A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case–control study

Abstract

Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other 'traditional risk factors', also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case-control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029-1.147) per SD increase in the GRS P = 0.003) with similar trends in all three samples: LSR (1.050 (0.967-1.140); P = 0.25), MDC (1.168 (1.060-1.288); P = 0.002) and SAHLSIS (1.124 (0.997-1.267); P = 0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case-control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension. INTRODUCTIONStroke is one of the leading causes of mortality, morbidity and disability worldwide. 1 Thanks to genome-wide association studies (GWAS), genetics of complex diseases has made dramatic steps forward in the last few years 2 but very few single-nucleotide polymorphisms (SNPs) have been invariantly associated with ischemic stroke. [3][4][5][6][7] Moreover, the relative risk conferred by individual genetic variants is usually low. Thus, in an attempt to estimate the aggregate effect of several gene variants, different genetic risk scores (GRS) have been constructed including a few studies on stroke with inconsistent results. [8][9][10][11][12][13][14][15] Interestingly, the selection of the SNPs to be included in GRS calculation have been based on different criteria: SNPs detected by GWAS either associated or not associated with known cardiovascular risk factors, as well as SNPs in candidate genes or pathways. [8][9][10][11][12][13][14][15] High blood pressure (BP) is the major risk factors for stroke and among the most important ones for other cardiovascular events. 16,17 Despite BP and hypertension being heritable traits, 18 the search for genetic variants associated with these traits has been more challenging compared with other cardiovascular risk factors. Only in recent years, GWAS have discovered several genetic variants which associate with BP-related ...

Genetic risk analysis of coronary artery disease in Pakistani subjects using a genetic risk score of 21 variants

“…The GRS is a multi-locus profile used to transpose the discoveries from candidate gene studies and GWASs into population health tools (Belsky et al, 2013;Fava et al, 2014). A GRS summarizes the effect of multiple variants in a quantitative manner and hence is superior over the predictive power of a single SNP.…”

Prediction model for the efficacy of folic acid therapy on hyperhomocysteinaemia based on genetic risk score methods

“…However, it is not the more significant results you will get when adjusting for more factors. A study had showed that when they adjusted for more factors, the association was somewhat attenuated (21) .…”

“…To combine the relatively small effects of individual SNP and to better capture the complex relationship between genetics and the folic acid efficacy, the use of genetic risk score (GRS) has been proposed. There are two common approaches that can be used to determine the genetic risk based on risk-related SNP: (a) simple count genetic risk score (SC-GRS) and (b) weighted genetic risk score (wGRS) (20)(21)(22)(23) .…”

Gene–environment interactions related to blood pressure traits in two community‐based Korean cohorts

“…The uGRS was generated by summing the number of risk alleles of each SNP (0, 1 or 2). The wGRS was calculated as published by Fava et al (). We summarized beta coefficients for SBP using previous blood pressure GWASs (Ehret et al, , ; Kato et al, ; Liu et al, ; Lu et al, ; Surendran et al, ; Wain et al, ).…”