Genetic Epidemiological Studies Research Articles

Lumpy skin disease in cattle in Sharkia, Egypt: epidemiological and genetic characterization of the virus.

Lumpy skin disease virus (LSDV) continues to threaten the cattle industry in Egypt. This survey investigated the epidemiological risk factors and the genetic characterization of circulating strains by partial sequencing of the P32 gene on cattle farms in the Sharkia Governorate, Egypt. Out of 600 cattle examined, morbidity, mortality, and case fatality were 31.2%, 1.8%, and 5.9%, respectively. Risk of LSD was higher among unvaccinated cattle kept outdoors compared to vaccinated cattle kept indoors, and the prevalence rates were statistically significantly different (P < 0.05). Regarding seasonal distribution, the highest number of cases was in June and July, and the lowest was in November. The P32 gene sequences showed that two LSDV isolates were 100% identical and 99.26% identical with 2017 Russian LSDV. Phylogenetic analysis revealed that two local isolates in this study were grouped together with other LSDVs from Russia (Saratov), Kenya, Greece, and Israel. The sequences in the study and other Egyptian sequences were grouped into two clusters with low genetic divergence, indicating that different strains are spreading in Egypt and that LSDV is more genetically related to sheep poxviruses than goat poxviruses. Our study confirms the necessity of evaluating the vaccination strategy adopted in Egypt, and sequence analysis based on the P32 gene is appropriate for genetic epidemiological studies of the local LSDVs.

An exploration of the genetic epidemiology of non-suicidal self-harm and suicide attempt

BackgroundEmpirical evidence supporting the distinction between suicide attempt (SA) and non-suicidal self-harm (NSSH) is lacking. Although NSSH is a risk factor for SA, we do not currently know whether these behaviours lie on a continuum of severity, or whether they are discrete outcomes with different aetiologies. We conducted this exploratory genetic epidemiology study to investigate this issue further.MethodsWe explored the extent of genetic overlap between NSSH and SA in a large, richly-phenotyped cohort (the Avon Longitudinal Study of Parents and Children; N = 4959), utilising individual-level genetic and phenotypic data to conduct analyses of genome-wide complex traits and polygenic risk scores (PRS).ResultsThe single nucleotide polymorphism heritability of NSSH was estimated to be 13% (SE 0.07) and that of SA to be 0% (SE 0.07). Of the traits investigated, NSSH was most strongly correlated with higher IQ (rG = 0.31, SE = 0.22), there was little evidence of high genetic correlation between NSSH and SA (rG = − 0.1, SE = 0.54), likely due to the low heritability estimate for SA. The PRS for depression differentiated between those with NSSH and SA in multinomial regression. The optimal PRS prediction model for SA (Nagelkerke R2 0.022, p < 0.001) included ADHD, depression, income, anorexia and neuroticism and explained more variance than the optimal prediction model for NSSH (Nagelkerke R2 0.010, p < 0.001) which included ADHD, alcohol consumption, autism spectrum conditions, depression, IQ, neuroticism and suicide attempt.ConclusionsOur findings suggest that SA does not have a large genetic component, and that although NSSH and SA are not discrete outcomes there appears to be little genetic overlap between the two. The relatively small sample size and resulting low heritability estimate for SA was a limitation of the study. Combined with low heritability estimates, this implies that family or population structures in SA GWASs may contribute to signals detected.

