The β‐Thalassemia Mutation/Haplotype Distribution in the Moroccan Population

The present study compiles the results of our own research and of a prior study on β‐thalassemia (thal) in Morocco, comprising a total of 187 β‐thalassemic chromosomes. Six major mutations: (β⁰) codon 39 (C→T), (β⁺) IVS‐I‐6 (T→C), (β⁰) frameshift codon (FSC) 6 (? A), (β⁰) FSC 8 (? AA), (β⁰) IVS‐I‐1 (G→A) and (β⁺) ? 29 (A→G) account for 75.7% of the independent chromosomes studied. A regional predominance was observed (Gharb and West regions) for the (β⁺) IVS‐I‐6 (T→C) mutation. Despite an observed heterogeneity of molecular anomalies, a direct method of diagnosis of the prevalent mutations is feasible in this population. The distributions of mutations and haplotypes are in conformity with the geographical location of Morocco and the historical links with both the Mediterranean communities that have successively interspersed with the Berbers, the Phoenicians, the Carthaginians, the Romans, the Arabs, the population of the Iberian Peninsula and, to a lesser degree, the Vandals and the Byzantines and permanently, with the Sub‐Saharan Africans. In the adult population, the levels of fetal hemoglobin (Hb) in heterozygotes vary from trace quantities to 2.38 g/dL of total Hb. With the exception of the (β⁰) codon 39 (C→T) nonsense mutation, no statistically significant correlation was found, neither between mutation and Hb F levels, nor gender and Hb F levels in heterozygotes. The genetic markers for Hb F increase, located within cis active sites such as the XmnI site at ? 158 bp of the ^Gγ‐globin gene and the AT_XT_Y repeat region at ? 540 bp of the β‐globin gene, were assessed. The polymorphism XmnI shows linkage disequilibrium with haplotypes III, IV and IX, as previously observed in the Algerian, Sicilian and Portuguese β‐thal populations. Contrary to what has previously been reported for a population of β‐thal carriers of European descent, this sample does not show a statistically significant correlation between Hb F levels and the presence of the genetic markers XmnI restriction site at ? 158 bp of the ^Gγ‐globin gene and AT_XT_Y alleles at 5′ of the β‐globin gene.     

165例正常人V7,V8,V9导联心电图分析

本文分析165例正常人的V₇,V₈,V₉导联心电图,结果显示:①V₇,V₈,V₉导联P波形态由直立为主逐渐过渡到以平坦为主;②QRS波型形态以正向波占优势逐渐过渡到以负向波为主;③V₇,V₈,V₉导联Q波时间有逐渐延长趋势;④ST段抬高或下移均未超过0.05 mV。⑤由V₇,V₈,V₉直立的T波逐渐减少,低平、平坦及双相T波有逐渐增多的趋势。     

Origin of the Frameshift Codons 41/42 (–TCTT) Mutation in the First Cases Described in the Spanish Population

Thalassemias are hereditary anemias. In β-thalassemia (β-thal), β-globin synthesis is either deficient or absent. A high incidence of β-thal is found in populations of Mediterranean and African origin. Smaller, but significant concentrations of β-thal are present throughout the Middle East, India, Pakistan and China, while sporadic cases have been reported in most ethnic groups. Over 200 β-thal mutations have been described so far. But each population group displays its own mutations. In Spain, as in other countries of the Mediterranean region, the most often seen mutations are codon 39 (C?>?T); IVS-I-1 (G?>?A); IVS-I-6 (T?>?C) and IVS-I-110 (G?>?A). However, a large number of rarer alleles have been observed both in Spain and other populations. The frameshift codons (FSC) 41/CD42 (–TCTT) mutation is a rather common allele in individuals of Chinese origin, but rare in the Mediterranean region, although, it has been recorded in East Asian populations.

We describe the first eight Spanish patients displaying the FSC 41/42 mutation. This mutation was initially detected with a real-time polymerase chain reaction (PCR) method on a LightCycler?, using a probe designed to detect mutations in codons 37 and 39, and subsequently specifically characterized by automatic sequencing. The haplotype found in our patients suggested that this mutation has not arisen independently in our population but must be taken into account when identifying most β-thal mutations.     

