At-risk Genotypes Research Articles

Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder. The only established epidemiological risk factors for ALS are male sex and increasing age. The role of physical activity has been debated as an environmental risk factor. Over the last decade multiple studies have attempted to delineate the architecture of ALS. These have not yet established definite risk factors, often due to low-powered studies, lack of focus on at-risk genotypes and sub-optimal methodology. We have conducted a review of all the studies published between 2009 and December 2021. The free text search terms were [(motor neuron disease) OR (MND) OR (Amyotrophic Lateral Sclerosis) OR (ALS)] AND [(Exercise) or (Physical Activity) or (PA) or (sport)]. We identified common themes, for example soccer, head injury and the physiological mechanisms that differ in ALS patients. We have analysed the relevant, available studies (n = 93), highlighting the underlying reasons for any reported discrepancies. Overall, we have found that the more highly powered studies using validated exposure methodologies, linked strenuous, anaerobic physical activity as a risk factor for ALS. Future large-scale studies focusing on specific at-risk genotypes and physical activity should be conducted to confirm this finding. This will strengthen the evidence already surrounding strenuous physical activity as an environmental risk factor for ALS and allow advice to be given to at-risk family members. Increasing our understanding of the genetic-environmental interactions in the pathophysiology of ALS will allow for the possibility of developing preventative therapeutic approaches.

The pituitary adenylate cyclase-activating polypeptide system as a sex-specific modulator of hippocampal response to threat stimuli

BackgroundPituitary adenylate cyclase-activating polypeptide (PACAP) receptor gene polymorphism has been postulated as a potential sex-specific diagnostic biomarker of trauma-related disorders. However, no research to date has evaluated whether the PACAPergic system may act as a vulnerability/resilience neuromechanism to trauma-induced psychopathology in healthy participants without heightened risk to experience traumatic events. MethodsHere, we compared the amygdala and hippocampus response to fearful faces in participants with at-risk genotype versus non-risk participants from the Human Connectome Project (n = 991; 53.4% female). ResultsIncreased hippocampal response to fearful faces in the female risk group emerged in sex by genetic risk interaction. ConclusionsOur findings revealed the first sex-specific neurogenetic vulnerability factor to trauma-related disorders, and emphasize the importance of prevention-based strategies to ameliorate neuropsychiatric pathophysiology.

Biochip-based approach for comprehensive pharmacogenetic testing.

Individual sensitivity to many widely used drugs is significantly associated with genetic factors. The purpose of our work was to develop an instrument for simultaneous determination of the most clinically relevant pharmacogenetic markers to allow personalized treatment, mainly in patients with cardiovascular diseases. Multiplex one-step polymerase chain reaction (PCR) followed by hybridization on a low-density biochip was applied to interrogate 15 polymorphisms in the following eight genes: VKORC1-1639G>A, CYP4F2 1297G>A, GGCX 2374C>G, CYP2C9 *2,*3 (430C>T, 1075A>C), CYP2D6 *3,*4, *6, *9, *41 (2549delA, 1846G>A, 1707delT, 2615_2617delAAG, 2988G>A), CYP2C19 *2,*3,*17 (681G>A, 636G>A,-806C>T), ABCB1 (3435C>T), SLCO1B1 *5. Two hundred nineteen patients with cardiovascular diseases (CVD) and 48 female patients with estrogen receptor (ER)-positive breast cancer (BC) were genotyped. Of the 219 CVD patients, 203 (92.7%) carried one or more actionable at-risk genotypes based on VKORC1/CYP2C9, CYP2C9, CYP2C19, SLCO1B1, and CYP2D6 genotypes. Among them, 67 patients (30.6%) carried one, 58 patients (26.5%) carried two, 51 patients (23.3%) carried three, 26 patients (11.9%) carried four, and one patient (0.4%) carried five risk actionable genotypes. In the ER-positive BC group 12 patients (25%) were CYP2D6 intermediate or poor metabolizers. The developed biochip is applicable for rapid and robust genotyping of patients who were taking a wide spectrum of medications to optimize drugs and dosage and avoid adverse drug reactions in cardiology, oncology, psychiatry, rheumatology and gastroenterology.

