Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations

Fernández-Rhodes, Lindsay; Young, Kristin L.; Lilly, Adam G.; Raffield, Laura M.; Highland, Heather M.; Wojcik, Genevieve L.; Agler, Cary S.; Love, Shelly Ann; Okello, Samson; Petty, Lauren E.; Graff, Mariaelisa; Below, Jennifer E.; Divaris, Kimon; North, Kari E.

doi:10.1161/circresaha.120.315893

Cited by 21 publications

(19 citation statements)

References 184 publications

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“…Genetic factors are involved in the development of both CMDs 10 and dementia, 11 , 12 but whether and to what extent genetic background contributes to the association between CMDs and dementia is uncertain. Twin studies provide a unique opportunity to address this question.…”

Section: Introductionmentioning

confidence: 99%

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Dove

Guo

Marseglia

et al. 2022

European Heart Journal

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Aims Cardiometabolic diseases (CMDs), including diabetes, heart disease, and stroke, are established risk factors for dementia, but their combined impact has been investigated only recently. This study aimed to examine the association between mid- and late-life cardiometabolic multimorbidity and dementia and explore the role of genetic background in this association. Methods and results Within the Swedish Twin Registry, 17 913 dementia-free individuals aged ≥60 were followed for 18 years. CMDs [including age of onset in mid (60) or late (≥60) life] and dementia were ascertained from medical records. Cardiometabolic multimorbidity was defined as having ≥2 CMDs. Cox regression was used to estimate the CMD–dementia association in (i) a classical cohort study design and (ii) a co-twin study design involving 356 monozygotic and dizygotic pairs. By comparing the strength of the association in the two designs, the contribution of genetic background was estimated. At baseline, 3,312 (18.5%) participants had 1 CMD and 839 (4.7%) had ≥2 CMDs. Over the follow-up period, 3,020 participants developed dementia. In the classic cohort design, the hazard ratio (95% confidence interval) of dementia was 1.42 (1.27–1.58) for 1 CMD and 2.10 (1.73–2.57) for ≥2 CMDs. Dementia risk was stronger with mid-life as opposed to late-life CMDs. In the co-twin design, the CMD–dementia association was attenuated among monozygotic [0.99 (0.50–1.98)] but not dizygotic [1.55 (1.15–2.09)] twins, suggesting that the association was in part due to genetic factors common to both CMDs and dementia. Conclusion Cardiometabolic multimorbidity, particularly in mid-life, is associated with an increased risk of dementia. Genetic background may underpin this association.

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Section: Introductionmentioning

confidence: 99%

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Dove

Guo

Marseglia

et al. 2022

European Heart Journal

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“…Our findings add to the growing body of evidence that the current definition of metabolic syndrome inadequately characterizes the burden of cardiometabolic disease among non-Hispanic Black individuals because it relies on HDL-C and TG levels. 15,37–39…”

Section: Discussionmentioning

confidence: 99%

Genetic European Ancestry and Incident Diabetes in Black Individuals: Insights From the SPRINT Trial