A Novel Mutation in the Promoter Region of the β-Globin Gene: HBB: c.-127G > C

Novel β-globin gene mutations are still occasionally being reported, especially when evaluating milder phenotypes. We report here a novel putative mutation in the promoter region of the β-globin gene and assess its clinical implications. A family, parents and four siblings, with hematological and clinical features suspected of being β-globin gene mutation(s), were involved in this study. In addition to hematological and clinical evaluations of the whole family, molecular analyses of the β-globin gene were performed by direct sequencing. Sequencing of the β-globin gene revealed a novel genomic alteration in the regulatory region of the gene. This novel genomic alteration was defined as HBB: c.-127G?>?C according to the Human Genome Variation Society (HGVS) nomenclature. Two siblings were found to be carriers of the HBB: c.-127G?>?C mutation, while the other two siblings were carriers of the codon 8 (?AA) (HBB: c.25_26delAA) deletion of the β-globin gene. The mother was a compound heterozygote for the codon 8 and HBB: c.-127G?>?C mutations. Based on hematological and clinical evaluations, we conclude that this novel β-globin gene promoter region change would be associated with a mild phenotype of β-thalassemia (β-thal).     

Interferon-γ (+874 T/A) and interleukin-10 (−1082 G/A) genes polymorphisms are associated with active tuberculosis in the Algerian population of Oran's city

Background and aimsPolymorphisms within genes encoding the cytokines involved in anti-tuberculosis immunity have been widely studied and sometimes associated with an increased risk of developing the active form of tuberculosis (TB). This study analyzes for the first time the impact of two polymorphisms, namely IFNG+874 T/A and IL10-1082 G/A, in the Algerian population where tuberculosis is moderately endemic.MethodsThis case–control study included 104 healthy controls and 141 active TB patients: 75 extrapulmonary (EPTB) and 66 pulmonary (PTB). They were all genotyped by refractory mutational system-PCR amplification. In order to measure the functional impact of IFNG+874 T/A on the production rate of IFN-γ, 43 patients performed a QuantiFERON®Gold In-tube test.ResultsThe IFNG+874 AA genotype was associated with a higher risk of developing EPTB (OR = 2.52; 95%CI = 1.23–5.18; p = 0.012) while the IFNG+874 TA genotype was associated with a greater protection (OR = 0.34, 95%CI = 0.16–0.74; p = 0.006) which was further characterized by a high production of IFN-γ (p = 0.001). Similarly, the allele A of SNP IL10-1082 G/A, especially in its homozygous form (AA), were overrepresented in PTB patients (p = 0.010 and 0.019, respectively). The combination of both susceptibility genotypes (AA/AA) was strongly associated with risk of development of active TB (OR = 8.58; 95% C.I = 1.95–37.70, p = 0.004). This susceptibility combination was only significant in men regarding PTB (OR = 11.05; 95% C.I = 1.32–92.72, p = 0.027). Additionally, IFNG+874 TA and IL10-1082G1 genotypes combination was mostly encountered in men controls and conferred the highest protection rate against EPTB (OR = 0.25; 95% C.I = 0.08–0.76, p = 0.015).ConclusionThese two cytokines genes polymorphisms are associated with active TB susceptibility in the Algerian population. They act synergistically in terms of protection and susceptibility regarding the two forms of the disease. Moreover, these associations were more marked among males suggesting a potential role of gender.     

Non-Thalassemic Phenotype Associated With the -83 (G > A) Mutation of the β-Globin Gene Promoter (HBB: c.-133G > A)

The -83 (G?>?A) mutation of the β-globin gene promoter (HBB: c.-133G?>?A) was first reported in an adult male patient with mild thalassemic indices, suggesting that this may be a mild β⁺-thalassemia (β⁺-thal) allele. In this report, we present data from several patients who are simple heterozygotes for the -83 mutation, or compound heterozygotes for -83 and Hb S (HBB: c.20A?>?T) or β-thal. These cases illustrate that the -83 sequence variant is not associated with a thalassemic phenotype. This has important implications for carrier screening and genetic counseling, particularly since the -83 mutation is relatively common in African and Hispanic populations.     

