Epidemiology and genetic architecture of blood pressure: a family based study of Generation Scotland

Hypertension is a major risk factor for cardiovascular disease and mortality, and a growing global public health concern, with up to one-third of the world’s population affected. Despite the vast amount of evidence for the benefits of blood pressure (BP) lowering accumulated to date, elevated BP is still the leading risk factor for disease and disability worldwide. It is well established that hypertension and BP are common complex traits, where multiple genetic and environmental factors contribute to BP variation. Furthermore, family and twin studies confirmed the genetic component of BP, with a heritability estimate in the range of 30-50%. Contemporary genomic tools enabling the genotyping of millions of genetic variants across the human genome in an efficient, reliable, and cost-effective manner, has transformed hypertension genetics research. This is accompanied by the presence of international consortia that have offered unprecedentedly large sample sizes for genome-wide association studies (GWASs). While GWAS for hypertension and BP have identified more than 60 loci, variants in these loci are associated with modest effects on BP and in aggregate can explain less than 3% of the variance in BP. The aims of this thesis are to study the genetic and environmental factors that influence BP and hypertension traits in the Scottish population, by performing several genetic epidemiological analyses. In the first part of this thesis, it aims to study the burden of hypertension in the Scottish population, along with assessing the familial aggregation and heritialbity of BP and hypertension traits. In the second part, it aims to validate the association of common SNPs reported in the large GWAS and to estimate the variance explained by these variants. In this thesis, comprehensive genetic epidemiology analyses were performed on Generation Scotland: Scottish Family Health Study (GS:SFHS), one of the largest population-based family design studies. The availability of clinical, biological samples, self-reported information, and medical records for study participants has allowed several assessments to be performed to evaluate factors that influence BP variation in the Scottish population. Of the 20,753 subjects genotyped in the study, a total of 18,470 individuals (grouped into 7,025 extended families) passed the stringent quality control (QC) criteria and were available for all subsequent analysis. Based on the BP-lowering treatment exposure sources, subjects were further classified into two groups. First, subjects with both a self-reported medications (SRMs) history and electronic-prescription records (EPRs; n =12,347); second, all the subjects with at least one medication history source (n =18,470). In the first group, the analysis showed a good concordance between SRMs and EPRs (kappa =71%), indicating that SRMs can be used as a surrogate to assess the exposure to BP-lowering medication in GS:SFHS participants. Although both sources suffer from some limitations, SRMs can be considered the best available source to estimate the drug exposure history in those without EPRs. The prevalence of hypertension was 40.8% with higher prevalence in men (46.3%) compared to women (35.8%). The prevalence of awareness, treatment and controlled hypertension as defined by the study definition were 25.3%, 31.2%, and 54.3%, respectively. These findings are lower than similar reported studies in other populations, with the exception of controlled hypertension prevalence, which can be considered better than other populations. Odds of hypertension were higher in men, obese or overweight individuals, people with a parental history of hypertension, and those living in the most deprived area of Scotland. On the other hand, deprivation was associated with higher odds of treatment, awareness and controlled hypertension, suggesting that people living in the most deprived area may have been receiving better quality of care, or have higher comorbidity levels requiring greater engagement with doctors. These findings highlight the need for further work to improve hypertension management in Scotland. The family design of GS:SFHS has allowed family-based analysis to be performed to assess the familial aggregation and heritability of BP and hypertension traits. The familial correlation of BP traits ranged from 0.07 to 0.20, and from 0.18 to 0.34 for parent-offspring pairs and sibling pairs, respectively. A higher correlation of BP traits was observed among first-degree relatives than other types of relative pairs. A variance-component model that was adjusted for sex, body mass index (BMI), age, and age-squared was used to estimate heritability of BP traits, which ranged from 24% to 32% with pulse pressure (PP) having the lowest estimates. The genetic correlation between BP traits showed a high correlation between systolic (SBP), diastolic (DBP) and mean arterial pressure (MAP) (G: 81% to 94%), but lower correlations with PP (G: 22% to 78%). The sibling recurrence risk ratio (λS) for hypertension and treatment were calculated as 1.60 and 2.04 respectively. These findings confirm the genetic components of BP traits in GS:SFHS, and justify further work to investigate genetic determinants of BP. Genetic variants reported in the recent large GWAS of BP traits were selected for genotyping in GS:SFHS using a custom designed TaqMan® OpenArray®. The genotyping plate included 44 single nucleotide polymorphisms (SNPs) that have been previously reported to be associated with BP or hypertension at genome-wide significance level. A linear mixed model that is adjusted for age, age-squared, sex, and BMI was used to test for the association between the genetic variants and BP traits. Of the 43 variants that passed the QC, 11 variants showed statistically significant association with at least one BP trait. The phenotypic variance explained by these variant for the four BP traits were 1.4%, 1.5%, 1.6%, and 0.8% for SBP, DBP, MAP, and PP, respectively. The association of genetic risk score (GRS) that were constructed from selected variants has showed a positive association with BP level and hypertension prevalence, with an average effect of one mmHg increase with each 0.80 unit increases in the GRS across the different BP traits. The impact of BP-lowering medication on the genetic association study for BP traits has been established, with typical practice of adding a fixed value (i.e. 15/10 mmHg) to the measured BP values to adjust for BP treatment. Using the subset of participants with the two treatment exposure sources (i.e. SRMs and EPRs), the influence of using either source to justify the addition of fixed values in SNP association signal was analysed. BP phenotypes derived from EPRs were considered the true phenotypes, and those derived from SRMs were considered less accurate, with some phenotypic noise. Comparing SNPs association signals between the four BP traits in the two model derived from the different adjustments showed that MAP was the least impacted by the phenotypic noise. This was suggested by identifying the same overlapped significant SNPs for the two models in the case of MAP, while other BP traits had some discrepancy between the two sources