Impact of MnSOD and GPx1 Genotype at Different Levels of Enteral Nutrition Exposure on Oxidative Stress and Mortality: A Post hoc Analysis From the FeDOx Trial.

Converting nutrition support to energy results in mitochondrial free radical production, possibly increasing oxidative stress. Highly prevalent single nucleotide variants (SNV) exist for the genes encoding antioxidant enzymes responsible for the detoxification of reactive oxygen species. Our objective was to explore the interaction between nutrition support and genetic SNV's for two anti-oxidant proteins (rs4880 SNV for manganese superoxide dismutase and rs1050450 SNV for glutathione peroxidase 1) on oxidative stress and secondarily on intensive care unit (ICU) mortality. We performed a post-hoc analysis on 34 mechanically ventilated sepsis patients from a randomized control feeding trial. Participants were dichotomized into those who carried both the rs4880 and the rs1050450 at-risk alleles (Risk Group) versus all others (Nonrisk Group). We explored the interaction between genotype and percent time spent in the upper median of energy exposure on oxidative stress and ICU mortality. Adjusting for confounders, the slope of log F2-isoprostane levels across percentage of days spent in the upper median of daily kilocalories per kilogram (kcal/kg) was 0.01 higher in the Risk Group compared to the Non-Risk Group (p=0.01). Every 1 percent increase in days spent in the upper median of daily kcal/kg was associated with an adjusted 10.3 percent increased odds of ICU mortality amongst participants in the Risk Group (odds ratio [OR]=1.103, p=0.06) but was highly insignificant in the Nonrisk group (OR=0.991, P=0.79). Nutrition support may lead to increased oxidative stress and worse clinical outcomes in a large percent of ICU patients with an at-risk genotype.

A Low ω-6 to ω-3 PUFA Ratio (n–6:n–3 PUFA) Diet to Treat Fatty Liver Disease in Obese Youth

ABSTRACTBackgroundRecent literature suggests that the Western diet's imbalance between high ω-6 (n–6) and low ω-3 (n–3) PUFA intake contributes to fatty liver disease in obese youth.ObjectivesWe tested whether 12 wk of a low n–6:n–3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response.MethodsIn a single-arm unblinded study, obese youth 9–19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n–6:n–3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann–Whitney U test, and covariance pattern modeling were used.ResultsTwenty obese adolescents (median age: 13.3 y; IQR: 10.5–16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time.ConclusionsThese data suggest that, independently of weight loss, a low n–6:n–3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113.

Prenatal maternal organophosphorus pesticide exposures, paraoxonase 1, and childhood adiposity in the Mount Sinai Children’s Environmental Health Study

