Insight into genetic determinants of resting heart rate

Background

Recent studies suggested that resting heart rate (RHR) might be an independent predictor of cardiovascular mortality and morbidity. Nonetheless, the interrelation between RHR and cardiovascular diseases is not clear. In order to resolve this puzzle, the importance of genetic determinants of RHR has been recently suggested, but it needs to be further investigated.

Objective

The aim of this study was to estimate the contribution of common genetic variations on RHR using Genome Wide Association Study.

Methods

We performed a Genome Wide Association Study in an isolated population cohort of 1737 individuals, the Italian Network on Genetic Isolates — Friuli Venezia Giulia (INGI-FVG). Moreover, a haplotype analysis was performed. A regression tree analysis was run to highlight the effect of each haplotype combination on the phenotype.

Results

A significant level of association (p < 5 × 10^− 8) was detected for Single Nucleotide Polymorphisms (SNPs) in two genes expressed in the heart: MAML1 and CANX. Founding that the three different variants of the haplotype, which encompass both genes, yielded a phenotypic correlation. Indeed, a haplotype in homozygosity is significantly associated with the lower quartile of RHR (RHR ≤ 58 bpm). Moreover no significant association was found between cardiovascular risk factors and the different haplotype combinations.

Conclusion

Mastermind-like 1 and Calnexin were found to be associated with RHR. We demonstrated a relation between a haplotype and the lower quartile of RHR in our populations. Our findings highlight that genetic determinants of RHR may be implicated in determining cardiovascular diseases and could allow a better risk stratification.     

The BGN and ACAN genes and carpal tunnel syndrome

The causes of idiopathic carpal tunnel syndrome (CTS) remain unknown and the involvement of the tendons within the carpal tunnel structure in the aetiology of CTS cannot be excluded. Variants within the COL5A1 gene, an important regulator of fibril assembly in tendons, have previously been associated with modulating the risk of CTS. Furthermore, proteoglycans are also important structural components of tendons and variants within the aggrecan gene are associated with musculoskeletal soft tissue injuries. The aim of this study was to determine whether ACAN and BGN variants are associated with CTS.     

BMI1基因下调使宫颈癌和子宫内膜癌对紫杉醇敏感

目的 研究B细胞特异性莫洛尼鼠白血病病毒插入位点1（BMI1）基因对宫颈癌及子宫内膜癌增殖浸润及紫杉醇耐受的影响及其机制。方法 首先利用Cbioportal、TCGA和CPTAC数据库分析BMI1基因在宫颈癌和子宫内膜癌中的突变及表达情况。接着对人宫颈癌组织样本和人子宫内膜癌组织样本中BMI1的蛋白质表达水平进行免疫组化分析。采用蛋白质印迹法（Western blot)检测BMI1敲低后宫颈癌及子宫内膜癌细胞中BMI1下游调控因子的蛋白质水平变化。此外,通过细胞功能实验研究了BMI1在宫颈癌HeLa及子宫内膜癌HEC-1-A细胞中的功能。最后,通过实验评估siBMI1联合紫杉醇治疗的协同抗生长作用。结果 数据库分析结果显示,BMI1在1.5%的子宫颈癌患者及1.9%的子宫内膜癌的患者中存在不同程度的扩增、错义及剪接突变。此外,高mRNA水平的BMI1与宫颈癌的病理类型相关,且高蛋白质水平的BMI1与子宫内膜癌的病理类型和肿瘤分级及较低的生存率相关。进一步的免疫组化分析发现,与正常组织相比,宫颈癌和子宫内膜癌组织中BMI1蛋白水平表达升高,且与肿瘤的病理分化及浸润深度相关。药物敏感性实验显示,BMI1过表达导致HeLa及HEC-1-A细胞对多种抗癌药物的敏感性下降,其中包括紫杉醇。为了进一步分析BMI1与紫杉醇耐受的关系,通过Western blot检测BMI1敲除后HeLa及HEC-1-A细胞中BMI1下游因子的蛋白质水平变化。结果显示,抗凋亡相关蛋白Bcl-2随着BMI1的敲低而表达水平下降,而促凋亡相关蛋白BAX则显著升高。此外,细胞功能实验结果显示,体外过表达BMI1可促进HeLa及HEC-1-A细胞的增殖和迁移,且BMI1低表达的HeLa及HEC-1-A细胞对紫杉醇更敏感。结论 BMI1在宫颈癌和子宫内膜癌患者的肿瘤组织中过表达,BMI1的下调通过调控凋亡通路使CC和EC细胞对紫杉醇更加敏感。     

Is CD36 gene polymorphism in region encoding lipid-binding domain associated with early onset CAD?

