Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Genetic Dissection of Complex Traits

Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function.

Iron regulatory proteins 1 and 2 (IRP1 and IRP2) post-transcriptionally control the expression of several mRNAs encoding proteins of iron, oxygen and energy metabolism. The mechanism involves their binding to iron responsive elements (IREs) in the untranslated regions of target mRNAs, thereby controlling mRNA translation or stability. Whereas IRP2 functions solely as an RNA-binding protein, IRP1 operates as either an RNA-binding protein or a cytosolic aconitase. Early experiments in cultured cells established a crucial role of IRPs in regulation of cellular iron metabolism. More recently, studies in mouse models with global or localized Irp1 and/or Irp2 deficiencies uncovered new physiological functions of IRPs in the context of systemic iron homeostasis. Thus, IRP1 emerged as a key regulator of erythropoiesis and iron absorption by controlling hypoxia inducible factor 2α (HIF2α) mRNA translation, while IRP2 appears to dominate the control of iron uptake and heme biosynthesis in erythroid progenitor cells by regulating the expression of transferrin receptor 1 (TfR1) and 5-aminolevulinic acid synthase 2 (ALAS2) mRNAs, respectively. Targeted disruption of either Irp1 or Irp2 in mice is associated with distinct phenotypic abnormalities. Thus, Irp1-/- mice develop polycythemia and pulmonary hypertension, while Irp2-/- mice present with microcytic anemia, iron overload in the intestine and the liver, and neurologic defects. Combined disruption of both Irp1 and Irp2 is incombatible with life and leads to early embryonic lethality. Mice with intestinal- or liver-specific disruption of both Irps are viable at birth but die later on due to malabsorption or liver failure, respectively. Adult mice lacking both Irps in the intestine exhibit a profound defect in dietary iron absorption due to a “mucosal block” that is caused by the de-repression of ferritin mRNA translation. Herein, we discuss the physiological function of the IRE/IRP regulatory system.

/pdf/the-irp-ire-system-in-vivo-insights-from-mouse-models-543yob2sif.pdf

The IRP/IRE system in vivo: insights from mouse models

CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves' disease

https://www.internationaljournalofcardiology.com/article/S0167-5273(14)00731-1/pdf

Contemporary prevalence of pulmonary arterial hypertension in adult congenital heart disease following the updated clinical classification

Aim The appropriate selection of hospitalized patients for venous thromboembolism(VTE) prophylaxis is an important unresolved issue. We sought to validate the Caprini model, a famous individual VTE risk assessment model(RAM), in hospitalized Chinese patients. Methods We performed a retrospective case-control study among unselected hospitalized patients admitted to a comprehensive hospital in China. A total of 347 patients were confirmed to have VTE during hospitalization, and 651 controls were randomly selected to match the patients according to medical service. Both the patients and controls were retrospectively assessed for the risk of VTE using the Caprini RAM. Results The average Caprini cumulative risk score in the patients was significantly higher than that observed in the controls(4.69±2.58 vs 3.16±1.82, p＜0.0001). Compared with that observed in the low-risk group, a classification of high-risk according to the Caprini model was associated with a 1.65-fold increased risk of VTE(95%CI 1.05-2.61), while that of highest-risk was associated with a 4.84-fold increased risk of VTE(95%CI 3.06-7.64). After further stratifying the highest risk level with a cumulative risk score of ≥5 into scores of 5-6, 7-8 and ≥9, the patients with a score of 5-6 were found to exhibit a 3.33-fold increased risk of VTE(95%CI 2.06-5.40), those with a score 7-8 exhibited a 9.41-fold increased risk of VTE(95%CI 4.90-18.08) and those with a score of ≥9 exhibited a 24.69-fold(95%CI 7.98-76.40) increased risk of VTE compared with their low-risk counterparts. Conclusions Our study suggests that the Caprini RAM can be used to effectively stratify hospitalized Chinese patients into VTE risk categories based on individual risk factors. The classification of the highest risk level with a cumulative risk score of ≥5 provided significantly more clinical information, and further stratification of this group of patients is needed.

Validation of a venous thromboembolism risk assessment model in hospitalized chinese patients: a case-control study.

