BACKGROUND:Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of ...the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN.
METHODS:In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between ValMet and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background.
FINDINGS:Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, ValMet was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNPlifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4. Stratified by genetic ancestry, the association between ValMet and DNP was significant in European and African genetic ancestry.
INTERPRETATION:ValMet may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.
Previous research has shown that attention can be biased to targets appearing near the hand that require action responses, arguing that attention to the hand facilitates upcoming action. It is ...unclear whether attention orients to non-targets near the hand not requiring responses. Using electroencephalography/event-related potentials (EEG/ERP), this study investigated whether hand position affected visual orienting to non-targets under conditions that manipulated the distribution of attention. We modified an attention paradigm in which stimuli were presented briefly and rapidly on either side of fixation; participants responded to infrequent targets (15%) but not standard non-targets and either a hand or a block was placed next to one stimulus location. In Experiment 1, attention was distributed across left and right stimulus locations to determine whether P1 or N1 ERP amplitudes to non-target standards were differentially influenced by hand location. In Experiment 2, attention was narrowed to only one stimulus location to determine whether attentional focus affected orienting to non-target locations near the hand. When attention was distributed across both stimulus locations, the hand increased overall N1 amplitudes relative to the block but not selectively to stimuli appearing near the hand. However, when attention was focused on one location, amplitudes were affected by the location of attentional focus and the stimulus, but not by hand or block location. Thus, hand position appears to contribute only a non-location-specific input to standards during visual orienting, but only in cases when attention is distributed across stimulus locations.
Although the inverse association between high-density lipoprotein cholesterol (HDL-C) and risk of cardiovascular disease (CVD) has been long established, it remains unclear whether low HDL-C remains ...a CVD risk factor when levels of low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) are not elevated. This is a timely issue because recent studies have questioned whether HDL-C is truly an independent predictor of CVD.
3590 men and women from the Framingham Heart Study offspring cohort without known CVD were followed between 1987 and 2011. Low HDL-C (<40 mg/dL in men and <50 mg/dL in women) was defined as isolated if TG and LDL-C were both low (<100 mg/dL). We also examined higher thresholds for TG (150 mg/dL) and LDL-C (130 mg/dL) and compared low versus high HDL-C phenotypes using logistic regression analysis to assess association with CVD. Compared with isolated low HDL-C, CVD risks were higher when low HDL-C was accompanied by LDL-C ≥100 mg/dL and TG <100 mg/dL (odds ratio 1.3 1.0, 1.6), TG ≥100 mg/dL and LDL-C <100 mg/dL (odds ratio 1.3 1.1, 1.5), or TG and LDL-C ≥100 mg/dL (odds ratio 1.6, 1.2, 2.2), after adjustment for covariates. When low HDL-C was analyzed with higher thresholds for TG (≥150 mg/dL) and LDL-C (≥130 mg/dL), results were essentially the same. In contrast, compared with isolated low HDL-C, high HDL-C was associated with 20% to 40% lower CVD risk except when TG and LDL-C were elevated.
CVD risk as a function of HDL-C phenotypes is modulated by other components of the lipid panel.
Genome-wide association studies (GWAS) are a powerful tool for investigators to examine the human genome to detect genetic risk factors, reveal the genetic architecture of diseases and open up new ...opportunities for treatment and prevention. However, despite its successes, GWAS have not been able to identify genetic loci that are effective classifiers of disease, limiting their value for genetic testing. This chapter highlights the challenges that lie ahead for GWAS in better identifying disease risk predictors, and how we may address them. In this regard, we review basic concepts regarding GWAS, the technologies used for capturing genetic variation, the missing heritability problem, the need for efficient study design especially for replication efforts, reducing the bias introduced into a dataset, and how to utilize new resources available, such as electronic medical records. We also look to what lies ahead for the field, and the approaches that can be taken to realize the full potential of GWAS.
Recently, the development of biobanks linked to electronic medical records has presented new opportunities for genetic and epidemiological research. Studies based on these resources, however, present ...unique challenges, including the accurate assignment of individual-level population ancestry. In this work we examine the accuracy of administratively-assigned race in diverse populations by comparing assigned races to genetically-defined ancestry estimates. Using 220 ancestry informative markers, we generated principal components for patients in our dataset, which were used to cluster patients into groups based on genetic ancestry. Consistent with other studies, we find a strong overall agreement (Kappa = 0.872) between genetic ancestry and assigned race, with higher rates of agreement for African-descent and European-descent assignments, and reduced agreement for Hispanic, East Asian-descent, and South Asian-descent assignments. These results suggest caution when selecting study samples of non-African and non-European backgrounds when administratively-assigned race from biobanks is used.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lung cancer is a leading cause of cancer-related death worldwide. Racial disparities in lung cancer survival exist between blacks and whites, yet they are limited by categorical definitions of race. ...We sought to examine the impact of African ancestry on overall survival among blacks and whites with NSCLC cases.
