Internal heating method of loop-mediated isothermal amplification for detection of HPV-6 DNA.

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.

Health Care Provider Intervention and Utilization of Cessation Assistance in 12 Low- and Middle-Income Countries.

Background and Aim: There is a need to improve utilization of cessation assistance in low- and middle-income countries (LMICs), and tobacco cessation research has been identified as priority in LMICs. This study evaluates the relationship between health care provider intervention and cessation assistance utilization in LMICs. Methods: Data from 13 967 participants (aged ≥15 years, 90.3% males) of the Global Adults Tobacco Survey conducted in 12 LMICs (74.3%-97.3% response rates) were analyzed with utilization of counseling/cessation clinic, WHO-recommended medications, and quitline as outcome variables. Health care provider intervention ("no intervention," only "tobacco screening," "quit advice") was the exposure variable. Weighted multiple logistic regression models were used to examine the relationship between each outcome variable and the exposure variable, adjusting for other covariates. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Results: Approximately 52%, 8%, and 40% of participants received no intervention, only tobacco screening, and advice to quit, respectively. Overall, 0.4%, 1.9%, 3.0%, and 4.5% used quitline, WHO-recommended medications, counseling/cessation clinic, and any cessation assistance, respectively. Compared with no intervention, quit advice was associated with increased utilization of quitline (OR = 2.24, 95% CI = 1.2 to 4.4), WHO-recommended medications (OR = 1.67, 95% CI = 1.2 to 2.3), counseling/cessation clinic (OR = 4.41, 95% CI = 3.2 to 6.1), and any assistance (any of the three types) (OR = 2.80, 95% CI = 2.2 to 3.6). Conclusion: The findings of this study suggest that the incorporation of quit advice by health care providers in tobacco control programs and health care systems in LMICs could potentially improve utilization of cessation assistance to improve smoking cessation in LMICs. Implications: This first study of association between health care provider intervention and the utilization of cessation assistance in LMICs reports that there was a missed opportunity to provide quit advice to about 60% of smokers who visited a health care provider in the past year. The odds of utilization of counseling/cessation clinic, WHO-recommended medications, and quitline were significantly increased in participants who were advised to quit smoking. The results suggest that effective integration and implementation of advice to quit in tobacco control programs and the national health care systems may increase the use of cessation assistance to quit smoking.

Gender Differences in HIV Sexual Risk Behaviors Among Clients of Substance Use Disorder Treatment Programs in the U.S.

This study examined differences in sexual risk behaviors by gender and over time among 1281 patients (777 males and 504 females) from 12 community-based substance use disorder treatment programs throughout the United States participating in CTN-0032, a randomized control trial conducted within the National Drug Abuse Treatment Clinical Trials Network. Zero-inflated negative binomial and negative binomial models were used in the statistical analysis. Results indicated significant reductions in most types of sexual risk behaviors among substance users regardless of the intervention arms. There were also significant gender differences in sexual risk behaviors. Men (compared with women) reported more condomless sex acts with their non-primary partners (IRR = 1.80, 95 % CI 1.21-2.69) and condomless anal sex acts (IRR = 1.74, 95 % CI 1.11-2.72), but fewer condomless sex partners (IRR = 0.87, 95 % CI 0.77-0.99), condomless vaginal sex acts (IRR = 0.83, 95 % CI 0.69-1.00), and condomless sex acts within 2 h of using drugs or alcohol (IRR = 0.70, 95 % CI 0.53-0.90). Gender-specific intervention approaches are called for in substance use disorder treatment.

Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p < 2 × 10(-3). The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10(-4)). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p < 0.05). Furthermore, Kaplan-Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

Age Differences in the Trends of Smoking Among California Adults: Results from the California Health Interview Survey 2001-2012.

