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Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

ABSTRACT: The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions from the NHGRI genome-wide association study (GWAS) catalog, in an attempt to replicate the established notion of shared pathophysiology and risk. We used pathway-based analyses to detect subsets of pleiotropic genes involved in similar biological processes. We identified 107 eligible GWAS studies related to CVD and its established comorbidities and risk factors and assigned genes that correspond to the associated signals based on their position. We found 44 positional genes shared across at least two CVD-related phenotypes that independently recreated the established relationship between the six phenotypes, but only if studies representing non-European populations were included. Seven genes revealed pleiotropy across three or more phenotypes, mostly related to lipid transport and metabolism. Yet, many genes had no relationship to each other or to genes with established functional connection. Whilst we successfully reproduced established relationships between CVD risk factors using GWAS findings, interpretation of biological pathways involved in the observed pleiotropy was limited. Further studies linking genetic variation to gene expression, as well as describing novel biological pathways will be needed to take full advantage of GWAS results.

SUBMITTER: Gottesman O

PROVIDER: S-EPMC3460880 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

Gottesman Omri O Drill Esther E Lotay Vaneet V Bottinger Erwin E Peter Inga I

PloS one 20120928 9

The relationship between obesity, diabetes, hyperlipidemia, hypertension, kidney disease and cardiovascular disease (CVD) is established when looked at from a clinical, epidemiological or pathophysiological perspective. Yet, when viewed from a genetic perspective, there is comparatively little data synthesis that these conditions have an underlying relationship. We sought to investigate the overlap of genetic variants independently associated with each of these commonly co-existing conditions fr ...[more]

PMID: 23029515

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Project description:Lipoprotein(a) is a highly heritable biomarker independently associated with atherosclerotic cardiovascular disease (ASCVD). It is unclear whether measured lipoprotein(a) or genetic factors associated with lipoprotein(a) can provide comparable or additional prognostic information for primary prevention. To determine whether a genetic risk score (GRS) comprising 43 variants at the LPA gene, which encodes apolipoprotein(a), has clinical utility in assessing ASCVD risk compared with and in addition to lipoprotein(a) measurement. The UK Biobank is a prospective observational study of approximately 500 000 volunteers aged 40 to 69 years who were recruited from 22 sites across the United Kingdom between 2006 and 2010. Using externally derived weights, an LPA GRS was calculated for 374 099 unrelated individuals with array-derived genotypes and lipoprotein(a) measures. Data were analyzed from April 2020 to March 2020. Measured lipoprotein(a) and LPA GRS. We estimated the associations between measured lipoprotein(a) and LPA GRS with the incidence of ASCVD (peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, and cardiovascular mortality) using Cox proportional hazards models. To determine the utility of using measured lipoprotein(a) and LPA GRS as risk enhancers for ASCVD, we assessed the potential improvement in ASCVD risk discrimination by QRISK3 and Pooled Cohort Equations among individuals with borderline to intermediate risk (n = 113 703 and 144 350, respectively). The mean age of the overall study population was 57.6 years, and 204 355 individuals were female (54.6%). During a median follow-up of 11.1 years (interquartile range, 1.4 years), 15 444 individuals developed an incident ASCVD event (5.1%). The LPA GRS explained approximately 60% of the variation in measured lipoprotein(a) for White/European individuals. Independently, both lipoprotein(a) and LPA GRS were associated with incident, composite ASCVD (hazard ratio per 120 nmol/L increase, 1.26; 95% CI, 1.23-1.28 vs hazard ratio, 1.29; 95% CI, 1.26-1.33; P < .001). The association between LPA GRS and ASCVD was substantially attenuated after adjusting for measured lipoprotein(a). Adding measured lipoprotein(a) or LPA GRS to QRISK3 provided modest improvements to the risk discrimination of incident ASCVD events (area under the receiver operating curve, 0.640; 95% CI, 0.633-0.647 vs 0.642; 95% CI, 0.635-0.649 for both; P = .005 and P = .01, respectively). When indicated, cardiovascular risk assessment with lipoprotein(a) at middle-age may include direct measurement or an LPA GRS.

Dataset Information

Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

Publications

Can genetic pleiotropy replicate common clinical constellations of cardiovascular disease and risk?

Similar Datasets

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