Incident cases of NSCLC in blacks and whites from the prospective Southern Community Cohort Study (N = 425) were identified through linkage with state cancer registries in 12 southern states. Vital status was determined by linkage with the National Death Index and Social Security Administration. We evaluated the impact of African ancestry (as estimated by using genome-wide ancestry-informative markers) on overall survival by calculating the time-dependent area under the curve (AUC) for Cox proportional hazards models, adjusting for relevant covariates such as stage and treatment. We replicated our findings in an independent population of NSCLC cases in blacks.
Global African ancestry was not significantly associated with overall survival among NSCLC cases. There was no change in model performance when Cox proportional hazards models with and without African ancestry were compared (AUC = 0.79 for each model). Removal of stage and treatment reduced the average time-dependent AUC from 0.79 to 0.65. Similar findings were observed in our replication study.
Stage and treatment are more important predictors of survival than African ancestry is. These findings suggest that racial disparities in lung cancer survival may disappear with similar early detection efforts for blacks and whites.
Protein function can be impacted by changes in protein structure stability, but determining which change has impact is complex. Stability can be affected by a large change in the tertiary (3D) ...structure of the protein or due to free-energy changes caused by single amino acid substitutions. Changes in the DNA sequence can have minor or major impact on protein stability, which can lead to disease. Inherited retinal degenerations are generally caused by single mutations which are mostly located in protein-coding regions, while age-related macular degeneration (AMD) is a complex disorder that can be influenced by some genetic variants impacting proteins involved in the disease, although not all AMD risk variants lead to amino acid changes. Here, we review ways that proteins may be affected, the identification and understanding of these changes, and how to identify causal changes that can be targeted to develop treatments to alleviate retinal degenerative disease.
Variations in the KCNJ6 gene appear to influence both acute and chronic pain phenotypes.
G-protein coupled inwardly rectifying potassium (GIRK) channels are effectors determining degree of analgesia ...experienced upon opioid receptor activation by endogenous and exogenous opioids. The impact of GIRK-related genetic variation on human pain responses has received little research attention. We used a tag single nucleotide polymorphism (SNP) approach to comprehensively examine pain-related effects of KCNJ3 (GIRK1) and KCNJ6 (GIRK2) gene variation. Forty-one KCNJ3 and 69 KCNJ6 tag SNPs were selected, capturing the known variability in each gene. The primary sample included 311 white patients undergoing total knee arthroplasty in whom postsurgical oral opioid analgesic medication order data were available. Primary sample findings were then replicated in an independent white sample of 63 healthy pain-free individuals and 75 individuals with chronic low back pain (CLBP) who provided data regarding laboratory acute pain responsiveness (ischemic task) and chronic pain intensity and unpleasantness (CLBP only). Univariate quantitative trait analyses in the primary sample revealed that 8 KCNJ6 SNPs were significantly associated with the medication order phenotype (P<.05); overall effects of the KCNJ6 gene (gene set-based analysis) just failed to reach significance (P=.054). No significant KCNJ3 effects were observed. A continuous GIRK Related Risk Score (GRRS) was derived in the primary sample to summarize each individual’s number of KCNJ6 “pain risk” alleles. This GRRS was applied to the replication sample, which revealed significant associations (P<.05) between higher GRRS values and lower acute pain tolerance and higher CLBP intensity and unpleasantness. Results suggest further exploration of the impact of KCNJ6 genetic variation on pain outcomes is warranted.
Anemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain.
Participants included ...1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression.
The mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05).
Anemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.
Reading frame altering genomic variants can impact gene expression levels and the structure of protein products, thus potentially inducing disease phenotypes. Current annotation approaches report the ...impact of such variants in the context of altered DNA sequence only; attributes of the resulting transcript, reading frame and translated protein product are not reported. To remedy this shortcoming, we present a new genetic annotation approach termed Codon Consequence Scanner (COCOS). Implemented as an Ensembl variant effect predictor (VEP) plugin, COCOS captures amino acid sequence alterations stemming from variants that produce an altered reading frame, such as stop-lost variants and small insertions and deletions (InDels). To highlight its significance, COCOS was applied to data from the 1000 Genomes Project. Transcripts affected by stop-lost variants introduce a median of 15 amino acids, while InDels have a more extensive impact with a median of 66 amino acids being incorporated. Captured sequence alterations are written out in FASTA format and can be further analyzed for impact on the underlying protein structure.
COCOS is available to all users on github: https://github.com/butkiem/COCOS.
mariusz.butkiewicz@case.edu.
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