BackgroundAnimal studies suggest that organophosphorus pesticides (OPs) may be environmental obesogens. While prenatal OP exposures have been associated with altered infant glucose metabolism, associations with pediatric adiposity remain unknown. MethodsWe summed concentrations of three dimethylphosphate (∑DMP) and three diethylphosphate (∑DEP) metabolites of OPs measured in third trimester spot urine samples collected from pregnant women enrolled in New York City, 1998–2002. We measured percent fat mass using bio-electrical impedance analysis and calculated age- and sex-standardized body mass index (BMI) z-scores from anthropometric measurements collected at approximately 4, 6, and 7–9 years of age (166 children, 333 observations). We assessed covariate-adjusted associations of OPs with repeated adiposity measures using linear mixed models and evaluated effect measure modification (EMM) by sex and paroxonase (PON) 1 –108C/T and Q192R polymorphisms measured in maternal peripheral blood samples. ResultsThe geometric mean urinary concentration of ∑DMP metabolites (29.9 nmol/L, IQR: 105.2 nmol/L) was higher than ∑DEP metabolites (8.8 nmol/L, IQR: 31.2 nmol/L). Adjusted associations were null, with differences in fat mass per 10-fold increase in prenatal ∑DMP and ∑DEP concentrations of 0.7% (95% CI: −0.6, 2.0) and 0.8% (95% CI: −0.4, 2.0), respectively. Maternal PON1-108C/T polymorphisms modified relationships of prenatal ∑DMP with percent fat mass (EMM p-value = 0.18) and ∑DEP with BMI z-scores (EMM p-value = 0.12). For example, ∑DMP was modestly associated with increased percent fat mass among children of mothers with the at-risk CT or TT genotype (β = 1.2%, 95% CI: −0.6, 3.0) but not among those whose mothers had the CC genotype (β = −0.4%, 95% CI: −2.4, 1.5). Associations were not modified by sex or maternal PON1 Q192R polymorphisms. ConclusionsWe observed little evidence of a relationship between prenatal OP exposures and child adiposity, although there was some suggestion of increased risk among offspring of mothers who were slow OP metabolizers. Larger studies are warranted to further evaluate possible associations of prenatal OP exposures with child adiposity and differences by maternal PON1 genotype, which regulates OP metabolism and may increase susceptibility to exposure.

NOD2 Gene Status in Pediatric and Adult Crohn Disease Patients in Algerian Population

Background: Chronic Inflammatory Bowel Diseases (IBD), including Crohn disease (CD) and ulcerative colitis (UC) are gastrointestinal disorders under the influence of a complex genetic basis. One hundred sixty-three predisposition loci were identified by genome-wide association (GWAS) studies, refocusing the pathogenesis of IBD on immunity genes. The NOD2 gene has been widely implicated in the pathogenesis of IBD in different geographical populations. Three most common mutations within NOD2 gene were selected, namely SNP8, C/T (R702W variant), SNP12, G/C (G908R variant) and SNP13, (1007fsinsC variant). We investigated these three SNP in a pediatric Algerian cohort for the first time, since no previous association studies between pediatric IBD and the NOD2 gene were available for the Algerian population. Methods: A case-control study was performed in the pediatric IBD population. PCR-RFLP was used to detect the three NOD2 gene mutations in 46 CD patients and 100 healthy control subjects. All samples were genotyped for the NOD2 gene Polymorphisms by the PCR-RFLP method. Statistical study was performed by the Fisher exact test or Chi-2 using the GraphPad Prism 7.0 software. Then data from the pediatric cohort were compared to our precedent published data from a case-control study performed on a cohort including 132 IBD patients and 114 healthy control subjects. Results: In the pediatric cohort, there is no statistically differences in allelic frequencies between cases and controls respectively R702W (6.36% vs. 6.38%; p=1), G908R (2.72% vs. 1.06%; p=0.6) and 1007fsinsC mutation was found neither in the CD patients nor in control. In the adult cohort, the R702W allelic variant showed the highest frequency in CD patients (8%) (p = 0.09, OR = 3.67, 95%CI: 0.48-4.87) but its frequency was also high in controls (5%) (p = 0.4; OR = 1.4; 95%CI: 0.65-3.31). Likewise, G908R and 1007fsinsC mutations showed similar frequency in CD patients and in controls (3% vs. 2%; p= 0.5; OR=1.67; 95%CI: 0.44-6.34; 2% vs.1%; p=0.4, OR=2.69; 95%CI: 0.48-14.87, respectively). The total frequency of the mutated NOD2 chromosomes was higher in adult CD patients (13%) than in pediatric CD patients (9%). In our precedent study on the adult cohort, we have confirmed that the NOD2 gene is significantly associated with a specific clinical sub-phenotype in CD, indicating that the NOD2 gene is involved in IBD susceptibility across Algerian adult population. However, we failed to show any association between the three variants of the NOD2 gene across Algerian pediatric CD patients. Conclusion: In our precedent study, we have confirmed that the NOD2 gene is significantly associated with a specific clinical sub-phenotype in adult CD patients. Here, our results show no association of NOD2 gene variants with pediatric MC. The low penetrance of the at-risk genotypes we observed indicates that the NOD2 gene does not delineate a subgroup of simple Mendelian diseases.

