Investigating blood pressure determinants using genetic epidemiology

The heritability of blood pressure (BP) and hypertension is mainly due to a polygenic background. Thanks to the advance of Genome-wide association studies (GWAS, over the last two decades, more than 1,000 single nucleotide polymorphisms (SNPs) have been identified to be associated with BP traits. These, taken singularly, have a small effect on BP, but when grouped, they can explain 30-50% of the heritability of BP. Different strategies, classified under the field of genetic epidemiology, have evolved to exploit and interpret the genetic determinants of complex diseases. These include the construction of genetic risk scores (GRS), summing up all the risk alleles of the SNPs associated with a trait, and Mendelian Randomization (MR) to assess if an association between a modifiable exposure and an outcome is causal. In this thesis, I am presenting four works in which these approaches were used to investigate the genetic determinants of blood pressure and hypertension. In the first study, a GRS was constructed including more than 800 SNPs associated with either systolic BP (SBP) or diastolic BP (DBP) and we evaluated how it is associated with BP traits, hypertension, and cardiovascular disease (CVD) risk, in two Swedish cohorts, the Malmö Diet and Cancer (MDC) study and the Malmö Preventive Project (MPP). In the following three studies, we used MR methods to assess the causal association of different exposures, i) different adiposity traits in study II, ii) thyroid hormones in study III, iii) serum calcium and calciotropic hormones in study IV, with BP traits, hypertension, and CVD in MDC and MPP. As a result, we found that the GRS built with more than 800 SNPs can discriminate clinically meaningful differences in mmHg between individuals classified as being low-risk versus high-risk based on their GRS. Moreover, the score was independently associated with hypertension risk and CVDs, and with the same order of magnitude as traditional non-genetic risk factors. In the first MR study, the four adiposity traits exhibited a different causal role on the risk of prevalence and incidence of hypertension. This result could reflect distinct pathological mechanisms linking obesity and hypertension. Then we found that low TSH is slightly inversely associated with SBP, while a strong association in the same direction was reported with atrial fibrillation. Finally, serum calcium level showed a causal association with DBP while fibroblast growth factor 23 (FGF23) was inversely associated with SBP. In conclusion, genetic epidemiology provides useful techniques that help in stratifying individuals based on their genetic risk and providing new insight into the pathophysiology of hypertension. Since genetic information is available from birth, it is possible to speculate that personalized prevention and intervention strategies could be developed in the future even early in life.