POS-428 PROTEIN-TRUNCATING PKD1 MUTATIONS YET MILD AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE IS UNDER-RECOGNIZED

Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable between patients. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes, yet within family disease variability is a recognized feature of ADPKD. The penetrance of protein-truncating PKD1 mutations cannot be adequately evaluated if only index probands with severe disease are tested. Here, we evaluated the patients with protein-truncating PKD1 mutations yet mild kidney disease from the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease. The extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease cohort included probands with ADPKD (n=612) and their affected relatives (n=778) from a total of 612 unrelated families. 487 patients from 442 unrelated families had both PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification based on age- and height-adjusted total kidney volume was used to assess their cystic disease severity. Among 174 study patients with protein-truncating PKD1 mutations, 32 (18%) from 27 families were found to have mild disease based on imaging results (i.e. Mayo Clinic Imaging Class 1A-1B), with their mutations spanning across the entire gene. 23 of 32 were over the age of 30 making incorrect risk stratification unlikely. In patients with Mayo Clinic Imaging Class 1A-1B, the slopes of log-transformed height-adjusted total kidney volume (βPKD1= 1.0% larger kidney per year vs. βPKD2= 1.3% larger per year, P=0.3) and eGFR (βPKD1= -1.29 ml/min/1.73m2 per year vs. βPKD2= -1.46 ml/min/1.73m2 per year, P=0.6) overlap regardless of whether they had protein-truncating PKD1 or PKD2 mutation. Comparing patients with Mayo Clinic Imaging Class 1A-1B by multivariable analyses, patients with PKD2 mutations had only marginally smaller kidney volumes (β = -7.7%; 95% CI: -13.9% to -0.01%; P=0.02) and their eGFR was not significantly different (β = 9.0 ml/min/1.73m2; 95% CI: -0.4 to 18.3 ml/min/1.73m2, P=0.06) compared to those with protein-truncating PKD1 mutations. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intra-familial disease variability. One patient had confirmed somatic mosaicism. Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease based on clinical and imaging assessment that was similar to patients with PKD2 mutations. The presence of a positive family history of ADPKD in most of these patients makes somatic mosaicism an unlikely explanation for their mild disease. By contrast, significant within-family variability suggests a protective modifier effect from yet unknown genetic and environmental factors.

Automated CT Staging of Chronic Obstructive Pulmonary Disease Severity for Predicting Disease Progression and Mortality with a Deep Learning Convolutional Neural Network

To develop a deep learning-based algorithm to stage the severity of chronic obstructive pulmonary disease (COPD) through quantification of emphysema and air trapping on CT images and to assess the ability of the proposed stages to prognosticate 5-year progression and mortality. In this retrospective study, an algorithm using co-registration and lung segmentation was developed in-house to automate quantification of emphysema and air trapping from inspiratory and expiratory CT images. The algorithm was then tested in a separate group of 8951 patients from the COPD Genetic Epidemiology study (date range, 2007-2017). With measurements of emphysema and air trapping, bivariable thresholds were determined to define CT stages of severity (mild, moderate, severe, and very severe) and were evaluated for their ability to prognosticate disease progression and mortality using logistic regression and Cox regression. On the basis of CT stages, the odds of disease progression were greatest among patients with very severe disease (odds ratio [OR], 2.67; 95% CI: 2.02, 3.53; P < .001) and were elevated in patients with moderate disease (OR, 1.50; 95% CI: 1.22, 1.84; P = .001). The hazard ratio of mortality for very severe disease at CT was 2.23 times the normal ratio (95% CI: 1.93, 2.58; P < .001). When combined with Global Initiative for Chronic Obstructive Lung Disease (GOLD) staging, patients with GOLD stage 2 disease had the greatest odds of disease progression when the CT stage was severe (OR, 4.48; 95% CI: 3.18, 6.31; P < .001) or very severe (OR, 4.72; 95% CI: 3.13, 7.13; P < .001). Automated CT algorithms can facilitate staging of COPD severity, have diagnostic performance comparable with that of spirometric GOLD staging, and provide further prognostic value when used in conjunction with GOLD staging.Supplemental material is available for this article.© RSNA, 2021See also commentary by Kalra and Ebrahimian in this issue.

Assessment of Bidirectional Relationships Between Polycystic Ovary Syndrome and Periodontitis: Insights From a Mendelian Randomization Analysis.