Recognising the potential role of native ponies in conservation management

Population control of feral horses has been the subject of public debate in many parts of the world in recent years due to wide-reaching ecological and societal impacts. However, the feral populations in these high-profile cases are not ‘native’ but are instead descended from animals which escaped from or were released by settlers. This paper considers i) the potential role of indigenous equids as conservation grazers within native ecosystems currently in poor condition, and ii) the value of supporting semi-wild native ponies specifically. We argue that the high ecological overlap between ponies and cattle reported in a range of studies means that they should be considered as alternative tools for conservation management, particularly in scenarios where there is a need to reduce the dominance of plant species avoided by more-selective small ruminants such as sheep. Semi-wild ponies could be particularly suited to conservation grazing because their genomes have been predominately shaped by natural and not artificial selection, meaning they may have adaptations no longer present in domesticated equids. With agricultural and environmental policy in the EU and UK under major review, it is anticipated that the wider delivery of public goods, rather than primary production, will be prioritised under future subsidy payment schemes. Recognising the value of native ponies as conservation grazers would broaden the range of routes by which land managers could achieve biodiversity gain, whilst simultaneously supporting at-risk equine genotypes.

Projected impact of a multigene pharmacogenetic test to optimize medication prescribing in cardiovascular patients.

Aim:To determine the projected impact of a multigene pharmacogenetic (PGx) test on medication prescribing.Materials & methods:A retrospective analysis was conducted with 122 cardiac catheterization laboratory patients undergoing angiography for eligibility of potential PGx-guided interventions that could have occurred if multigene PGx information was pre-emptively available at the time of the procedure. Medication data and presence of actionable at-risk genotypes were used to determine eligibility of a PGx intervention.Results:20% of the study population (n = 24) would have qualified for at least one PGx-based medication intervention per US FDA or Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines within 6 months of their cardiac catheterization procedure. Commonly encountered gene–drug pairs for these interventions included: CYP2C19 for clopidogrel and antidepressants, CYP2D6 for antidepressants and codeine, SLCO1B1 for simvastatin, and VKORC1/CYP2C9 for warfarin.Conclusion:Pre-emptive use of a multigene PGx test in the cardiac catheterization laboratory offers potential to reduce adverse medication outcomes.