CD36 is a fatty acid translocase in striated muscle cells and cardiomyocytes. Some study suggested that alterations in CD36 gene may be associated with coronary artery disease (CAD) risk. The aim of the current study was to compare the frequency of CD36 variants in region encoding lipid-binding domain in Caucasian patients with early-onset CAD, no-CAD adult controls and neonates. The study group comprised 100 patients with early onset CAD. The genetic control groups were 306 infants and 40 no-CAD adults aged over 70 years. Exons 4, 5 and 6 including fragments of flanking introns were studied using the denaturing high-performance liquid chromatography technique and direct sequencing. Changes detected in analyzed fragment of CD36: IVS3-6 T/C (rs3173798), IVS4-10 G/A (rs3211892), C311T (Thr104Ile, not described so far) in exon 5, G550A (Asp184Asn, rs138897347), C572T (Pro191Leu, rs143150225), G573A (Pro191Pro, rs5956) and A591T (Thr197Thr, rs141680676) in exon 6. No significant differences in the CD36 genotype, allele and haplotype frequencies were found between the three groups. Only borderline differences (p = 0.066) were found between early onset CAD patients and newborns in the frequencies of 591T allele (2.00% vs 0.50%) and CGCGCGT haplotype (2.00% vs 0.50%) with both IVS3-6C and 591T variant alleles. In conclusion, CD36 variants: rs3173798, rs3211892, rs138897347, rs5956, rs143150225 rs141680676 and C311T do not seem to be involved in the risk of early-onset CAD in Caucasian population.     

Identification of glyoxalase 1 polymorphisms associated with enzyme activity

The glyoxalase system and its main enzyme, glyoxalase 1 (GLO1), protect cells from advanced glycation end products (AGEs), such as methylglyoxal (MG) and other reactive dicarbonyls, the formation of which is increased in diabetes patients as a result of excessive glycolysis. MG is partly responsible for harmful protein alterations in living cells, notably in neurons, leading to their dysfunction, and recent studies have shown a negative correlation between GLO1 expression and tissue damage. Neuronal dysfunction is a common diabetes complication due to elevated blood sugar levels, leading to high levels of AGEs. The aim of our study was to determine whether single nucleotide polymorphisms (SNPs) in the GLO1 gene influence activity of the enzyme. In total, 125 healthy controls, 101 type 1 diabetes, and 100 type 2 diabetes patients were genotyped for three common SNPs, rs2736654 (A111E), rs1130534 (G124G), and rs1049346 (5′-UTR), in GLO1. GLO1 activity was determined in whole blood lysates for all participants of the study.     

Targeting cancer stemness mediated by BMI1 and MCL1 for non‐small cell lung cancer treatment

Lung cancer is the leading cause of cancer‐associated death, with a global 5‐year survival rate <20%. Early metastasis and recurrence remain major challenges for lung cancer treatment. The stemness property of cancer cells has been suggested to play a key role in cancer plasticity, metastasis and drug‐resistance, and is a potential target for drug development. In this study, we found that in non‐small cell lung cancer (NSCLC), BMI1 and MCL1 play crucial roles of cancer stemness including invasion, chemo‐resistance and tumour initiation. JNK signalling serves as a link between oncogenic pathway or genotoxicity to cancer stemness. The activation of JNK, either by mutant EGFR or chemotherapy agent, stabilized BMI1 and MCL1 proteins through suppressing the expression of E3‐ubiquitin ligase HUWE1. In lung cancer patient samples, high level of BMI1 is correlated with poor survival, and the expression of BMI1 is positively correlated with MCL1. A novel small‐molecule, BI‐44, was developed, which effectively suppressed BMI1/MCL1 expressions and inhibited tumour formation and progression in preclinical models. Targeting cancer stemness mediated by BMI1/MCL1 with BI‐44 provides the basis for a new therapeutic approach in NSCLC treatment.     