Phosphodiesterase 4 (PDE4) inhibitors are a novel medication approved for airway inflammatory diseases including chronic obstructive pulmonary disease. Their role and application in asthma are controversial and not defined. A comprehensive search was performed in major databases (1946-2016) using the keywords: 'phosphodiesterase 4 inhibitor' or 'roflumilast' and 'asthma'. Placebo-controlled trials reporting lung function, airway hyperresponsiveness by direct challenge, asthma control and exacerbations, and adverse events were included. Random or fixed-effects models were used to calculate odds ratios (OR) and mean differences between the two treatment groups. Statistical analyses were conducted using Mann-Whitney U-tests and Cochrane systematic review software, Review Manager. Seventeen studies were included in the systematic review, of which 14 studies were included in the meta-analysis. Except for significant statistical heterogeneity in pre- and post-challenge predicted percentage of forced expiratory volume in 1 s (FEV1 %; I2  = 72%, χ2  = 3.35, P = 0.06), there was no heterogeneity in outcome measures. Roflumilast (500 μg) significantly improved FEV1 (mean difference: 0.05, 95% CI: 0.01-0.09, Z = 2.50, P = 0.01), peak expiratory flow, asthma control and exacerbations, but showed variable effects on airway responsiveness to methacholine and a 20% fall in FEV1 .Of note, PDE4 inhibitors were accompanied with significantly higher adverse events such as headache (OR: 3.99, 95% CI: 1.65-9.66, Z = 3.07, P = 0.002) and nausea (OR: 5.53, 95% CI: 1.38-22.17, Z = 2.41, P = 0.02). In patients with mild asthma, oral PDE4 inhibitors can be considered as an alternative treatment to regular bronchodilators and inhaled controllers.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/resp.13276

Efficacy and safety of phosphodiesterase 4 inhibitors in patients with asthma: A systematic review and meta-analysis.

Genome-wide association studies and integrative genomics approaches have demonstrated significant associations between chronic obstructive pulmonary disease (COPD) and single-nucleotide polymorphisms (SNPs) in the chromosome 15q25 region that includes iron-responsive element binding protein 2 gene (IREB2) and CHRNA3/5 in non-Asian populations. We investigated whether IREB2 and CHRNA3/5 polymorphisms would be associated with COPD susceptibility and COPD-related phenotypes in a Chinese Han population. Eight SNPs (rs2568494, rs2656069, rs10851906, rs1964678, rs12593229, rs965604, rs13180, rs17483929) in IREB2 gene and four SNPs (rs16969968, rs1051730, rs938682, rs8034191) in or near CHRNA3/5 locus were genotyped in a case–control study (680 COPD patients and 687 controls). No significant associations were found between any of the SNPs and COPD in either former-smokers or current-smokers. Two SNPs (rs2656069 and rs10851906) in IREB2 were associated with COPD (P=0.045 and 0.032, respectively) in non-smoker. Four SNPs (rs1964678, rs12593229, rs965604 and rs13180) in IREB2 were associated with forced expiratory volume in 1 s (FEV1)% predicted and three SNPs (rs16969968, rs8034191 and rs1051730) in CHRNA3/5 were both associated with FEV1% predicted and FEV1/FVC in COPD cases (P range 0.007–0.050). The SNP rs8034191 near CHRNA3/5 locus was significantly associated with pack-years of smoking in COPD patients (P=0.033). We demonstrated IREB2 polymorphisms were associated with COPD in non-smoking subjects, and the effect of IREB2 gene on COPD may be independent from smoking and independent from CHRNA3/5 gene cluster. Besides, we confirmed that SNPs in these two gene loci were associated with pulmonary function and CHRNA3/5 polymorphism was associated with pack-year of smoking in COPD patients in the Chinese Han population.

/pdf/association-of-ireb2-and-chrna3-5-polymorphisms-with-copd-2br8fxatuy.pdf

Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population

The effect of in vitro digestion on the chemical and antioxidant properties of Lycium barbarum polysaccharide

The molecular weight, the triple-helix conformation, the monosaccharide content, the manner of glycosidic linkages, and the polysaccharide conjugates of polysaccharides all affect bioactivity. The purpose of this study was to determine how different molecular weights affected the bioactivity of the Lycium barbarum polysaccharides (LBPs). By ethanol-graded precipitation and ultrafiltration membrane separation, one oligosaccharide (LBPs-1, 1.912 kDa) and two polysaccharides (LBPs-2, 7.481 kDa; LBPs-3, 46.239 kDa) were obtained from Lycium barbarum. While the major component of LBPs-1 and LBPs-2 was glucose, the main constituents of LBPs-3 were arabinose, galactose, and glucose. LBPs-2 and LBPs-3 exhibited triple-helix conformations, as evidenced by the Congo red experiment and AFM data. Sugar residues of LBPs-2 and LBPs-3 were elucidated by NMR spectra. The polysaccharides (LBPs-2 and LBPs-3) exhibited much higher antioxidant capacities than oligosaccharide (LBPs-1). LBPs-3 showed higher oxygen radical absorbance capacity (ORAC) and superoxide dismutase (SOD) activity than LBPs-2, but a lower capability for scavenging ABTS+ radicals. In zebrafish, LBPs-2 and LBPs-3 boosted the growth of T-lymphocytes and macrophages, enhanced the immunological response, and mitigated the immune damage generated by VTI. In addition to the molecular weight, the results indicated that the biological activities would be the consequence of various aspects, such as the monosaccharide composition ratio, the chemical composition, and the chemical reaction mechanism.

/pdf/comparative-study-on-the-structural-properties-and-1zvqhf36.pdf

Comparative Study on the Structural Properties and Bioactivities of Three Different Molecular Weights of Lycium barbarum Polysaccharides

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