by BDNF and KIBRA polymorphisms.

Losses in dopamine (DA) functioning may contribute to aging-related decline in cognition. Hippocampal DA is necessary for successful episodic memory formation. Previously, we reported that higher DA D2 receptor (D2DR) availability in hippocampus is beneficial for episodic memory only in older carriers of more advantageous genotypes of well-established plasticity-related genetic variations, the brain-derived neurotrophic factor (BDNF, rs6265) and the kidney and brain expressed protein (KIBRA, rs17070145) polymorphisms. Extending our observations to the longitudinal level, the current data show that individuals with one or no beneficial BDNF and KIBRA genotype (n = 80) decline more in episodic memory across five years, without any contribution of losses in hippocampal D2DR availability to memory decline. Although carriers of two beneficial genotypes (n = 39) did not decline overall in episodic memory, losses of hippocampal D2DR availability were predictive of episodic-memory decline among these individuals. Our findings have implications for interventions targeting DA modulation to enhance episodic memory in aging, which may not benefit all older individuals.

Serum Apo Lipoprotein E, Apo Lipoprotein E Gene Polymorphisms, and Parkinson's Disease.

BACKGROUND: A central role for apolipoprotein E (APOE) has been suggested in modulating processes of neurodegeneration. OBJECTIVE: To study the association between serum APOE levels, APOE gene polymorphisms, and Parkinson's disease (PD). MATERIAL AND METHODS: Fifty-five patients with PD and 30 healthy subjects were enrolled. PD patients were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS), Modified Hoehn and Yahr scale, and Schwab-England Activities of Daily Living scale. Serum APOE level and genotyping for APOE polymorphisms were done for PD patients and controls using enzyme-linked immunosorbent assay and polymerase chain reaction, respectively. RESULTS: Mean serum APOE level was significantly higher in PD patients compared with healthy controls. APOE ε2/4 genotype was present in a significantly higher proportion of patients compared with controls. APOE ε4 allele was significantly associated with a higher score on the "mentation, behavior, and mood section" of UPDRS compared with ε2 allele. APOE ε2 allele was significantly associated with a shorter disease duration compared with ε3 and ε4 alleles. Mean serum APOE level was significantly higher in patients presenting predominantly by rigidity and bradykinesia compared with those presenting predominantly by tremors. Serum APOE level was positively correlated with mean scores of "mentation, behavior, and mood section" of UPDRS and disease duration. Serum APOE level was a significant predictor for the scores of "mentation, behavior, and mood section" of UPDRS. CONCLUSION: APOE ε2/4 genotype might be a susceptibility variant for PD. There may be a possible role for APOE in modulating the process of neurodegeneration in PD.

Role of PON1 L55M Gene Polymorphism in Parkinson's Disease among North Indian Population.

BACKGROUND AND OBJECTIVES: The role of various genetic markers including alpha synuclein, Parkin, etc., is known in the pathogenesis of Parkinson's disease (PD). Novel genetic markers including paraoxonase 1 (PON1) have also been linked to PD pathogenesis in recent studies. The PON1 L55M allele carriers may have defective clearance of environmental toxins and may result in increased susceptibility to PD. Hence, we studied the role of PON1 L55M polymorphism in PD among a North Indian population. MATERIALS AND METHOD: Seventy-four PD patients and 74 age- and sex-matched controls were recruited in this hospital-based case-control study. Baseline characteristics were recorded using structured questionnaire. DNA was extracted from 3-4 ml of venous blood, followed by PCR and restriction digestion. PON1 L55M genotypes were visualized as bands: LL (177 bp), LM (177, 140 bp) and MM (140,44 bp) on 3% agarose gel. Mann-Whitney U test and Chi-squared test were used for comparing two groups of skewed and categorical variables, respectively. Measures of strength of association were calculated by binary regression analysis. P value < 0.05 was considered as significant. RESULTS: Parkinson's disease patients had significantly higher exposure to pesticides (12.2%; P (organophosphate exposure) < 0.001) and well water drinking (28.4%; P = 0.006) compared to controls. Frequency distribution of LL, LM, MM genotypes was 67.5% (50/74), 28.4% (21/74), and 4.1% (3/74), respectively, for cases and 72.6% (54/74), 26% (19/74) and 1.4% (1/74), respectively, for controls. PON1 L55M genotype distribution between Parkinson's disease cases and controls was not significant (P = 0.53). PON1 L55M polymorphism was not associated with PD after adjusting for confounders by binary regression analysis. CONCLUSION: There was no significant association between PON1 L55M polymorphism and PD. Larger population-based studies would be required from India before drawing any definite conclusions.