Relationships of Age and Weekly Running Distance to BMI and Circumferences in 41, 582 Physically Active Women

Objective: To assess in women whether age‐related increases in adiposity are dependent on exercise, and, contrariwise, whether exercise‐related declines in adiposity are dependent on age. Research Methods and Procedures: Cross‐sectional analyses were conducted of 41, 582 female runners. Results: Age affected the relationships between vigorous exercise and adiposity. The decline in BMI per kilometer per week run was linear in 18 to 23 year olds and became increasingly non‐linear (convex) with age. Waist, hip, and chest circumferences declined significantly with running distance across all age groups, but the declines were significantly greater in older than younger women, particularly among shorter distance runners. The relationships between body circumferences and running distance became increasingly convex in older women. Conversely, vigorous exercise diminished the apparent increase in adiposity with age. The increase in average BMI with age was greatest in women who ran <8 km/wk, intermediate in women who ran 8 to 15 km/wk or 16 to 31 km/wk, and least in those who averaged over 32 km/wk. Before age 45, waist circumference rose for those who ran 0 to 7 km/wk, showed no significant relationship to age for those who ran 8 to 39 km/wk, and declined in those who ran 40 to 55 and 56 km/wk and more. Age related‐increases in hip and chest circumferences before 45 years old were significantly less in women who ran longer weekly distances. Discussion: These cross‐sectional associations are consistent with the hypothesis that exercise may mitigate age‐related increases in adiposity and that age affects exercise‐induced reductions in adiposity (although causality remains to be determined experimentally).     

Cigarette Smoking and Fat Distribution in 21, 828 British Men and Women: A Population‐based Study

Objective: To examine the relationship between cigarette smoking habits and fat distribution in a population‐based cohort of men and women. Research Methods and Procedures: We analyzed cross‐sectional data from 21, 828 men and women who were 45 to 79 years of age, residents in Norfolk, United Kingdom, and were recruited between 1993 and 1997. Cigarette smoking habits and other lifestyle factors were assessed using self‐reported questionnaires. Anthropometric measures were obtained during a health examination. Results: Waist‐hip ratio was highest among current smokers and least among never smokers after adjusting for age, BMI, alcohol intake, total energy intake, physical activity, and education. Higher waist‐hip ratio was directly associated with higher smoking pack‐years in current and former smokers and inversely with duration since quitting smoking in former smokers. Adjusting for age, BMI, and other covariates, current smokers had higher waist circumference but lower hip circumference compared with former or never smokers. Discussion: Cigarette smoking habits seem to influence fat distribution patterns. Although smokers have lower mean BMI compared with nonsmokers, they have a more metabolically adverse fat distribution profile, with higher central adiposity. The explanation for this association may help elucidate the mechanisms underlying the adverse health consequences of cigarette smoking and abdominal obesity.     

Height, weight and earnings among coalminers in India

This paper analyses earning/wage differentials by height among coalmine workers in India. Our findings suggest that workers of above average height earn 9-17% more than their shorter counterparts and 6-13% more than average reference height. The results suggest that long-term investments in health human capital might ensure increase of labour productivity and thereby earnings, particularly in underdeveloped economies.     

Association of ATM and BMI‐1 genetic variation with breast cancer risk in Han Chinese

We tested the hypothesis that genetic variation in ATM and BMI‐1 genes can alter the risk of breast cancer through genotyping 6 variants among 524 breast cancer cases and 518 cancer‐free controls of Han nationality. This was an observational, hospital‐based, case–control association study. Analyses of single variant, linkage, haplotype, interaction and nomogram were performed. Risk was expressed as odds ratio (OR) and 95% confidence interval (CI). All studied variants were in the Hardy‐Weinberg equilibrium and were not linked. The mutant allele frequencies of rs1890637, rs3092856 and rs1801516 in ATM gene were significantly higher in cases than in controls (P = .005, <.001 and .001, respectively). Two variants, rs1042059 and rs201024480, in BMI‐1 gene were low penetrant, with no detectable significance. After adjustment, rs189037 and rs1801516 were significantly associated with breast cancer under the additive model (OR: 1.37 and 1.52, 95% CI: 1.10‐1.71 and 1.14‐2.04, P: .005 and .005, respectively). In haplotype analysis, haplotypes A‐C‐G‐G (in order of rs189037, rs3092856, rs1801516 and rs373759) and A‐C‐A‐A in ATM gene were significantly associated with 1.98‐fold and 6.04‐fold increased risk of breast cancer (95% CI: 1.36‐2.90 and 1.65‐22.08, respectively). Nomogram analysis estimated that the cumulative proportion of 3 significant variants in ATM gene was about 12.5%. Our findings collectively indicated that ATM gene was a candidate gene in susceptibility to breast cancer in Han Chinese.