BackgroundObservational studies have indicated an association between polycystic ovary syndrome (PCOS) and periodontitis, but it is unclear whether the association is cofounded or causal. We conducted a two-sample Mendelian randomization (MR) study to investigate the bidirectional relationship between genetically predicted PCOS and periodontitis.MethodsFrom two genome-wide association studies we selected 13 and 7 single nucleotide polymorphisms associated with PCOS and periodontitis, respectively, as instrumental variables. We utilized publicly shared summary-level statistics from European-ancestry cohorts. To explore the causal effect of PCOS on periodontitis, 12,289 cases of periodontitis and 22,326 controls were incorporated, while 4,890 cases of PCOS and 20,405 controls in the reverse MR. Inverse-variance weighted method was employed in the primary MR analysis and multiple sensitivity analyses were implemented.ResultsGenetically determined PCOS was not causally associated with risk of periodontitis (odds ratio 0.97; 95% confidence interval 0.88–1.06; P = 0.50) per one-unit increase in the log-odds ratio of periodontitis. Similarly, no causal effect of periodontitis on PCOS was shown with the odds ratio for PCOS was 1.17 (95% confidence interval 0.91–1.49; P = 0.21) per one-unit increase in the log-odds ratio of periodontitis. Consistent results were yielded via additional MR methods. Sensitivity analyses demonstrated no presence of horizontal pleiotropy or heterogeneity.ConclusionThe bidirectional MR study couldn’t provide convincing evidence for the causal relationship between genetic liability to PCOS and periodontitis in the Europeans. Triangulating evidence across further observational and genetic-epidemiological studies is necessary.

Genetic markers for preeclampsia in Peruvian women.

Background: Preeclampsia is a multiorgan disorder associated with maternal and perinatal morbi-mortality. In Peru, incidence is 10% and accounts for 22% of maternal deaths. Genome and genetic epidemiological studies have found an association between preeclampsia and genetic polymorphisms. Objective: To determine the association of the vascular endothelial growth factor (VEGF) +936 C/T and +405 G/C, interleukine-6 (IL-6) -174 G/C, IL-1β-511 C/T, Apo A-1-75 G/A, Apo B-100 2488 C/T (Xbal) polymorphisms with preeclampsia in pregnant Peruvian women.Methods: Were included preeclamptic and healthy (control) pregnant women. Maternal blood samples were subjected to DNA extraction, and molecular genetic analysis was conducted using the PCR-RFLP technique and following a specific protocol for each gene. Allele and genotypic frequencies in the cases and controls were compared.Results: No association was found between the VEGF+936C/T and VEGF+405 polymorphisms and preeclampsia. The frequencies of the GG genotypes and the G allele of the -174 G/C polymorphism in the IL6 gene in preeclamptic and controls showed significant differences, with higher frequencies in cases. For the -511 C/T polymorphism of the IL-1β gene, no significant differences were found in the frequencies of TT genotypes compared with CT+CC. The genotypes and alleles of the Apo-A1-75 G/A and Apo-B100 Xbal variants showed no significant differences between cases and controls.Conclusion: No association was found between the studied genetic markers and preeclampsia. However, in the -174G/C polymorphism of the IL-6 gene, significant differences were found mainly in the GG genotype and G allele.

Characterization of genetic diversity and population structure within Staphylococcus chromogenes by multilocus sequence typing.