Parcha

Heindl

Kalra

et al. 2022

Circ: Genomic and Precision Medicine

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Background: Black individuals have high incident diabetes risk, despite having paradoxically lower triglyceride and higher HDL (high-density lipoprotein) cholesterol levels. The basis of this is poorly understood. We evaluated the participants of SPRINT (Systolic Blood Pressure Intervention Trial) to assess the association of estimated European genetic ancestry with the risk of incident diabetes in self-identified Black individuals. Methods: Self-identified non-Hispanic Black SPRINT participants free of diabetes at baseline were included. Black participants were stratified into tertiles (T1–T3) of European ancestry proportions estimated using 106 biallelic ancestry informative genetic markers. The multivariable-adjusted association of European ancestry proportion with indices of baseline metabolic syndrome (ie, fasting plasma glucose, triglycerides, HDL cholesterol, body mass index, and blood pressure) was assessed. Multivariable-adjusted Cox regression determined the risk of incident diabetes (fasting plasma glucose ≥126 mg/dL or self-reported diabetes treatment) across tertiles of European ancestry proportion. Results: Among 2466 Black SPRINT participants, a higher European ancestry proportion was independently associated with higher baseline triglyceride and lower HDL cholesterol levels ( P <0.001 for both). European ancestry proportion was not associated with baseline fasting plasma glucose, body mass index, and blood pressure ( P >0.05). Compared with the first tertile, those in the second (hazard ratio, 0.64 [95% CI, 0.45–0.90]) and third tertiles (hazard ratio, 0.61 [95% CI, 0.44–0.89]) of the European ancestry proportion had a lower risk of incident diabetes. A 5% point higher European ancestry was associated with a 29% lower risk of incident diabetes (hazard ratio, 0.71 [95% CI, 0.55–0.93]). There was no evidence of a differential association between the European ancestry proportion tertiles and incident diabetes between those randomized to intensive versus standard blood pressure treatment. Conclusions: The higher risk of incident diabetes in Black individuals may have genetic determinants in addition to adverse social factors. Further research may help understand the interplay between biological and social determinants of cardiometabolic health in Black individuals. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01206062.

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“…A ne-mapping analysis may enable the detection of mutations involving the candidate genes and thereby contribute to treatment based on genome-based precision medicine. Identifying the causal variants beyond GWAS provides a crucial blueprint in predicting disease risk and preventing IA as well as metabolic diseases and stroke 35 . To the best of our knowledge, this was the rst ne-mapping analysis based on the results of a GWAS of IA.…”

Section: Discussionmentioning

confidence: 99%

Fine Mapping of Intracranial Aneurysm Susceptibility Based on a Genome-wide Association Study

Hong

Youn

Kim

et al. 2021

Preprint

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In addition to conventional genome-wide association studies (GWAS), a fine-mapping is increasingly used to identify the genetic function of variants associated with disease susceptibilities. Here, we used a fine-mapping approach to evaluate the casual variants based on a previous GWAS involving patients with intracranial aneurysm (IA). Fine-mapping analysis was conducted based on the chromosomal data provided by GWAS consisting 250 patients diagnosed with IA and 296 controls using posterior inclusion probability (PIP) and log10 transformed Bayes factor (log10BF). The narrow sense of heritability (h2) explained by each casual variant was estimated. Subsequent gene expression and functional network analyses were used to calculate the transcripts per million (TPM) values. Twenty causal candidate single nucleotide polymorphisms (SNPs) surpassed a genome-wide significance threshold for creditable evidence (log10BF > 6.1). Four SNPs including rs75822236 (R535H, GBA; log10BF = 15.06), rs112859779 (G141S, TCF24; log10BF = 12.12), rs79134766 (A208T, OLFML2A; log10BF = 14.92), and rs371331393 (Q1932X, ARHGAP32; log10BF = 20.88) showed a completed PIP value in each chromosomal region, suggesting a high probability of variant causality associated with IA. Expression in GBA was highly enriched in the whole blood (TPM = 33.13), while TCF24 were rarely expressed in all tissues and cells. No direct interaction was observed between the four casual genes; however, PSAP appeared to be particularly important via indirect correlation between other genes. Our results suggested that four mutations of GBA, TCF24, OLFML2A, and ARHGAP32 were linked to IA susceptibility and pathogenesis. Our approach may promise more informative mutations in the following GWAS.

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Importance of Genetic Studies of Cardiometabolic Disease in Diverse Populations

Cited by 21 publications

References 184 publications

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Cardiometabolic multimorbidity and incident dementia: the Swedish twin registry

Genetic European Ancestry and Incident Diabetes in Black Individuals: Insights From the SPRINT Trial

Fine Mapping of Intracranial Aneurysm Susceptibility Based on a Genome-wide Association Study

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