PBPK modeling to predict the pharmacokinetics of venlafaxine and its active metabolite in different CYP2D6 genotypes and drug-drug interactions with clarithromycin and paroxetine.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and Cmax values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and Cmax were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.

Thymus algeriensis Boiss. et Reut., a north African endemic plant species: genetic diversity and population structure as assessed by molecular markers, a pioneer step for conservation implications.

BACKGROUND: Thymus algeriensis Boiss. et Reut. is one of the most widespread North African species of the genus Thymus L. The species is subshrub growing primarily in subtropical biome of Morocco, Algeria, Tunisia and Libya. In Tunisia, the plant species is under high pressure of anthropogenic activities including over-collecting. The assessment of genetic diversity and population structure of T. algeriensis is a pioneer step to retrace its evolutionary history and to perform appropriate conservation strategies of the plant species. METHODS AND RESULTS: Seven wild populations growing, widely, in different bioclimatic zones were selected and analysed using two molecular markers systems. Fifteen Simple Sequence Repeats (SSRs) and fifteen Inter-Simple Sequence Repeats (ISSRs) were used to characterize genetically 140 different genotypes. The results showed a high molecular variation within populations and among the studied genotypes. The intra-populations genetic diversity revealed by SSRs was higher (P = 80.95%, Na = 2.143 and He = 0.364) than that based on ISSRs (P = 78.12%, Na = 1.632, He = 0.265 and I = 0.398). As demonstrated by inbreeding coefficients, a significant level of differentiation and a low level of gene flow were detected among studied populations (FST = 0.161 for SSRs and ΦST = 0.197 for ISSRs). Furthermore, the results of ISSRs marker suggest land strips as barriers in population genetic structure. While SSRs marker reflects a relatively structured bioclimatic patterns of studied populations. The Bayesian analysis showed a specific adaptation of populations to local environments. CONCLUSIONS: The used molecular markers (ISSRs and SSRs) seem to be effective in deciphering genetic polymorphism of Tunisian genotypes of T. algeriensis. Therefore, the genetic structure of the studied genotypes could constitute a starting point for further conservation, characterization and breeding programs.

Vitamin D receptor gene BsmI (rs1544410) polymorphism: role in multiple sclerosis and genotype-phenotype correlations.

BACKGROUND: Multiple sclerosis (MS) has a complex pathophysiology which depends on many endogenous and exogenous factors. Vitamin D involvement has been largely studied in MS. The large distribution of the vitamin D receptor (VDR) in different immune cells is suggestive of an immunomodulatory role. The VDR gene polymorphisms have been proposed as potential risk factors for MS development or evolution with non-conclusive results. METHODS AND RESULTS: We conducted a cross-sectional study including patients ≥ 18 years, with a diagnosis of relapsing remitting MS according to the McDonald Criteria and having a minimum follow-up period of one year after starting a disease modifying therapy. Two study groups were compared based on the Multiple Sclerosis Severity Scale or MSSS: "a slow progressor" group for an MSSS ≤ 5, and a "fast progressor" group for an MSSS > 5. The rs1544410 VDR gene polymorphism was studied for all patients. Eighty patients were included. The fast progressor groups had a higher EDSS at onset, a higher total number of relapses, more frequent and shorter time to secondary progression. The progression profile was not statistically different between genotypes and alleles of the VDR gene polymorphism rs1544410. The CC genotype and wild-type allele exhibited a more aggressive disease phenotype with a higher number of relapses the first year, shorter time to secondary progression and cerebral atrophy on assessment. CONCLUSIONS: Our results suggest potential genotype-phenotype correlations for the rs1544410 VDR gene polymorphism in the disease course of MS. Future research on a larger scale is needed to confirm these findings.