Incidence of and Risk Factors Associated With Age-Related Macular Degeneration

While the prevalence of age-related macular degeneration (AMD) differs according to continents and races/ethnicities, its incidence in the European continent has been scarcely documented. To describe the incidence and associated risk factors of AMD in elderly French individuals. This population-based cohort study of 963 residents of Bordeaux, France, who were 73 years or older at baseline and participated in the Antioxydants, Lipides Essentiels, Nutrition et Maladies Oculaires (ALIENOR) Study between October 2, 2006, and December 21, 2012. Of 829 participants at risk for incident AMD, 659 (79.5%) were observed for a mean (SD) duration of 3.8 (1.1) years. Data were analyzed from August 2016 to March 2017. Age-related macular degeneration was graded from retinal photographs and spectral-domain optical coherence tomography into 5 exclusive stages: no AMD, early AMD1, early AMD2, late atrophic AMD, and late neovascular AMD. Of the 659 eligible participants, 413 (62.7%) were women, and the mean (SD; range) age was 79.7 (4.4; 73-94) years. A total of 120 incident cases of early AMD and 45 incident cases of advanced AMD were recorded. Incidence rates of early and advanced AMD were 79.9 (95% CI, 66.8-95.5) per 1000 person-years and 18.6 (95% CI, 13.9-24.9) per 1000 person-years, respectively, corresponding to 5-year risks of 32.9% and 8.9%. Incidence of advanced AMD per 1000 eye-years was 1.5 in eyes without any AMD at baseline, 42.4 in those with early AMD1, and 85.1 in those with early AMD2. In multivariate analysis without correction for multiple testing, progression from early to advanced AMD was associated with AMD grade in the fellow eye (hazard ratio [HR] according to grade, 13.0 [95% CI, 2.8-61.2] to 22.5 [95% CI, 2.6-195.9]), having smoked at least 20 pack-years (calculated as number of smoking years × mean number of cigarettes per day / 20; HR, 3.0; 95% CI, 1.4-6.5), and complement factor H (CFH) Y402H genotype (CC genotype: HR, 2.3; 95% CI, 1.0-5.3; TC genotype: HR, 1.5; 95% CI, 0.6-3.7). Incidence of early AMD was associated with early AMD in the fellow eye (early AMD1: HR, 2.6; 95% CI, 1.6-4.2; early AMD2: HR, 5.6; 95% CI, 3.3-9.4) and high plasma high-density lipoprotein cholesterol levels (HR, 1.2; 95% CI, 1.0-1.4). In this cohort, AMD incidence rates were similar to those observed in other European populations. This study suggests a high risk for incident early AMD in individuals with high plasma high-density lipoprotein cholesterol levels while confirming the high risk for progression from early to advanced AMD in heavy smokers and carriers of CFH Y402H at-risk genotypes.

Resolving incomplete single nucleotide polymorphism tagging of HLA-DQ2.2 for coeliac disease genotyping using digital droplet PCR.

A hallmark of coeliac disease (CD) is the exceptionally strong genetic association with HLA-DQ2.5, DQ8, and DQ2.2. HLA typing provides information on CD risk important to both clinicians and researchers. A method that enables simple and fast detection of all CD risk genotypes is particularly desirable for the study of large populations. Single nucleotide polymorphism (SNP)-based HLA typing can detect the CD risk genotypes by detecting a combination of six SNPs but this approach can struggle to resolve HLA-DQ2.2, seen in 4% of European CD patients, because of the low resolution of one negatively predicting SNP. We sought to optimise SNP-based HLA typing by harnessing the additional resolution of digital droplet PCR to resolve HLA-DQ2.2. Here we test this two-step approach in an unselected sample of Mexican DNA and compare its accuracy to DNA typed using traditional exon detection. The addition of digital droplet PCR for samples requiring negative prediction of HLA-DQ2.2 enabled HLA-DQ2.2 to be accurately typed. This technique is a simple addition to a SNP-based typing strategy and enables comprehensive definition of all at-risk HLA genotypes in CD in a timely and cost-effective manner.

CORR Insights®: Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs.

CORR Insights®: Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs.

Frank Stinchfield Award: Identification of the At-risk Genotype for Development of Pseudotumors Around Metal-on-metal THAs.