Staphylococcus chromogenes is a common skin commensal in cattle and has been identified as a frequent cause of bovine mastitis and intramammary infections. We have developed a seven locus Multilocus Sequence Typing (MLST) scheme for typing S. chromogenes. Sequence-based typing systems, such as MLST, have application in studies of genetic diversity, population structure, and epidemiology, including studies of strain variation as a factor in pathogenicity or host adaptation. The S. chromogenes scheme was tested on 120 isolates collected from three geographic locations, Vermont and Washington State in the United States and Belgium. A total of 46 sequence types (STs) were identified with most of the STs being location specific. The utility of the typing scheme is indicated by a discrimination power of 95.6% for all isolates and greater than 90% for isolates from each of the three locations. Phylogenetic analysis placed 39 of the 46 STs into single core group consistent with a common genetic lineage; the STs in this group differ by less than 0.5% at the nucleotide sequence level. Most of the diversification in this lineage group can be attributed to mutation; recombination plays a limited role. This lineage group includes two clusters of single nucleotide variants in starburst configurations indicative of recent clonal expansion; nearly 50% of the isolates sampled in this study are in these two clusters. The remaining seven STs were set apart from the core group by having alleles with highly variable sequences at one or more loci. Recombination had a higher impact than mutation in the diversification of these outlier STs. Alleles with hypervariable sequences were detected at five of the seven loci used in the MLST scheme; the average sequence distances between the hypervariable alleles and the common core alleles ranged from 12 to 34 nucleotides. The extent of these sequence differences suggests the hypervariable alleles may be remnants of an ancestral genotype.

Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development.

Drug development in cardiovascular disease is stagnating, with lack of efficacy and adverse effects being barriers to innovation. Human genetics can provide compelling evidence of causation through approaches such as Mendelian randomization, with genetic support for causation increasing the probability of a clinical trial succeeding. Mendelian randomization applied to quantitative traits can identify risk factors for disease that are both causal and amenable to therapeutic modification. However, important differences exist between genetic investigations of a biomarker (such as HDL cholesterol) and a drug target aimed at modifying the same biomarker of interest (such as cholesteryl ester transfer protein), with implications for the methodology, interpretation and application of Mendelian randomization to drug development. Differences include the comparative nature of the genetic architecture - that is, biomarkers are typically polygenic, whereas protein drug targets are influenced by either cis-acting or trans-acting genetic variants - and the potential for drug targets to show disease associations that might differ from those of the biomarker that they are intended to modify (target-mediated pleiotropy). In this Review, we compare and contrast the use of Mendelian randomization to evaluate potential drug targets versus quantitative traits. We explain how genetic epidemiological studies can be used to assess the aetiological roles of biomarkers in disease and to prioritize drug targets, including designing their evaluation in clinical trials.

Inference of a causal relation between low-density lipoprotein cholesterol and hypertension using mendelian randomization analysis

BackgroundIt is known in some studies that higher the LDL-C, the greater the risk of developing cardiovascular disease. However, studies of the causal effects between LDL-C and hypertension are limited by their observational study design, and genetic epidemiology studies of associations between LDL-C and hypertension are lacking, as are studies using data for Koreans. In this study, we confirmed the causal effect of LDL-C on hypertension using Korean chip data.MethodThe epidemiology and genotype data were collected from the Korean Genome and Epidemiology Study conducted by the Korea National Institute of Health and covered 20,701 subjects. Single-nucleotide polymorphisms associated with LDL-C were selected (p-value < 5 × 10− 8) from the Global Lipids Genetics Consortium database, and Mendelian randomization analysis (MRA) was performed with counted genetic risk scores and weighted genetic risk scores (WGRSs) for 24 single-nucleotide polymorphisms.ResultThe assumptions for MRA were statistically confirmed, and WGRSs showed a strong association with LDL-C. Interestingly, while the relationship between LDL-C and hypertension was not statistically significant in the observational study, MRA study demonstrated that the risk of hypertension increased as LDL-C increased in both men and women.ConclusionsThe results of this study confirmed that the relationship between LDL-C and hypertension is greatly influenced by genetic information.

Body mass index and colorectal cancer risk: A Mendelian randomization study

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two‐sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome‐wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP‐BMI associations, we undertook a meta‐analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J‐CGE), comprising normal populations. For the analysis of SNP‐CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta‐analysis. Mendelian randomization analysis of inverse‐variance weighted method indicated that a one‐unit (kg/m2) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06‐1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03‐1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one‐unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.