The aim is to study the trends of cigarette smoking from 2001 to 2012 using a California representative sample in the US. Data was taken from the California Health Interview Survey (CHIS) from 2001 to 2012, which is a population-based, biennial, random digit-dial telephone survey of the non-institutionalized population. The CHIS is the largest telephone survey in California and the largest state health survey in the US. 282,931 adults (n = 184,454 with age 18-60 and n = 98,477 with age >60) were included in the analysis. Data were weighted to be representative and adjusted for potential covariance and non-response biases. During 2001-2012, the prevalence of current smoking decreased from 18.86 to 15.4 % among adults age 18-60 (ß = -0.8, p = 0.0041). As for adults age >60, the prevalence of current smoking trend decreased with variations, started from 9.66 % in 2001, slightly increased to 9.74 % in 2003, but then gradually decreased, falling to 8.18 % in 2012. In 2012, there was a 14 % reduction of daily smoking adults age 18-60 (OR 0.84, 95 % CI 0.76-0.93, p = 0.0006) compared to 2001, while no significant reduction of daily smoking was observed for those age >60. The reductions of smoking prevalence for adults younger than 60 are encouraging. However, there is a concern for smoking cessation rates among those older than 60 years of age, particularly for African Americans.

Association between DPYSL2 gene polymorphisms and alcohol dependence in Caucasian samples.

The DPYSL2 gene at 8p22-p21 is expressed widely in neuronal tissues and has been implicated in multiple psychiatric disorders such as Alzheimer's disease and schizophrenia. We therefore hypothesized that DPYSL2 gene polymorphisms may play a role in alcohol dependence (AD). We investigated the genetic associations of 57 single-nucleotide polymorphisms (SNPs) within the DPYSL2 gene with AD using two Caucasian samples-the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls), and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). The SNP rs11995227 was most significantly associated with AD (p = 0.000122) in the COGA sample while one flanking SNP rs7832576 revealed the second most significant association with AD (p = 0.00163) in the COGA sample and association with AD (p = 0.0195) in the SAGE sample. Meta-analysis of two samples showed both rs119952227 and rs7832576 were associated with AD (p = 0.000363 and 0.000184, respectively). Furthermore, the C-A haplotype from rs11995227 and rs7832576 revealed significant association with AD (p = 0.0000899) in the COGA sample while the T-G haplotype revealed association with AD both in the COGA and SAGE samples (p = 0.00098 and 0.021, respectively). These findings suggest that genetic variants in DPYSL2 may play a role in susceptibility to AD.

NRG3 gene is associated with the risk and age at onset of Alzheimer disease.

The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10(-5)). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.

Associations of alcohol consumption and mental health with the prevalence of arthritis among US adults: data from the 2012 National Health Interview Survey.

The findings of association between alcohol consumption and arthritis are mixed while little is known about age differences in the associations of mental health and behavioral factors with arthritis. This study aimed to estimate the prevalence and associated factors of arthritis among US adults using data from the 2012 National Health Interview Survey. In total, 8,229 adults with arthritis and 26,256 controls were selected from the adult respondents. Weighted univariate and multiple logistic regression analyses were used to estimate the odds ratios (ORs) with 95 % confidence intervals. The overall prevalence of arthritis was 22.1 %. The prevalence increased with age (6.8, 29.6, and 47.9 % for 18-49, 50-64, and 65+ years of age, respectively). The prevalence of mental problems was higher in cases than controls [4 vs. 1 % for serious psychological distress (SPD), 29 vs. 16 % for anxiety, and 26 vs. 11 % for depression, respectively]. Multiple logistic regression analyses showed that being female, older age, smoking, alcohol consumption, obesity, SPD, depression, and anxiety were positively associated with arthritis. Stratified by age, SPD was associated with arthritis only in young adults (18-49 years old) while the ORs of anxiety and depression with arthritis decreased as age increased. Alcohol consumption revealed stronger associations in middle-aged adults and elderly. Using a large nationally representative sample in the USA, alcohol consumption, smoking, SPD, anxiety, and depression were associated with arthritis, and the associations varied across different age groups.

Rare SERINC2 variants are specific for alcohol dependence in individuals of European descent.

OBJECTIVES: We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS: A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0

Age differences in the associations of behavioral and psychosocial factors with stroke.