Once touted as the future of hip arthroplasty, metal-on-metal (MoM) bearing surfaces have fallen sharply from favor with the emergence of a strong body of evidence demonstrating unacceptably high premature implant failure rates. The previously unpredictable development of adverse local tissue reactions (ALTRs) has been a substantive contributor to this. Although the underlying pathophysiology of these so-called "pseudotumors" is now well understood, the fundamental predisposing patient risk factors have remained elusive. The aim of this research, as a clinical-genotype correlation analysis, was to identify specific alleles (genes) associated with the development of ALTRs in patients with in situ MoM THAs. A case-control study of patients who received a large-head, primary MoM THA between 2005 and 2008 was performed with a minimum followup of 5 years. Twenty-six patients who had undergone revision of a primary MoM THA secondary to symptomatic ALTRs were recruited. The mean timeframe from primary MoM THA to symptomatic revision was 5.5 years (range, 1-10 years). Twenty-eight control subjects were randomly selected asymptomatic patients with no evidence of ALTRs on protocol-specific screening. Baseline demographics and high-resolution genotype (human leukocyte antigen [HLA] Class II) were collected for all patients. Cohorts were similar with respect to age at the time of primary MoM THA (mean, 54.8 versus 54.9 years, p = 0.95) and serum cobalt (mean, 5.5 versus 8.5 μg/L, p = 0.09) and chromium concentrations (mean, 2.9 versus 4.2 μg/L, p = 0.27). The association between genotype and revision surgery secondary to ALTRs was determined with gender as a covariate. The prevalence of the risk genotype was 30% (16 of 54) among the entire cohort. Adjusting for sex, the odds of revision were 6.1 times greater among patients with the risk genotype present than among patients without (95% confidence interval [CI], 1.5-25.4; p = 0.01). Among females, the specificity of the risk genotype was 1.0 (95% CIexact, 0.5-1.0; pexact = 0.03), and for males, it was 0.8 (95% CIexact, 0.6-0.9; pexact < 0.01). The findings of this study suggest that, among patients with a primary MoM THA, allelic variation within the HLA Class II loci may be a strong, independent risk factor associated with the need for subsequent revision surgery secondary to pseudotumor formation. Given the hypothesis-generating nature of this novel undertaking, confirmatory prospective clinical studies are required to further elucidate this correlation and to explore the clinical utility of targeted genetic screening in this specific population. This research may, however, represent a key missing piece in the puzzle that is metal ion-induced pseudotumor formation.

Genotypic carriers of the obesity-associated FTO polymorphism exhibit different cardiometabolic profiles after an intervention.

Children and adolescents with at-risk genotypes (AA/AT) of the rs9939609 polymorphism in FTO, a fat mass and obesity-associated gene, may exhibit different cardiometabolic profile responses than subjects with the TT genotype after an interdisciplinary intervention. The sample consisted of 36 school children from southern Brazil. We used DNA quantitation and real-time polymerase chain reaction (PCR) for polymorphism genotyping. We measured anthropometric parameters (body mass index (BMI), waist circumference, hip circumference, waist-hip ratio, body fat percentage and skinfold sum), biochemical parameters (glucose, lipid profile, ultra-sensitive C-reactive protein, uric acid, alanine aminotransferase, aspartate aminotransferase, insulin and adiponectin) and blood pressure. The 4-month intervention consisted of physical education classes, nutritional counseling, and postural and oral health counseling. We observed no significant differences among the groups (AA, AT and TT) after the intervention. However, we observed improvements in three parameters (waist circumference, hip circumference and C-reactive protein) in the AT/AA genotype group and in two parameters (hip circumference and uric acid) in the TT genotype group. After an intervention program, carriers of at-risk genotypes for obesity (AA/AT) do not exhibit differences in biochemical parameters, blood pressure and anthropometric parameters compared with carriers of the TT genotype.

MiR-608, pre-miR-124-1 and pre-miR26a-1 polymorphisms modify susceptibility and recurrence-free survival in surgically resected CRC individuals.

Genetic variation within microRNA (miRNA) may result in its abnormal folding or aberrant expression, contributing to colorectal turmorigenesis and metastasis. However, the association of six polymorphisms (miR-608 rs4919510, miR-499a rs3746444, miR-146a rs2910164, pre-miR-143 rs41291957, pre-miR-124-1 rs531564 and pre-miR-26a-1 rs7372209) with colorectal cancer (CRC) risk, therapeutic response and survival remains unclear. A retrospective study was carried out to investigate the association in 1358 0-III stage resected CRC patients and 1079 healthy controls using Sequenom's MassARRAY platform. The results showed that rs4919510 was significantly associated with a decreased susceptibility to CRC in co-dominant, allele and recessive genetic models, and the protective role of rs4919510 allele G and genotype GG was more pronounced among stage 0-II cases; significant association between rs531564 and poor RFS was observed in cases undergoing adjuvant chemo-radiotherapy in co-dominant, allele and dominant models; moreover, there was a positive association between rs7372209 and recurrence-free survival in stage II cases in co-dominant and over-dominant models; additionally, a cumulative effect of rs531564 and rs7372209 at-risk genotypes with hazard ratio at 1.30 and 1.95 for one and two at-risk genotypes was examined in stage II cases, respectively. Our findings indicated that rs4919510 allele G and genotype GG were protective factors for 0-II stage CRC, rs7372209 and rs531564 could decrease RFS in II stage individuals and resected CRC patients receiving adjuvant chemo-radiology.

