1,721,051 research outputs found
Reply to Larcombe and Orr: Still seeing the big picture
No full textI greatly thank Larcombe and Orr for correcting the inaccurate statement we reported in our paper (Napolioni and MacMurray, 2015) on the adaptation of high-producing IL6-174G allele (rs1800795) to tuberculosis. ‘‘Errare humanum est” (Lucius Annaeus Seneca, 4 BC to 45 AD), but this inconsistency does not affect the ‘‘take home message” our paper tries to offer the readers. Indeed, multiple evidence supports the association of IL6 genetic variability with infectious diseases.
Beside the comprehensive study carried out by Fumagalli et al. (2011) that provides evolutionary evidence of a pathogendriven natural selection at the IL6 locus, several studies support the role of IL6 rs1800795 in shaping the susceptibility to infective agents
The relevance of checking population allele frequencies and Hardy-Weinberg Equilibrium in genetic association studies: The case of SLC6A4 5-HTTLPR polymorphism in a Chinese Han Irritable Bowel Syndrome association study
No full textDuring this genomic era, where genetics is assuming a crucial
role both in clinical management of patients and in determining
the best pharmacological therapy according to each subject’s
genetic background, correcting errors assumes a fundamental relevance.
Genetic association studies test for a correlation between
disease status and genetic variation to identify candidate genes
or genome regions that contribute to a specific disease and/or to
a specific quantitative trait of clinical/pharmacological relevance.
Despite the incredible advances achieved during the last three
decades of genetic research, several association studies still yield
conflicting results. These inconsistencies raise several concerns
and reduce the potential clinical/translational impact of such findings
ADA (22G>A) polymorphism: A possible genetic marker for predictive medicine of human reproduction?
No full textOverall, the data reported by Wen et al [1] seem to further
support the role of ADA genetic polymorphism on human
reproduction and call for future research in this area. We may
speculate that ADA polymorphism could be considered, in
the future, an important parameter in clinical practice and
genetic counseling either for in vitro fertilization programs or
for the control of pregnancy outcome, further improving
maternal and newborn health care
Recent patents on epilepsy genetics
No full textThe field of epilepsy genetics is contentious, particularly when it concerns the common epilepsies. More than a dozen loci have been suggested, the result of either linkage analysis and/or association analysis, but few of these findings have been replicated, let alone proven, and those that have are mostly for rare forms of epilepsy. Molecular genetics has revolutionised the understanding of epilepsy genetics and is beginning to have a significant clinical impact. Technological advances have resulted in new high-throughput approaches that promise to further our understanding of the molecular genetics of the epilepsies. The patents discussed in this review highlight the important discoveries that have contributed to our understanding of epilepsy genetics and provide valuable information as to where research in this area will be heading in the future. This knowledge not only informs clinicians about the biology of the epilepsies but also has important consequences for clinical practice and genetic counselling. © 2009 Bentham Science Publishers Ltd
Infectious diseases, IL6 −174G > C polymorphism, and human development
No full textInterleukin-6 (IL6) is a pro-inflammatory cytokine that is required for resistance against many pathogens. However, sustained IL6 activity can cause tissue damage in the periphery and brain. Previous studies have shown that populations in disease-endemic regions adapt by selecting the high-producing G-allele at the −174G > C (rs1800795) polymorphism, while others have linked increased IL6 to cognitive impairments. The present study sought to determine whether up-regulation of IL6 by the G-allele at rs1800795 polymorphism in disease-endemic regions was associated with increased cognitive deficits and corollary reductions in social, economic, and political development. We tested these hypotheses in a global sample of 189 nations with World Health Organization ratings for infectious diseases. We also included the Historical Pathogen Prevalence index, a measure of national average intelligence (IQ), and the United Nation Human Development Index (HDI) including per capita income, life expectancy, child mortality, and fertility rate. IL6 −174G?> C allele frequencies were obtained from 171,168 individuals spanning 84 nations. The high-producing G-allele frequency was positively correlated with infectious disease ranking (r = 0.745, P < 0.001) and negatively with IQ (r = −0.524, P < 0.001) and HDI (r = −0.671, P < 0.001). These robust findings suggest that in regions with a high pathogen burden the need for a strong IL6 response is accompanied by cognitive deficits and reduced HDI ranking
Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment.