Association of Polymorphic Variants of TCF7L2 and PPARG Genes with Metabolic Markers in Patients with Early Disorders of Carbohydrate Metabolism.

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and ß-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin.

The Influence of Genetic Polymorphic Variability of the Catechol-O-methyltransferase Gene in a Group of Patients with a Diagnosis of Behavioural Addiction, including Personality Traits.

Gambling Disorder (GD) is characterised by a harmful, enduring, and recurrent involvement in betting-related behaviours. Therefore, GD shares similar biological mechanisms and symptoms to substance use disorders (SUD). Therefore, in this study, we chose the behavioural addictions group. During the examination and recruitment to the study, it turned out that all the people undergoing treatment for gambling addiction were also addicted to amphetamines, which is consistent with the biological mechanism related to cerebral neurotransmission. The aim of the study was to investigate the association of the COMT gene polymorphism with behavioral addiction. The study group consisted of 307 participants: 107 men with gambling disorder and amphetamine dependency (mean age = 27.51, SD = 5.25) and 200 non-addicted, nor dependent, free from neuro-psychiatric disorders control group men (mean age = 20.20, SD = 4.51). Both groups were subjected to psychometric evaluation using the State-Trait Anxiety Inventory and the NEO Five-Factor Personality Inventory. Genomic DNA was extracted from venous blood following standard protocols. Determination of the rs4680 polymorphism in the COMT gene was performed using the real-time PCR technique. Statistically significant differences in the frequency of rs4680 genotypes were found in the tested sample of subjects compared with the control group (p = 0.03543). Subjects with gambling disorder and amphetamine use disorder compared to the control group obtained higher scores in the assessment of the STAI trait scale (p = 0.0019), state scale (p < 0.0000), and NEO-FFI Neuroticism scale (p < 0.0000). Significantly lower results were obtained for the NEO-FFI Agreeability scale (p < 0.0000). Additionally, a significant statistical impact of gambling disorder and amphetamine use disorder, and the COMT rs4680 genotype was demonstrated for the score of the STAI trait (p = 0.0351) and state (p = 0.0343) and the NEO-FFI Conscientiousness scale (p = 0.0018). We conclude that COMT and its polymorphic variant influence the development of addiction. Still, considering its multifactorial and polygenic nature, it should be combined with other factors such as personality.

HLA Gene Polymorphisms in Romanian Patients with Chronic Lymphocytic Leukemia.

Materials and Methods: This study included 66 patients with CLL, diagnosed between 2020 and 2022, and 100 healthy controls. HLA class I and class II genes (HLA-A/B/C, HLA-DQA1/DQB1/DPA1/DPB1, and HLA-DRB1/3/4/5) were investigated using next-generation sequencing technology. Results: Several HLA alleles were strongly associated with CLL. The most important finding was that HLA-DRB1∗04:02:01 (p=0.001, OR = 1.05) and HLA-DRB3∗02:01:01 (p=0.009, OR = 1.03) have a predisposing role in CLL development. Moreover, we identified that HLA-A∗24:02:01 0.01 (p=0.01, OR = 0.38), HLA-DQA1∗05:05:01 (p=0.01, OR = 0.56), HLA-DQB1∗03:02:01 (p=0.03, OR = 0.40), and HLA-DRB4∗01:03:01 (p=0.03, OR = 0.54 alleles have protective roles. Correlations between HLA expression and gender showed that women had a higher expression of protective HLA alleles when compared to men. Conclusions: Our data are the first to indicate that in Romanian patients with CLL, the HLA-A∗24:02:01 and HLA-DQA1∗05:05:01 alleles have a protective role against CLL development, whereas HLA-DRB1∗04:02:01 and HLA-DRB3∗02:01:01alleles are positively associated with CLL.

Development and characterization of 40 InDel markers from the major histocompatibility complex genes of largemouth bass (Micropterus salmoides).