Basic Science Liver.

Basic Science Liver.

STK39 and WNK1 Are Potential Hypertension Susceptibility Genes in the BELHYPGEN Cohort.

The serine/threonine kinase With-No-Lysine (K) Kinase 1 (WNK1) activates the thiazide-sensitive Na+/Cl− cotransporter through phosphorylation of STE20/SPS1-related proline/alanine-rich kinase, another serine/threonine kinase encoded by STK39. The aim of this study was to look for association between WNK1 and STK39 gene variants, and blood pressure (BP) and hypertension.Seven hundred seventy-nine Caucasian hypertensive patients (HYP) recruited in 6 academic centers from Belgium, and 906 normotensive (NT) controls were genotyped for 5 single nucleotide polymorphisms—rs3754777, rs6749447, rs35929607 (STK39), rs1468326, and rs765250 (WNK1)—using the Snapshot method.The rare TT genotype at the rs3754777 locus (STK39) was overrepresented in HYP versus NT (7.3% vs 3.0%, P = 0.0002). In the whole study population, the multivariable-adjusted odds ratio (OR) for having hypertension associated with the TT genotype was 5.9 (95% confidence interval: 2.2–15.6), and systolic BP was 10 mm Hg higher in TT compared with wild-type subjects (140.1 vs 130.4 mm Hg, P = 0.002). Similarly, the AA genotype at the rs1468326 locus (WNK1) was twice as frequent in HYP versus NT (5.5% vs 2.3%, P < 0.0001), and associated with an increased adjusted OR of hypertension (4.1; 1.5–11.7) and a higher systolic BP (139.8 vs 130.1 mm Hg, P = 0.003). In the whole cohort, a dose-dependent increase in systolic BP was observed according to the number of at-risk genotypes (0: 129.8 mm Hg; 1: 133.0 mm Hg; 2: 149.3 mm Hg, P = 0.02).Single nucleotide polymorphisms rs3754777 (STK39) and rs1468326 (WNK1) were associated with hypertension and BP in our multicenter Belgian case-control study, which supports the role of STK39 and WNK1 as potential hypertension susceptibility genes. Replication in different clinical settings and study of other candidate loci belonging to the same molecular pathway is warranted.

Using Linkage Analysis to Detect Gene-Gene Interactions. 2. Improved Reliability and Extension to More-Complex Models.

