Many comorbidities of the aging process, including cardiovascular disease, cognitive decline, and metabolic dysregulation, are thought to be significantly influenced by genetic factors. Type 2 diabetes (T2D), a disease which affects more than 25% of adults over age 65 in the United States, is also thought to have a significant genetic component, and individuals with T2D are at high risk for age-related comorbidities. Common and uncommon coding genetic variants may play a significant role in these age-related comorbidities, and this project aims to elucidate coding variants which are significantly associated with a wide range of biomedical measures characteristic of aging and with mortality. Illumina(R) HumanExome BeadChips, which include over 240,000 coding variants, will allow rapid and comprehensive analysis of relevant coding variants in the Diabetes Heart Study cohort, an extensively phenotyped family-based cohort enriched for patients with T2D. Our initial focus will be on the C1q and tumor necrosis factor (TNF) superfamily of genes. Uncommon coding variants in a member of this family, adiponectin, which lead to a dramatic reduction in plasma levels of this protein have recently been discovered, and we hypothesize that coding variants in other C1q/TNF superfamily members, which have diverse roles in metabolism, inflammation, and other processes, may contribute to age-related phenotypes. Genes related to inflammation, such as cytokines and their receptors, will also be of particular interest, as inflammatory processes are key to the pathogenesis of many age-related diseases, including T2D. Interesting findings from the Exome Chip data from the Diabetes Heart Study will be replicated in other cohorts relevant to aging. The proposed research will further my development as an independent investigator and give me valuable experience in the meaningful application of human genetics tools to aging research.

Public Health Relevance

The goal of this project is to better understand how coding genetic variants may contribute to complex age-related phenotypes, with a particular emphasis on patients with Type 2 Diabetes, a disease which accelerates many aspects of the aging process. Knowledge of which variants are associated with age-related phenotypes, such as vascular calcification, cognitive declines, and bone mineral density, could improve risk prediction and allow for more personalized care, as well as potentially leading to new drugs and therapies through the elucidation of which genes and pathways are important for a particular age-related phenotype.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Guo, Max
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Wake Forest University Health Sciences
Schools of Medicine
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Raffield, Laura M; Cox, Amanda J; Criqui, Michael H et al. (2018) Associations of coronary artery calcified plaque density with mortality in type 2 diabetes: the Diabetes Heart Study. Cardiovasc Diabetol 17:67
Martelle, Susan E; Raffield, Laura M; Palmer, Nichole D et al. (2016) Dopamine pathway gene variants may modulate cognitive performance in the DHS - Mind Study. Brain Behav 6:e00446
Nielson, Carrie M; Liu, Ching-Ti; Smith, Albert V et al. (2016) Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. J Bone Miner Res 31:2085-2097
Raffield, Laura M; Cox, Amanda J; Freedman, Barry I et al. (2016) Analysis of the relationships between type 2 diabetes status, glycemic control, and neuroimaging measures in the Diabetes Heart Study Mind. Acta Diabetol 53:439-47
Pattaro, Cristian (see original citation for additional authors) (2016) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun 7:10023
Adams, Jeremy N; Martelle, Susan E; Raffield, Laura M et al. (2016) Analysis of advanced glycation end products in the DHS Mind Study. J Diabetes Complications 30:262-8
Raffield, Laura M; Brenes, Gretchen A; Cox, Amanda J et al. (2016) Associations between anxiety and depression symptoms and cognitive testing and neuroimaging in type 2 diabetes. J Diabetes Complications 30:143-9
Adams, Jeremy N; Raffield, Laura M; Martelle, Susan E et al. (2016) Genetic analysis of advanced glycation end products in the DHS MIND study. Gene 584:173-9
Raffield, Laura M; Cox, Amanda J; Hugenschmidt, Christina E et al. (2015) Heritability and genetic association analysis of neuroimaging measures in the Diabetes Heart Study. Neurobiol Aging 36:1602.e7-15
Hsu, Fang-Chi; Raffield, Laura M; Hugenschmidt, Christina E et al. (2015) Relationships between Cognitive Performance, Neuroimaging and Vascular Disease: The DHS-MIND Study. Neuroepidemiology 45:1-11

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