Patients with Protein-Truncating PKD1 Mutations and Mild ADPKD.

Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3.

Epidemiology of thalassemia among the hill tribe population in Thailand.

Thalassemia is a severe disease that occurs due to abnormalities in hemoglobin genes. Various genetic factors in different populations lead to different clinical manifestations of thalassemia disease, particularly among people who have a long history of migration and who have married among tribes, such as the hill tribe people in Thailand. This genetic epidemiological study aimed to estimate the prevalence of various forms of thalassemia among the six main hill tribe populations in Thailand. A cross-sectional study was conducted to obtain information and blood specimens from school children belonging to one of the six main hill tribes in Thailand: Akha, Lau, Hmong, Yao, Karen, and Lisu. Hill tribe children who were attending grades 4-6 in 13 selected schools in Chiang Rai Province, Thailand, were invited to participate in the study. A validated questionnaire and 3 mL blood specimens were collected after obtaining information consent forms from both the children and their parents on a voluntary basis. A complete blood count (CBC) was performed, followed by osmotic fragility (OF) and dichlorophenol indophenol precipitation (DCIP) tests to screen for thalassemia. High-performance liquid chromatography (HPLC) and real-time quantitative polymerase chain reaction (qPCR) were used to identify hemoglobin type and α-thalassemia, respectively. A t-test, chi-square and logistic regression were used to detect the associations between variables at the significance level of α = 0.05. A total of 1,200 participants from 6 different tribes were recruited for the study; 50.0% were males, and 67.3% were aged 11-12 years. The overall prevalence of thalassemia carriers according to the screening tests was 9.8% (117 of 1,200). Among the cases, 83 were A2A (59 cases were α-thalassemia 1 carrier or α-thalassemia 2 carrier or homozygous α-thalassemia 2, and 24 cases were β-thalassemia trait with or without α-thalassemia); 1 case was EE (homozygous Hb E with or without α-thalassemia); 31 cases were EA (30 cases were the Hb E trait, and 1 case was Hb E trait with or without α-thalassemia); 1 case was A2A Bart's H (Hb H disease α-thalassemia 1/α-thalassemia 2); and 1 case was A2A with abnormal Hb. The prevalence of the α-thalassemia 1 trait among the hill tribe population was 2.5%. The greatest prevalence of the α-thalassemia 1 trait was found in the Karen (3.0%) and Hmong (3.0%) tribes. The prevalence of some forms of thalassemia in the hill tribe population is higher than that in the Thai and other populations. Effective and available thalassemia screening tests, including essential information to protect the next generation through the specific counseling clinic, are crucial, particularly due to increasing marriages within these populations.

Impact of a Medical Diagnosis on Decision to Stop Smoking and Successful Smoking Cessation.

Smoking cessation counseling is a central part of the Medicare guidelines for lung cancer screening. With increasing age, many heavy smokers eventually stop smoking, however, factors influencing the decision to stop smoking are poorly understood. We postulated that declining health or physician-diagnosis of a medical condition may be associated with successful smoking cessation. A total of 4448 current and former smokers in Phase 2 of the COPD Genetic Epidemiology (COPDGene®) study answered a question about reasons for stopping smoking. Participants were classified as successful quitters (n=3345), and unsuccessful quitters (n=1003). Reasons cited for quitting were grouped as: medical diagnoses, social factors, symptoms. Logistic modeling of factors associated with successful quitting were adjusted for age, gender, race, and education. The most common factors cited for a quit attempt by all respondents were medical diagnoses (48%), followed by social factors (47%), and respiratory symptoms (36%). Successful quitters were more likely to be older, male, and non-Hispanic White. An adjusted model found increased age, White race, education beyond high school, and male sex favored successful quitting while the cited medical diagnoses, social factors, and "other" reasons were associated with unsuccessful quitting. Fagerstrom Nicotine Dependence scores were ³ 5 in 54% of the unsuccessful group compared to 45% for successful quitters(p<0.0001) suggesting some increased nicotine dependence in the unsuccessful quitters. Medical diagnosis was the most common factor cited for considering a quit attempt by both successful and unsuccessful quitters; however, successful quitting was influenced by demographic factors and potentially the severity of nicotine dependence.