Detecting gene-gene interaction in complex diseases has become an important priority for common disease genetics, but most current approaches to detecting interaction start with disease-marker associations. These approaches are based on population allele frequency correlations, not genetic inheritance, and therefore cannot exploit the rich information about inheritance contained within families. They are also hampered by issues of rigorous phenotype definition, multiple test correction, and allelic and locus heterogeneity. We recently developed, tested, and published a powerful gene-gene interaction detection strategy based on conditioning family data on a known disease-causing allele or a disease-associated marker allele4. We successfully applied the method to disease data and used computer simulation to exhaustively test the method for some epistatic models. We knew that the statistic we developed to indicate interaction was less reliable when applied to more-complex interaction models. Here, we improve the statistic and expand the testing procedure. We computer-simulated multipoint linkage data for a disease caused by two interacting loci. We examined epistatic as well as additive models and compared them with heterogeneity models. In all our models, the at-risk genotypes are “major” in the sense that among affected individuals, a substantial proportion has a disease-related genotype. One of the loci (A) has a known disease-related allele (as would have been determined from a previous analysis). We removed (pruned) family members who did not carry this allele; the resultant dataset is referred to as “stratified.” This elimination step has the effect of raising the “penetrance” and detectability at the second locus (B). We used the lod scores for the stratified and unstratified data sets to calculate a statistic that either indicated the presence of interaction or indicated that no interaction was detectable. We show that the new method is robust and reliable for a wide range of parameters. Our statistic performs well both with the epistatic models (false negative rates, i.e., failing to detect interaction, ranging from 0 to 2.5%) and with the heterogeneity models (false positive rates, i.e., falsely detecting interaction, ≤1%). It works well with the additive model except when allele frequencies at the two loci differ widely. We explore those features of the additive model that make detecting interaction more difficult. All testing of this method suggests that it provides a reliable approach to detecting gene-gene interaction.

The prevalence of cervical human papillomavirus infection and the most at-risk genotypes among Iranian healthy women: A systematic review and meta-analysis

Background:One of the most common sexual-transmitted infections among women is human papillomavirus (HPV) infection which is associated with genital cancers. Different studies in Iran reported various prevalences, and combining their results could be important for health policy makers. This study aims to determine the total prevalence of HPV infection as well as its related genotypes, particularly HPV16 and HPV18 among Iranian healthy women.Methods:Searching the Scientific Information Database, Iranmedex, Magiran, Irandoc, PubMed, Google Scholar, Scopus, and ScienceDirect databanks using relevant keywords and excluding duplicates and irrelevant evidence followed by applying exclusion criteria and quality assessment, eligible articles were selected. Standard error of the prevalence was calculated based on binomial distribution. Random effects model was used because of the high heterogeneity among the results.Results:Of 14 studies entered into the systematic review, 24 pieces of evidence reported the HPV prevalence among 7655 healthy and noncancerous women in different Provinces of Iran. Total prevalence of HPV, 9.4% (95% confidence interval [CI]: 6.8–12.02); HPV16, 2.03% (95% CI: 1.3–2.8); HPV18, 1.7% (95% CI: 0.9–2.5); and other genotypes of HPV, 5.3% (95% CI: 3.6–6.9) were estimated.Conclusions:Our meta-analysis showed that the total prevalence of HPV and its high-risk genotypes (16 and 18) among healthy noncancerous Iranian women was very high.

Polymorphisms in mismatch repair genes are associated with risk and microsatellite instability of gastric cancer, and interact with life exposures

BackgroundEpigenetic alterations of DNA mismatch repair (MMR) genes are associated with risk of gastric cancer (GC) by causing microsatellite instability (MSI). Less understood is the association of common polymorphisms in MMR genes with the risk and MSI phenotype of GC. MethodsA hospital-based study was conducted in China with 423 cases and 454 matched controls. Four potentially functional polymorphisms were selected and analyzed: rs1800734 in MLH1, rs2303428 in MSH2, rs735943 in EXO1, and rs11797 in TREX1. ResultsThe rs1800734 G-allele was associated with decreased risk of GC (GA or GG vs AA, OR=0.72; 95% CI: 0.50–1.05; Ptrend=0.029). For combined effects, a dose–response manner was observed in which GC risk was increased with increasing number of at-risk genotypes (Ptrend=0.039); this manner mainly existed in MSI GC (Ptrend=0.047) rather than in microsatellite stability GC, though neither single polymorphism was linked with MSI. For exposures, modified effects were observed from green tea drinking and soy foods intake on rs11797 (P for interaction=0.007 and 0.016, respectively). ConclusionsThe MLH1 rs1800734 polymorphism is associated with GC risk. Those at-risk genotypes have a joint effect on GC risk, which contributes to the MSI phenotype of GC. Life exposures modify GC risk, stratified by MMR genotypes.