Clinical characteristics and analysis of HFE gene variants (C282Y and H63D) in Jordanian Arab patients with age-related macular degeneration

Age-related macular degeneration (AMD) is a complex genetic disorder with multiple etiologies. Multiple genes as well as environmental effects are thought to play a role in causing AMD. Recent evidence pointed that elevated iron overload, resulting from hereditary defects of iron homeostasis, is associated with retinal degeneration and consequently plays a role in the pathogenesis of AMD. Hemochromatosis is a genetic disorder in which excess iron is absorbed from the diet and deposited in different tissues, primarily caused by mutations in HFE gene. Two major mutations in HFE are responsible for most hemochromatosis cases, namely, C282Y and H63D. In this work we gathered information relating to 37 AMD patients from Jordan, and investigated the potential association between hemochromatosis, or more specifically, carrier state for a mutation in HFE gene (which may moderately increase dietary iron absorption) and AMD, given the effect of elevated iron levels on AMD occurrence. Questionnaires and blood samples were collected from patients visiting the eye care clinic in the King Abdullah hospital in Jordan. DNA was extracted from patient samples and mutations in HFE were genotyped (using polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP), and DNA sequencing) and compared to 106 control samples. We could not detect C282Y (rs1800562) variant in our patient population or in the controls. For carrier status with H63D (rs1799945) we had 30.3% compared to a frequency of 22.7% in the controls (p= 0.37). H63D allele frequency was 15.2% in our patients compared to 11.8% in the controls (p=0.30). H63D variant seems to be more frequent in AMD patients though not reaching a significance of p= 0.05. To date, this is the first attempt to link HFE (particularly, H63D) mutation to AMD.Keywords: AMD; HFE; C282Y; H63D; Association; PolymorphismThe Egyptian Journal of Medical Human Genetics (2013) 14, 177–18

Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma

Polymorphisms in the interleukin-4 receptor α chain (IL-4Rα) have been linked to asthma incidence and severity, but a causal relationship has remained uncertain. In particular, a glutamine to arginine substitution at position 576 (Q576R) of IL-4Rα has been associated with severe asthma, especially in African Americans. We show that mice carrying the Q576R polymorphism exhibited intense allergen-induced airway inflammation and remodeling. The Q576R polymorphism did not affect proximal signal transducer and activator of transcription (STAT) 6 activation, but synergized with STAT6 in a gene target– and tissue-specific manner to mediate heightened expression of a subset of IL-4– and IL-13–responsive genes involved in allergic inflammation. Our findings indicate that the Q576R polymorphism directly promotes asthma in carrier populations by selectively augmenting IL-4Rα–dependent signaling

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold >75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold <0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold <1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill & Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

WOS: 000268860400023PubMed ID: 19577286Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. Objective: To elucidate mechanisms underlying different forms of HIES. Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome. (J Allergy Clin Immunol 2009;124:342-8.)National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI065617]Supported by National Institutes of Health grant 5R01AI065617 (T.C.)

Defects along the T(H)17 differentiation pathway underlie genetically distinct forms of the hyper IgE syndrome

WOS: 000268860400023PubMed ID: 19577286Background: The hyper IgE syndrome (HIES) is characterized by abscesses, eczema, recurrent infections, skeletal and connective tissue abnormalities, elevated serum IgE, and diminished inflammatory responses. It exists as autosomal-dominant and autosomal-recessive forms that manifest common and distinguishing clinical features. A majority of those with autosomal-dominant HIES have heterozygous mutations in signal transducer and activator of transcription (STAT)-3 and impaired T(H)17 differentiation. Objective: To elucidate mechanisms underlying different forms of HIES. Methods: A cohort of 25 Turkish children diagnosed with HIES were examined for STAT3 mutations by DNA sequencing. Activation of STAT3 by IL-6 and IL-21 and STAT1 by IFN-alpha was assessed by intracellular staining with anti-phospho (p)STAT3 and -pSTAT1 antibodies. T(H)17 and T(H)1 cell differentiation was assessed by measuring the production of IL-17 and IFN-gamma, respectively. Results: Six subjects had STAT3 mutations affecting the DNA binding, Src homology 2, and transactivation domains, including 3 novel ones. Mutation-positive but not mutation-negative subjects with HIES exhibited reduced phosphorylation of STAT3 in response to cytokine stimulation, whereas pSTAT1 activation was unaffected. Both patient groups exhibited impaired TH17 responses, but whereas STAT3 mutations abrogated early steps in TH17 differentiation, the defects in patients with HIES with normal STAT3 affected more distal steps. Conclusion: In this cohort of Turkish children with HIES, a majority had normal STAT3, implicating other targets in disease pathogenesis. Impaired TH17 responses were evident irrespective of the STAT3 mutation status, indicating that different genetic forms of HIES share a common functional outcome. (J Allergy Clin Immunol 2009;124:342-8.)National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [5R01AI065617]Supported by National Institutes of Health grant 5R01AI065617 (T.C.)