BACKGROUND: Stroke remains a major public health burden. Few studies have focused on the age differences in the associations of behavioral and psychosocial factors with stroke while no study focusing on the effect of severe psychological distress (SPD) on stroke has been conducted. The aim of this study was to examine the age differences in these risk factors for stroke as young (18-44 years), middle aged (45-64 years), and elderly (65 years or older). METHODS: A total of 1,258 adults with stroke and 39,985 controls were selected from the 2005 California Health Interview Survey. Multiple logistic regression analyses were used to estimate the associations of the factors with stroke at different ages. RESULTS: The prevalence of SPD was 10% in cases and 3.6% in controls, respectively. Overall, current smoking, lack of physical activity, alcohol consumption, SPD, type II diabetes, male, older age, and unemployment were all associated with a higher prevalence of stroke. Practically, we found that smoking and SPD were associated with the prevalence of stroke in young adults, lack of physical activity was associated with the prevalence of stroke in middle-aged adults, and lack of physical activity and SPD were associated with the prevalence of stroke in the elderly. CONCLUSIONS: Appropriate intervention for reducing stroke and eliminating its disparities may be developed separately at each age.

Genome-wide association study identifies 5q21 and 9p24.1 (KDM4C) loci associated with alcohol withdrawal symptoms.

Several genome-wide association (GWA) studies of alcohol dependence (AD) and alcohol-related phenotypes have been conducted; however, little is known about genetic variants influencing alcohol withdrawal symptoms (AWS). We conducted the first GWA study of AWS using 461 cases of AD with AWS and 408 controls in Caucasian population in the Collaborative Study on the Genetics of Alcoholism (COGA) sample. Logistic regression analysis of AWS as a binary trait, adjusted for age and sex, was performed using PLINK. We identified 51 SNPs associated with AWS with p < 10(-4). The first best signal was rs770182 (p = 3.65 × 10(-6)) at 5q21 near EFNA5 gene which was replicated in the Australian twin-family study of 273 families (p = 0.0172). Furthermore, three SNPs (rs10975990, rs10758821 and rs1407862) within KDM4C gene at 9p24.1 showed p < 10(-4) (p = 7.15 × 10(-6), 2.79 × 10(-5) and 4.93 × 10(-5), respectively) in the COGA sample while one SNP rs12001158 within KDM4C with p = 1.97 × 10(-4) in the COGA sample was replicated in the family sample (p = 0.01). Haplotype analysis further supported the associations of single-marker analyses of KDM4C in the COGA sample. Moreover, two SNPs (rs2046593 and rs10497668) near FSIP2 at 2q32.1 with moderate associations with AWS in the COGA sample (p = 2.66 × 10(-4) and 9.48 × 10(-5), respectively) were replicated in the family sample (p = 0.0013 and 0.0162, respectively). In addition, several SNPs in GABRA1, GABRG1, and GABRG3 were associated with AWS (p < 10(-2)) in the COGA sample. In conclusion, we identified several loci associated with AWS. These findings offer the potential for new insights into the pathogenesis of AD and AWS.

Parent-of-origin effects of FAS and PDLIM1 in attention-deficit/hyperactivity disorder.

BACKGROUND: Previous studies have suggested that there may be a parent-of-origin effect for attention-deficit/hyperactivity disorder(ADHD) candidate genes. The objective of the present study was to investigate parent-of-origin effects using a genome-wide association analysis of the International Multicentre ADHD Genetics (IMAGE) study sample. METHODS: Family-based association analysis for ADHD using 846 ADHD probands and their parents was performed using the PLINK program, and parent-of-origin effects were studied using a Z score for the difference in paternal versus maternal odds ratios. RESULTS: We identified 44 single nucleotide polymorphisms (SNPs) showing parent-of-origin effects at a significance level of p < 0.001. The most significant SNP, rs7614907, is at position 3q13.33 in the CDGAP gene (p = 0.000064 for parent-of-origin effect). Furthermore, 2 genes (FAS and PDLIM1) showed moderate parent-of-origin effects (p = 0.00086 for rs9658691 and p = 0.00077 for rs11188249) and strong maternal transmission (p = 0.000059 for rs9658691 and p = 0.0000068 for rs11188249). In addition, ZNF775 showed a moderate parent-of-origin effect (p = 0.00036 for rs7790549) and strong paternal transmission (p = 0.000041 for rs7790549). LIMITATIONS: We only had 1 sample available for analysis. CONCLUSION: These results suggest several genes or regions with moderate parent-of-origin effects, and these findings will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in ADHD.

The skeletal effects of thiazolidinedione and metformin on insulin-resistant mice.