Progression of Emphysema and Small Airways Disease in Cigarette Smokers.

Little is known about factors associated with emphysema progression in cigarette smokers. We evaluated factors associated with change in emphysema and forced expiratory volume in 1 second (FEV1) in participants with and without chronic obstructive pulmonary disease (COPD). This retrospective study included individuals participating in the COPD Genetic Epidemiology study who completed the 5-year follow-up, including inspiratory and expiratory computed tomography (CT) and spirometry. All paired CT scans were analyzed using micro-mapping, which classifies individual voxels as emphysema or functional small airway disease (fSAD). Presence and progression of emphysema and FEV1 were determined based on comparison to nonsmoker values. Logistic regression analyses were used to identify clinical parameters associated with disease progression. A total of 3088 participants were included with a mean ± SD age of 60.7±8.9 years, including 72 nonsmokers. In all Global initiative for chronic Obstructive Lung Disease (GOLD) stages, the presence of emphysema at baseline was associated with emphysema progression (odds ratio [OR]: GOLD 0: 4.32; preserved ratio-impaired spirometry [PRISm]; 5.73; GOLD 1: 5.16; GOLD 2: 5.69; GOLD 3/4: 5.55; all p ≤0.01). If there was no emphysema at baseline, the amount of fSAD at baseline was associated with emphysema progression (OR for 1% increase: GOLD 0: 1.06; PRISm: 1.20; GOLD 1: 1.7; GOLD 3/4: 1.08; all p ≤ 0.03).In 1735 participants without spirometric COPD, progression in emphysema occurred in 105 (6.1%) participants and only 21 (1.2%) had progression in both emphysema and FEV1. The presence of emphysema is an important predictor of emphysema progression. In patients without emphysema, fSAD is associated with the development of emphysema. In participants without spirometric COPD, emphysema progression occurred independently of FEV1 decline.

Chronic Bronchitis in COPD Patients Creates Worse Symptom Burden Regardless of the Presence of Bronchiectasis in the COPDGene Cohort.

To assess whether the presence or absence of bronchiectasis has an impact on the patient-reported symptoms of chronic obstructive pulmonary disease (COPD) patients. The study included participants from the COPD Genetic Epidemiology Study (COPDGene®) cohort with available high-resolution chest tomography reporting the presence or absence of bronchiectasis (BE+/BE-) and survey data reporting the presence or absence of chronic bronchitis symptoms (CB+/CB-). Patient symptoms based on the St George's Respiratory Questionnaire (SGRQ) were then compared for the different groups. The study population included 7976 participants, mean age 60, Global initiative for chronic Obstructive Lung Disease (GOLD) stages 0 to 4, 18.8% BE+, and 19.5% CB+. The presence or absence of radiographic bronchiectasis was not associated with higher frequency of chronic bronchitis (GOLD 0 group odds ratio [OR] 1.01 [0.78,1.31], GOLD 1-2 group OR 1.19 [0.95, 1.50], GOLD 3-4 group OR 1.26 [0.99, 1.60]). Similarly, CB+ participants had higher SGRQ scores than CB- participants regardless of the presence of BE. Across all GOLD stages, chronic bronchitis symptoms are associated with worse pulmonary symptoms and significant impairment in quality of life. For patients with chronic bronchitis, the presence or absence of bronchiectasis is not associated with a significant difference in SGRQ symptom scores. Symptoms of chronic bronchitis impose a heavy burden on patients and should be treated regardless of the presence or absence of underlying bronchiectasis.

Use of Genomic Information in Health Impact Assessment is Yet to Come: A Systematic Review.