BACKGROUND: The genetic improvement in growth and food habit domestication of largemouth bass (Micropterus salmoides) have made breakthroughs in past decades, while the relevant work on disease resistance were rarely carried out. Major histocompatibility complex (MHC) genes, which are well known as their numbers and high polymorphisms, have been used as candidate genes to mine disease-resistant-related molecular markers in many species. METHODS AND RESULTS: In present study, we developed and characterized 40 polymorphic and biallelic InDel markers from the major histocompatibility complex genes of largemouth bass. The minor allele frequency, observed heterozygosity, expected heterozygosity and polymorphic information content of these markers ranged from 0.0556 to 0.5000, 0.1111 to 0.6389, 0.1064 to 0.5070, and 0.0994 to 0.3750, respectively. Three loci deviated significantly from Hardy-Weinberg equilibrium, while linkage disequilibrium existed at none of these loci. CONCLUSION: These InDel markers might provide references for the further correlation analysis and molecular assisted selection of disease resistance in largemouth bass.

The association between Dental Fluorosis and COL1A2 gene polymorphism among a Tunisian Population.

Dental fluorosis (DF) is a prevalent developmental defect of tooth enamel caused by exposure to excessive fluoride, with the severity dependent on various factors. This study aimed to investigate the association between DF and a specific genetic polymorphism (rs412777) in the COL1A2 gene among a Tunisian population. A case-control study was conducted from July to November 2022, involving a total of 95 participants including 51 cases and 44 controls. Dental examinations and genetic analysis were performed to assess the relationship between the COL1A2 gene polymorphism and DF.The results of allelic distribution revealed that A allele carriers were significantly protected against (DF) when compared to those with the C allele (C vs. A, p = 0.001; OR = 0.375 (0.207-0.672)). This suggests a strong correlation between the presence of the C allele and the risk of developing DF. Additionally, significant association between the CC genotype of rs412777 and an increased risk of DF was found under both codominant and dominant genetic models (P = 0.002 and P < 0.001 respectively).The findings suggest that genetic predisposition plays a relevant role in the development of DF. Further research is needed to explore the potential use of genetic markers for DF and their implications for public health. This study provides the first insights into the genetic factors associated with DF in the Tunisian population, contributing to our understanding of this prevalent dental condition.

Gene‒environment interaction effect of hypothalamic‒pituitary‒adrenal axis gene polymorphisms and job stress on the risk of sleep disturbances.

Background: Studies have shown that chronic exposure to job stress may increase the risk of sleep disturbances and that hypothalamic‒pituitary‒adrenal (HPA) axis gene polymorphisms may play an important role in the psychopathologic mechanisms of sleep disturbances. However, the interactions among job stress, gene polymorphisms and sleep disturbances have not been examined from the perspective of the HPA axis. This study aimed to know whether job stress is a risk factor for sleep disturbances and to further explore the effect of the HPA axis gene × job stress interaction on sleep disturbances among railway workers. Methods: In this cross-sectional study, 671 participants (363 males and 308 females) from the China Railway Fuzhou Branch were included. Sleep disturbances were evaluated with the Pittsburgh Sleep Quality Index (PSQI), and job stress was measured with the Effort-Reward Imbalance scale (ERI). Generalized multivariate dimensionality reduction (GMDR) models were used to assess gene‒environment interactions. Results: We found a significant positive correlation between job stress and sleep disturbances (P < 0.01). The FKBP5 rs1360780-T and rs4713916-A alleles and the CRHR1 rs110402-G allele were associated with increased sleep disturbance risk, with adjusted ORs (95% CIs) of 1.75 [1.38-2.22], 1.68 [1.30-2.18] and 1.43 [1.09-1.87], respectively. However, the FKBP5 rs9470080-T allele was a protective factor against sleep disturbances, with an OR (95% CI) of 0.65 [0.51-0.83]. GMDR analysis indicated that under job stress, individuals with the FKBP5 rs1368780-CT, rs4713916-GG, and rs9470080-CT genotypes and the CRHR1 rs110402-AA genotype had the greatest risk of sleep disturbances. Conclusions: Individuals carrying risk alleles who experience job stress may be at increased risk of sleep disturbances. These findings may provide new insights into stress-related sleep disturbances in occupational populations.