To explore the skeletal effects and the potential underlying mechanisms of treatment with two thiazolidinediones (rosiglitazone and pioglitazone) or metformin in insulin-resistant mice, 24 female, 12-week-old C57BL6J ob/ob mice were evaluated according to the following treatment groups for 6 weeks: placebo group, pioglitazone group (Pio), rosiglitazone group (Rosi), and metformin group (Met). Bone mineral density (BMD), bone microarchitecture, bone histomorphometry, and expression of three phenotype-specific gene markers, including bone morphogenetic protein 2 (Bmp2), runt-related transcription factor 2 (Runx2), and fatty acid-binding protein 4 (Fabp4), were compared across the four groups. At the femur, the Met group had the highest BMD (0.084 ± 0.001 g/cm(2)) and trabecular bone volume/total volume (0.644 ± 0.018 %) and the lowest trabecular spacing (Tb.Sp.) (0.143 ± 0.008 µm), whereas the Rosi group had lower BMD (0.076 ± 0.003 g/cm(2)) and a relatively higher degree of Tb.Sp. (0.173 ± 0.024 µm). A histomorphometric analysis revealed that in the Rosi group the number of adipocytes was fourfold higher than in the placebo group and fivefold higher than in the Met group, whereas the highest osteoid width and mineral apposition rate were found in the Met group (49.88 ± 48.53 µm and 4.46 ± 1.72 µm/day). Furthermore, the Rosi group displayed the highest level of Fabp4 gene expression, which was accompanied by normal expression levels of Bmp2 and Runx2. Seemingly, metformin is a bone-friendly antidiabetic drug. Rosiglitazone had adverse effects on the skeleton at the trabecular bone even in insulin-resistant mice, whereas no evidence of adverse effects was found for pioglitazone.

Family-based association analysis of alcohol dependence in the COGA sample and replication in the Australian twin-family study.

Family, twin, and adoption studies have indicated that genetic and environmental factors contribute to the development of alcohol dependence (AD). We conducted a low-density genome-wide association analysis to identify genetic variants influencing AD. We used 11,120 SNPs from the Affymetrix 10K Genechips genotyped in 116 Caucasian pedigrees (272 nuclear families) from Genetic Analysis Workshop 14, a subset from the Collaborative Study on the Genetics of Alcoholism (COGA). Family-based association analyses for AD were performed by the PBAT program for autosomal SNPs and by the FBAT program for X-chromosome SNPs. We identified 37 SNPs associated with AD (P < 10(-3)), thirteen of which were located in known genes. The most significant association with AD was observed with SNP rs1986644 (P = 8.51 × 10(-6)) at 13q22 near EDNRB gene. The next best signal was at 1q41 in USH2A (rs532342, P = 1.07 × 10(-5)) and the third region was at 3q25.31 in TIPARP (rs1367311, P = 2.31 × 10(-5)). Furthermore, we found support for association of MAOA gene (P = 4.14 × 10(-4) for rs979606). Six of the 37 AD associated SNPs were confirmed to be associated with AD in Australian twin-family study sample (P < 0.05). Interestingly, four SNPs in DSCAML1 at 11q23 reached the genome-wide significance (the top SNP is rs10892169 with P = 5.31 × 10(-9)), while rs637547 in NKAIN2 at 6q21 showed strong association with AD (P = 5.11 × 10(-7)) in the replication sample. These findings offer the potential for new insights into the pathogenesis of AD and will serve as a resource for replication in other populations to elucidate the potential role of these genetic variants in AD.

The novel lipopolysaccharide-binding protein CRISPLD2 is a critical serum protein to regulate endotoxin function.