Information generated by genetic epidemiology and genomics studies has been accumulating at fast pace, and this knowledge opens new vistas in public health, allowing for the understanding of gene–environment interactions. However, the translation of genome-based knowledge and technologies to the practice of healthcare, and especially of public health, is challenging. Because health impact assessment (HIA) proved to be an effective tool to assist consideration of health issues is sectoral policymaking, this study aimed at exploring its role in the translational process by a systematic literature review on the use of genetic information provided by genetic epidemiology and genomics studies in HIA. PubMed, Scopus, and Web of Science electronic databases were searched and the findings systematically reviewed and reported by the PRISMA guidelines. The review found eight studies that met the inclusion criteria, most of them theoretically discussing the use of HIA for introducing genome-based technologies in healthcare practice, and only two articles considered, in short, the possibility for a generic application of genomic information in HIA. The findings indicate that HIA should be more extensively utilized in the translation of genome-based knowledge to public health practice, and the use of genomic information should be facilitated in the HIA process.

Associations between MTHFR gene polymorphisms and the risk of intracranial hemorrhage: Evidence from a meta-analysis.

IntroductionPreviously, a number of genetic epidemiological studies have evaluated associations between MTHFR gene polymorphisms and the risk of intracranial hemorrhage (ICH), with controversial results. Accordingly, we carried out this meta‐analysis to more conclusively evaluate associations between MTHFR gene polymorphisms and the risk of ICH.MethodsMEDLINE, EMBASE, Wanfang, VIP, and CNKI were searched comprehensively, and thirty‐one genetic association studies were finally selected to be included in this meta‐analysis.ResultsEight literatures (963 cases and 2,244 controls) assessed relationship between MTHFR rs1801131 (A1298C) polymorphism and the risk of ICH, and thirty‐one literatures (3,679 cases and 9,067 controls) assessed relationship between MTHFR rs1801133 (C677T) polymorphism and the risk of ICH. We found that AA genotype of rs1801131 polymorphism was significantly associated with a decreased risk of intraventricular hemorrhage (IH) compared with AC/CC genotypes (OR = 0.63; p = .003), AC genotype was significantly associated with an increased risk of IH compared with AA/CC genotypes (OR = 1.55; p = .005), and A allele was significantly associated with a decreased risk of IH compared with C allele (OR = 0.75; p = .02). Additionally, CC genotype of rs1801133 polymorphism was significantly associated with a decreased risk of cerebral hemorrhage (CH) compared with CT/TT genotypes (OR = 0.75; p = .04), TT genotype was significantly associated with an increased risk of CH compared with CC/CT genotypes (OR = 1.27; p = .02), and C allele was significantly associated with a decreased risk of CH compared with T allele (OR = 0.85; p = .007).ConclusionsThis meta‐analysis shows that rs1801131 polymorphism may influence the risk of IH, while rs1801133 polymorphism may influence the risk of CH.

Lipoprotein(a) and Cardiovascular Disease.

High lipoprotein(a) concentrations present in 10%-20% of the population have long been linked to increased risk of ischemic cardiovascular disease. It is unclear whether high concentrations represent an unmet medical need. Lipoprotein(a) is currently not a target for treatment to prevent cardiovascular disease. The present review summarizes evidence of causality for high lipoprotein(a) concentrations gained from large genetic epidemiologic studies and discusses measurements of lipoprotein(a) and future treatment options for high values found in an estimated >1 billion individuals worldwide. Evidence from mechanistic, observational, and genetic studies support a causal role of lipoprotein(a) in the development of cardiovascular disease, including coronary heart disease and peripheral arterial disease, as well as aortic valve stenosis, and likely also ischemic stroke. Effect sizes are most pronounced for myocardial infarction, peripheral arterial disease, and aortic valve stenosis where high lipoprotein(a) concentrations predict 2- to 3-fold increases in risk. Lipoprotein(a) measurements should be performed using well-validated assays with traceability to a recognized calibrator to ensure common cut-offs for high concentrations and risk assessment. Randomized cardiovascular outcome trials are needed to provide final evidence of causality and to assess the potential clinical benefit of novel, potent lipoprotein(a) lowering therapies.