Observation of a Rare Hemoglobin Variant [Hb Lulu Island, β107(G9)Gly→Asp,GGC→GAC] Co-Inherited With a β+-Thalassemia Mutation [IVS-I-110 (G→A)] or in the Heterozygous State in a Greek-Albanian Family

We report clinical, hematological, biochemical, functional and molecular studies carried out on two first cousins from a Greek-Albanian family who have clinical and hematological findings consistent with the diagnosis of thalassemia intermedia. DNA studies determined that they had co‐inherited a common Mediterranean β-thalassemia (thal) mutation, IVS-I-110 (G→A), in trans to a β-globin gene mutation at codon 107 (GGC→GAC), predicted to give rise to a rare unstable β chain variant Hb Lulu Island or β107(G9)Gly→Asp.     

A Novel α-Thalassemia Frameshift Mutation: Codon 8 (–C)

We report a novel α-thalassemia (α-thal) point mutation detected during newborn screening for hemoglobinopathies. Sequence analyses identified a frameshift mutation at codon 8 (–C) in exon 1 of the α2-globin gene. This mutation causes an α⁺-thal phenotype.     

Associations of the TNF-alpha -308 G/A, IL6 -174 G/C and AdipoQ 45 T/G polymorphisms with inflammatory and metabolic responses to lifestyle intervention in Brazilians at high cardiometabolic risk

Background

Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals.

Method

32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements.

Results

Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R?=?0.49, p?=?0.011) and protein (R?=?0.51, p?=?0.004) expression, as well as with circulating adiponectin levels (R?=?0.46, 0?=?0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R?=??0.61, 0?=?0.003) and adipocyte cell size (R?=??0.40, p?=?0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte dysregulation and HIF-1alpha in this group of non-obese individuals.

Conclusions

In conclusion, these findings support the concept that it is not obesity per se, but rather metabolic dysfunction of adipose tissue that is associated with systemic insulin resistance and the metabolic syndrome.     

308G/A and 238G/A polymorphisms in the TNF-α gene may not contribute to the risk of arthritis among Turkish psoriatic patients

IntroductionTumor necrosis factor-alpha (TNF-α) is an important proinflammatory cytokine playing a key role in the pathogenesis of psoriasis (Ps) and psoriatic arthritis (PsA). TNFα gene promoter region single nucleotide polymorphisms (SNPs) affect the clinical course, severity and the response to the treatment.Aim of the workTo find out whether TNF-α-238G/A and -308G/A promoter polymorphism in Ps patients increases arthritis risk.Patients and methodsThe study included 129 psoriatic patients (71 with psoriasis only and 58 with PsA). Two single nucleotide polymorphisms in the TNFα gene promoter region (238G/A and -308G/A) were genotyped by real-time polymerase chain reaction.ResultsPs patients without arthritis had a mean age of 44.20 ± 13.85 years (range 18–68 years), while PsA patients had a mean age of 49.15 ± 13.47 years (range 18–82 years) and presented by dactylitis (67.2%), enthesitis (62.1%) followed by spondylitis (60.3%). Periosteal reaction was present in 19%. The psoriatic arthritis severity index (PASI) was comparable between those with (8.2 ± 7.1) and without (7.3 ± 5.12.1) arthritis. The allele positivity of TNF-238A and -308A was not associated with the risk of arthritis among psoriatic patients (OR: 1.002; 95%CI: 0.38–2.6, p = 0.99 and OR: 1.27; 95%CI: 0.51–3.2, p = 0.6, respectively). In addition, none of the genotypes of the studied TNF-α polymorphisms were significantly associated with arthritis. Only spondylitis was significantly associated more frequently with the GG (67.3%) than the GA (22.2%) TNF-α-308G/A genotype (p = 0.02).ConclusionNone of the haplotypes nor alleles of TNF-α-238G/A and -308G/A polymorphisms were significantly associated with arthritis development among psoriatic patients.     

2016 FSH/FSC专家共识声明:难治性高血压管理要点

正在改善生活方式的基础上,应用足量且合理联合的3种降压药物(包括利尿剂)后,血压仍在参考范围之上,或至少需要4种药物才能使血压达标时,称为难治性高血压。最近,法国高血压学会/法国心血管学会(FSH/FSC)发布了难治性高血压专家共识声明,重点内容如下。1.推荐难治性高血压定义为在改善生活方式的基础上,应用了足量且合理联合的3种降压药物(包括一种噻嗪类利尿剂)至少治疗4周后,