No full textAutism spectrum disorders have been reported as being much more frequent in individuals with tuberous sclerosis than in the general population. Previous studies have implicated early seizure onset and the localization of cortical tubers in the temporal lobes as risk factors for autism. However, the underlying reasons for this association remain largely unclear. The dysregulation of intracellular signaling through the activation of mTOR pathway could play a direct role in determining susceptibility to autism. Early control of seizures and an early intensive behavioral intervention of autism during the period of brain plasticity can mitigate, but not reverse the final outcome. A greater understanding of the pathogenetic mechanisms underlying autism in tuberous sclerosis could help in devising targeted and potentially more effective treatment strategies. © The Author(s) 2010
Regarding “Haptoglobin 2-1 phenotype predicts rapid growth of abdominal aortic aneurysms”
No full textI have read with great interest the recent work of Wiernicki et
al, which reports a strong association of Hp 2*/1* phenotype
with increased rates of expansion of abdominal aortic aneurysm
(AAA) and higher serum elastase activity and C-reactive protein
levels. The authors report a detailed analysis of clinical biochemistry
markers and characteristics of patients enrolled in the study.
However, the interpretation of this study needs to take into
account the molecular and genetic complexity of haptoglobin
(Hp) polymorphism. The authors failed to explain why the Hp
2*/1* heterozygous phenotype was different from both homozygous
phenotypes, and speculated that Hp 2*/1* phenotype might
cumulate harmful features associated with allele Hp*1 (stimulation
of the elastin hydrolysis) and allele Hp*2 (increased risk of atherosclerosis)
to yield a combination that is particularly efficient in
promoting AAA growth.The reason underlying the association of Hp 2*/1* phenotype
with increased rates of expansion of AAA resides in the phenomenon
of molecular heterosis at Hp 1/2 polymorphism, reported by several
genetic association studies, and further confirmed by molecular
structure of haptoglobin protein. Molecular heterosis occurs when
subjects heterozygous for a specific genetic polymorphism show a
significantly greater effect (positive heterosis) or lesser effect (negative
heterosis) for a quantitative or dichotomous trait than subjects homozygous
for either allele. Comings and MacMurray estimated that
molecular heterosis may occur in up to 50% of gene associations
Age- and gender-specific association between ADA (22G>A) and TNF-α (-308G>A) genetic polymorphisms
No full textDuring the last years, several investigations have been performed to examine the influence of the tumor necrosis factor alpha (TNF-α) -308G>A single nucleotide polymorphism (SNP) in the susceptibility or severity of diseases and in many inflammatory conditions. However, the results of these studies have been conflicting, suggesting that, under normal/physiologic conditions, important disturbances in expression of major physiologic components can be compensated by mediators of the same system. In the present study, we evaluated the genetic relationship between the functional adenosine deaminase (ADA) (22G>A, rs73598374) and TNF-α (-308G>A, rs1800629) SNPs in a healthy population from central Italy. An association between ADA*2 and TNF-α*A was observed in males aged ≥50 [odds ratio (OR) = 5.16, P = 0.001]; a three-way contingency table analysis by a log-linear model shows a significant interaction between TNF-α genotype, ADA genotype, and age group (P = 0.012) for this gender. Overall, we may speculate that, in males, higher adenosine levels (conferred by ADA*2) may counteract the higher levels of TNF-α (conferred by TNF-α*A) in protective model of inheritance. © 2010 John Wiley & Sons A/S
Autism genetics
No full textAutism spectrum disorder (ASD) is a severe neuropsychiatric disease with strong genetic underpinnings. However, genetic contributions to autism are extremely heterogeneous, with many different loci underlying the disease to a different extent in different individuals. Moreover, the phenotypic expression (. i.e., "penetrance") of these genetic components is also highly variable, ranging from fully penetrant point mutations to polygenic forms with multiple gene-gene and gene-environment interactions. Furthermore, many genes involved in ASD are also involved in intellectual disability, further underscoring their lack of specificity in phenotypic expression. We shall hereby review current knowledge on the genetic basis of ASD, spanning genetic/genomic syndromes associated with autism, monogenic forms due to copy number variants (CNVs) or rare point mutations, mitochondrial forms, and polygenic autisms. Finally, the recent contributions of genome-wide association and whole exome sequencing studies will be highlighted. © 2013
Urinary p-cresol in autism spectrum disorder
No full textAutism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8. years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children. © 2012 Elsevier Inc
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