Cohort Profile: ZOE 2.0-A Community-Based Genetic Epidemiologic Study of Early Childhood Oral Health.

Early childhood caries (ECC) is an aggressive form of dental caries occurring in the first five years of life. Despite its prevalence and consequences, little progress has been made in its prevention and even less is known about individuals’ susceptibility or genomic risk factors. The genome-wide association study (GWAS) of ECC (“ZOE 2.0”) is a community-based, multi-ethnic, cross-sectional, genetic epidemiologic study seeking to address this knowledge gap. This paper describes the study’s design, the cohort’s demographic profile, data domains, and key oral health outcomes. Between 2016 and 2019, the study enrolled 8059 3–5-year-old children attending public preschools in North Carolina, United States. Participants resided in 86 of the state’s 100 counties and racial/ethnic minorities predominated—for example, 48% (n = 3872) were African American, 22% white, and 20% (n = 1611) were Hispanic/Latino. Seventy-nine percent (n = 6404) of participants underwent clinical dental examinations yielding ECC outcome measures—ECC (defined at the established caries lesion threshold) prevalence was 54% and the mean number of decayed, missing, filled surfaces due to caries was eight. Nearly all (98%) examined children provided sufficient DNA from saliva for genotyping. The cohort’s community-based nature and rich data offer excellent opportunities for addressing important clinical, epidemiologic, and biological questions in early childhood.

Genetic markers for hypertension – a genetic epidemiological study of 5000 Romanian individuals

Abstract Background During the past decades, genetic research has reached new heights as next generation sequencing has rapidly taken over and genome-wide association studies (GWAS) have broug. The purpose of the research is to determin high-risk variants (Single-Nucleotide-Variants,SNVs) associated with hypertension (HTA) in the Romanian population. The current presentation asseses the final results of a 3 part study comprising the first and the largest GWAS on hypertension in Romanians. Material Methods The total cohort includes a number of 5690 individuals, of which 2190 with hypertension and 3500 heathy controls. Genetic testing was performed at in Iceland. A multiple GWAS assay has been performed for the identification of variants associated with hypertension, hypertension risk factors and hypertension comorbidities. Results Environmental (lifestyle) risk factors, such as smoking, alcohol consumption and coffee consumption, and also pathological risk factors, as are obesity and ageing, were analyzed in association with hypertension. Tissue-specific protein expression, gene function and gene-gene interactions have been analyzed for assessing a possible biological explanation of the association between the identified related variants and HTA. Expression quantitative trait loci (eQTL) were assessed for variants in the reported locations for a better understanding of their involvement in HTA. The results of the analysis revealed a number of over 5000 genetic variants statistically correlated with hypertension in the studied cohort, some well documented and in genes known to be involved in hypertension pathophysiology (clusters on chromosomes 1p36, 1q24, 3q24, 4p16, 5q12, 7q36, 12p12, 15q, 17q, 20q12, a.o. or CRNKL1, C19Orf12, CCDC51, C20Orf26, ZNF420, ZNF571, a.o. intragenic variants). Approx. 4100 SNVs were identified in correlation with diabetes mellitus and obesity. Variants correlated with both hypertension and DM were identified (TBX20,ANK2, a.o. genes). Two other variant clusters (p=10–4–10–3) on chromosomes 19 (19q12) and 20 (20p11.21) revealed statistical correlations with both hypertension and obesity. Conclusions The present study found some important loci and clusters associated with HTA, which migh provide insights into the genetic architecture of this pathology. The validity of these results for the Romanian population need to be confirmed by replication studies. The current research is part of the EU ProMark, ROMCAN and AppGenEdu projects. Funding Acknowledgement Type of funding source: None