LPS is an immunostimulatory component of Gram-negative bacteria. Acting on the immune system in a systemic fashion, LPS exposes the body to the hazard of septic shock. In this study we report that cysteine-rich secretory protein LCCL domain containing 2 (CRISPLD2/Crispld2; human and mouse/rat versions, respectively), expressed by multitissues and leukocytes, is a novel LPS-binding protein. As a serum protein, median CRISPLD2 concentrations in health volunteers and umbilical cord blood samples are 607 microg/ml and 290 microg/ml, respectively. Human peripheral blood granulocytes and mononuclear cells including monocytes, NK cells, and T cells spontaneously release CRISPLD2 (range, 0.2-0.9 microg/ml) and enhance CRISPLD2 secretion (range, 1.5-4.2 microg/ml) in response to stimulation of both LPS and humanized anti-human TLR4-IgA Ab in vitro. CRISPLD2 exhibits significant LPS binding affinity similar to that of soluble CD14, prevents LPS binding to target cells, reduces LPS-induced TNF-alpha and IL-6 production, and protects mice against endotoxin shock. In in vivo experiments, serum Crispld2 concentrations increased in response to a nontoxic dose of LPS and correlated negatively with LPS lethality, suggesting that CRISPLD2 serum concentrations not only are indicators of the degree of a body's exposure to LPS but also reflect an individual's LPS sensitivity.

RNA interference targeting CITRON can significantly inhibit the proliferation of hepatocellular carcinoma cells.

CITRON (rho-interacting, serine/threonine kinase 21), which is a key component of the midbody, is essential for cytokinesis. However, the role of CITRON in hepatocellular carcinoma (HCC) is poorly understood. Here we first measured the expression of CITRON in HCC specimens by quantitative real-time RT-PCR and immunohistochemical staining. The results showed CITRON to be frequently up-regulated in HCC as compared with adjacent non-tumour tissues. Then we employed adenovirus-mediated RNA interference against CITRON to assess its anti-proliferation effect on SMMC-7721 cells, a representative HCC cell line. The resulting data demonstrated that CITRON knockdown was capable of inhibiting the proliferation and colony formation of SMMC-7721 cells, with an obvious increase of multinucleated cells. Furthermore, we subcutaneously injected the SMMC-7721 cells with the CITRON knockdown into nude mice to evaluate the tumourigenicity. The data indicated that adenovirus-mediated RNA interference can suppress tumourigenicity in vivo of HCC cells. Our data suggest that CITRON may be a potential target for therapeutic intervention in HCC.

Genome-wide association analysis of age at onset in schizophrenia in a European-American sample.

We performed a genome-wide association analysis to identify genetic variants influencing age at onset (AAO) and examine gene × gender interactions for AAO in schizophrenia (SCZ) using a European-American sample (1,162 cases). Linear regression model in PLINK was used to test for associations with AAO while the GxE option was chosen to test for the influence of gene × gender interactions. The most significant association with AAO was observed with SNP rs7819815 (P = 3.10×10(-7)) at 8q24.22. The next best signal was at 4q25 in COL25A1 gene (rs17039583, P = 4.30×10(-6)) and the third region was at 4p16.1 (rs17407555, P = 4.56×10(-6) , near RAF1P1, and rs4697924, P = 1.23×10(-5) within WDR1 gene). Conditional analysis on chromosome 4 indicated that 4p16.1 and 4q25 loci were independent. Furthermore, 2 SNPs (rs16834822 and rs16834824) at 1q43 in RYR2 showed strong associations in the female sample (P = 2.10×10(-6) and 2.33×10(-6) , respectively) and strong gene × gender interactions in influencing AAO (P = 9.23×10(-7) and 1.15×10(-6) , respectively) while the second best region showing gene × gender interaction was at 7q22.3 (rs179863, P = 2.33×10(-6) ). Using an independent sample of 1,068 cases, we could not replicate the associations for above top SNPs; however, we found nominal significance associations for their flanking SNPs (P < 0.05). These findings provide evidence of several genetic variants influencing AAO of SCZ.

HIV Integrase Inhibitor Pharmacogenetics: An Exploratory Study.