Recent educational changes at higher educational level in Pakistan: English language teachers' perceptions and practices

Higher Education Institutes (HEIs) of any country could be a source of providing professionals to the country in many fields. By doing so, HEIs could play a pivotal role in the economic growth of the country. In Pakistan, it seems that, in the wake of this realization, steps have been taken to reform Higher Education. Drawing on the Triple I model of educational change covering Initiation, Implementation and Institutionalization (Fullan, 2007) this study focuses on the planning and implementation of reforms in the Education system of Pakistan at higher education level that have been introduced by the Higher Education Commission (HEC) since its inception in 2002. Kennedy’s model of hierarchical subsystems affecting innovation and Chin and Benne’s (1985) description of strategies for implementing change also provided guidelines for analyzing the changes in education in the country to highlight the role that the authorities expect the language teacher to play in the process of implementing these changes. A qualitative method is followed in this study to gather data from English language teachers at three universities of the Khyber Pakhtunkhwa province of Pakistan. A questionnaire was developed to look into the perceptions of English language teachers regarding the impact of these reforms. This was followed up by interviews. Responses from 28 teachers were received through questionnaire out of which 9 teachers were interviewed for detailed analysis of their perceptions. Thematic Content analysis was used to analyze and interpret the data. Some of the most significant changes that the respondents reported knowledge of included the introduction of Semester System, extending the Bachelors degree to four years from two years, promotion of research culture, and increased teachers’ autonomy in classroom practices. Implications of these reforms for English teachers’ professional development were also explored. The data indicate that the teachers generally have a positive attitude towards the changes. However, the data also show concerns that teachers have about the practical effectiveness of these changes in improving English language teaching and learning in Pakistani Universities. Some of the areas of concern are worries regarding resources, the assessment system, the number of qualified teachers, and instability in the educational policy. They are concerned about the training facilities and quality of the professional training available to them. Moreover, they report that training opportunities for their professional development are not available to all the teachers equally. Despite the HEC claims of providing regular training opportunities, the majority of the teachers did not receive any formal training in the last three years, while some teachers were able to access these opportunities multiple times. Through the recent reforms HEC has empowered the teachers in conducting the learning/teacher processes but this extra power has reduced their accountability and they can exercise these powers without any check on them. This empowerment is limited to the classroom and there appears to be no or minimal involvement in decision making at the top level of policy making. Such lack of involvement in the policy decisions seems to be generating a lack of sense of ownership among the teachers (Fullan 2003a:6). Although Quality Enhancement Cells have been developed in the universities to assure the desired quality of education, they might need a more active role to contribute in achieving the level of enhancement in education expected from them. Based on the perceptions of the respondents of this study and the review of the relevant literature, it is argued that it is unlikely for the reforms to be institutionalized if teachers are not given the right kind of awareness at the initiation stage and are not prepared at the implementation stage to cope with the challenge of a complex process. The teachers participating in this study, in general, have positive and enthusiastic attitudes towards most of the changes, in spite of some reservations. It could also be interesting to see if the power centers of the Pakistani Higher Education appreciate this enthusiasm and channel it for a strong Higher Education system in the country.