BACKGROUND AND OBJECTIVES: Integrase strand transfer inhibitors (INSTIs), dolutegravir, elvitegravir, and raltegravir, have become integral in the treatment of HIV, with close monitoring of continued efficacy and tolerability. As side effect occurrence varies among subjects receiving these drugs, we sought to perform an exploratory analysis examining the role of several single-nucleotide polymorphisms (SNPs) on drug concentration changes, selected clinical outcomes, and the occurrence of subject-reported adverse events. METHODS: Adults (aged ≥ 18 years) receiving INSTI-based regimens for treatment of HIV were recruited and genotyped with an iPLEX ADME PGx Pro v1.0 Panel. Multiple linear or logistic regression with covariates [age, sex, BMI, regimen (in the across-regimen group), regimen duration, and baseline variables (for continuous parameters)] was used to detect significant (p < 0.05) association of selected clinical data with genetic variants within the study population. RESULTS: In a sample (n = 88) with a median age of 52.5 years (IQR 45.7-57.2) being predominately Caucasian (88.6%) and male (86.4%), this exploratory study discovered several associations between variables and SNPs, when using INSTIs. Abnormal dream occurrence was statistically different (p = 0.028) between regimens. Additionally, several SNPs were found to be associated with adverse event profiles primarily when all regimens were grouped together. CONCLUSION: The associations found in this study point to a need for further assessment, within the population living with HIV, of factors contributing to unfavorable subject outcomes. These exploratory findings require confirmation in larger studies, which then may investigate pharmacogenetic mechanisms.

Analysis of PTPRK polymorphisms in association with risk and age at onset of Alzheimer's disease, cancer risk, and cholesterol.

The human receptor-type protein-tyrosine phosphatase kappa (PTPRK) gene is highly expressed in human brain and was previously associated with an increased risk of neuropsychiatric disorders and cancer. This study investigated the association of 52 single nucleotide polymorphisms (SNPs) in PTPRK with the risk and age at onset (AAO) of Alzheimer's disease (AD) in 791 AD patients and 782 controls. Our data analysis showed that five SNPs (top SNP rs4895829 with p = 0.0125) were associated with the risk of AD based on a multiple logistic regression (p < 0.05); while six SNPs (top SNP rs1891150 with p = 8.02 × 10-6) were associated with AAO by using a multiple linear regression analysis. Interestingly, rs2326681 was associated with both the risk and AAO of AD (p = 4.65 × 10-2 and 5.18 × 10-3, respectively). In a replication study, the results from family-based association test - generalized estimating equation (GEE) statistics and Wilcoxon test showed that seven SNPs were associated with the risk of AD (top SNP rs11756545 with p = 1.02 × 10-2) and 12 SNPs were associated with the AAO (top SNP rs11966128 with p = 1.39 × 10-4), respectively. One additional sample showed that four SNPs were associated with risk of cancer (top SNP rs1339197 with p = 4.1 × 10-3), 12 SNPs associated with LDL-cholesterol (top SNP rs4544930 with p = 3.47 × 10-3), and eight SNPs associated with total cholesterol (top SNP rs1012049 with p = 6.09 × 10-3). In addition, the AD associated rs4895829 was associated with the gene expression level in the cerebellum (p = 7.3 × 10-5). The present study is the first study providing evidence of several genetic variants within the PTPRK gene associated with the risk and AAO of AD, risk of cancer, LDL and total cholesterol levels.

Polymorphisms Within RYR3 Gene Are Associated With Risk and Age at Onset of Hypertension, Diabetes, and Alzheimer's Disease.

BACKGROUND: Hypertension affects 33% of Americans while type 2 diabetes and Alzheimer's disease (AD) affect 10% of Americans, respectively. Ryanodine receptor 3 gene (RYR3) codes for the RYR which functions to release stored endoplasmic reticulum calcium ions (Ca2+) to increase intracellular Ca2+ concentration. Increasing studies demonstrate that altered levels of intracellular Ca2+ affect cardiac contraction, insulin secretion, and neurodegeneration. In this study, we investigated associations of the RYR3 genetic variants with hypertension, AD, and diabetes. METHODS: Family data sets were used to explore association of RYR3 polymorphisms with risk and age at onset (AAO) of hypertension, diabetes, and AD. RESULTS: Family-based association tests using generalized estimating equations (FBAT-GEE) showed several unique or shared disease-1 associated variants in the RYR3 gene. Three single nuclear polymorphisms (SNPs; rs2033610, rs2596164, and rs2278317) are significantly associated with risk for hypertension, diabetes, and AD. Two SNPs (rs4780174 and rs7498093) are significantly associated with AAO of the 3 diseases. CONCLUSIONS: RYR3 variants are associated with hypertension, diabetes, and AD. Replication of these results of this gene in these 3 complex traits may help to better understand the genetic basis of calcium-signaling gene, RYR3 in association with risk and AAO of these diseases.