Gene-Environment Interactions in Type 2 Diabetes Risk

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The complex gene-environment relationship is central to the systems biology approach of functional medicine and its patient-centered health care. The interactions between an individual’s genes and their environmental exposures, including nutrition, lifestyle-based behaviors, and social factors, are components that may influence disease development.1,2 As research advances in this area, quantifying the health impact of intricate gene-environment interactions has become more achievable. Most recently, a prospective cohort study calculated cumulative social risk scores, genetic risk scores, and healthy lifestyle scores to determine impacts on type 2 diabetes incidence and to more clearly understand any combined influence of social environment exposures and genetic predisposition on disease risk.3

The Polysocial Risk Score: Social Factors and T2D Risk

Social determinants of health influence the way people are born, grow, work, live, and age. This range of economic, social, and physical environment factors contribute to a patient’s overall wellness and may influence health outcomes.4-6 Quantifying the comprehensive contribution of interlinked social factors to an individual’s health has been a challenge in research;7 however, a newly implemented cumulative polysocial risk score has shown promise in filling this data gap. Modeled after the individualized polygenic risk score, which is used to estimate a patient’s genetic risk for a disease through compiling all known genetic factors relevant to the specific disease, the polysocial risk score aggregates interrelated social factors to estimate overall exposure and to help measure the impact on a patient’s health.7

A 2022 population-based cohort study applied the polysocial risk score to further understand an individual’s risk of developing type 2 diabetes.3 In addition, investigators overlapped polysocial and genetic risk scores to provide a deeper examination of potential gene-environment interactions. The 319,832 participants were from the UK Biobank study and were free of diabetes, cardiovascular disease, and cancer at baseline. They were followed for a median period of 8.7 years. Social, genetic, and lifestyle exposures were measured and scores calculated through methods briefly synopsized here:3

  • A polysocial risk score was calculated by determining a participant’s exposure to twelve social determinants of health from three social risk domains (i.e., socioeconomic status, psychosocial factors, and neighborhood and living environment). The included social determinants of health were chosen because they had a statistically significant association with incident type 2 diabetes. A low score indicated a lower estimated exposure level and was equal to or less than three, an intermediate score included four through six, and a high score was equal to or greater than seven.
  • A genetic risk score was calculated based on 403 SNPs that had significant genome-wide associations with type 2 diabetes. Participants were classified with a low, intermediate, or high genetic risk level for type 2 diabetes development.
  • A healthy lifestyle score was based on five modifiable lifestyle factors, including smoking status, alcohol intake, physical activity, diet quality, and sleep quality.

During the follow-up period, 4,427 participants were diagnosed with type 2 diabetes. Researchers adjusted for major confounders during their analysis and reported the following results and associations:3

  • Incidence of Type 2 Diabetes: In the studied population, the five-year cumulative incidence of type 2 diabetes was 2.74, 4.87, and 9.18 per 1,000 person-years for participants with low, intermediate, and high social risks, respectively. For each point increase in the polysocial risk score, a 13% higher incidence of type 2 diabetes was reported. In addition, an intermediate to high polysocial risk score accounted for approximately 34% of new-onset type 2 diabetes cases among participants in this study.
  • Disease Risk: Compared to those with low social risk scores, participants with intermediate and high social risk scores had significantly elevated risks of developing type 2 diabetes. The reported hazard ratios were 1.38 (CI: 1.26-1.52) for intermediate and 2.02 (CI: 1.83-2.22) for high.
  • Lifestyle Considerations: As expected, when compared to a less healthy lifestyle, participants who maintained a healthier lifestyle had a lower risk of developing type 2 diabetes (HR=0.61, CI: 0.54-0.69). Importantly, across all polysocial risk scores, a healthier lifestyle was associated with a lower incidence of type 2 diabetes. Specific to the high social risk score group, maintaining a healthier lifestyle was associated with only a 29% (CI: 4-61) increased risk of disease development, while maintaining an unhealthy lifestyle was associated with a 103% (CI: 72-140) higher risk of disease development.
  • Gene-Social Factor Relationship: Participants in the highest tertile of the genetic risk score had an increased risk of type 2 diabetes (HR=2.09, CI: 1.92-2.27). Interestingly, researchers reported a significant additive interaction between genetic predisposition and social factor exposures. Across all genetic risk scores, from low to high, a higher polysocial risk score was associated with an increased incidence of type 2 diabetes. Specifically, the additive gene-social factor interaction explained approximately 15% of new-onset diabetes cases.

Researchers concluded that compared to participants with a low polysocial risk score, those with a high score had an almost twofold higher risk of developing type 2 diabetes.3 In addition, increased exposure to negative social factors may compound the increased disease risk of those with genetic predisposition. On an impactful note, implementing healthier lifestyle behaviors indicated reduced disease risk even within the high social risk score group.3

An individual’s genes and their daily exposure to different environmental components are complex factors that overlap and influence health. In the functional medicine model, genetic risk factors are antecedents of potential disease development; lifestyle risk factors are mediators; and social environment factors are both antecedents and mediators. Investigative models such as the polysocial risk score appear to be helpful for quantifying these intricate gene-environment interactions, increasing their visibility in medical research, and emphasizing their influence on an individual’s health. Patient-centered care already recognizes the health importance of someone’s exposure to various social determinants of health. Yet, as they continue to be refined and validated through population-based studies for specific diseases,2 comprehensive tools such as the polysocial risk score may help to further assess the antecedents and mediators that play a part in a patient’s health story.


  1. Song C, Gong W, Ding C, Wang R, Fang H, Liu A. Gene-environment interaction on type 2 diabetes risk among Chinese adults born in early 1960s. Genes (Basel). 2022;13(4):645. doi:3390/genes13040645
  2. Javed Z, Valero-Elizondo J, Dudum R, et al. Development and validation of a polysocial risk score for atherosclerotic cardiovascular disease. Am J Prev Cardiol. 2021;8:100251. doi:1016/j.ajpc.2021.100251
  3. Zhao Y, Li Y, Zhuang Z, et al. Associations of polysocial risk score, lifestyle and genetic factors with incident type 2 diabetes: a prospective cohort study. Diabetologia. 2022;65(12):2056-2065. doi:1007/s00125-022-05761-y
  4. Parekh T, Xue H, Cheskin LJ, Cuellar AE. Food insecurity and housing instability as determinants of cardiovascular health outcomes: a systematic review. Nutr Metab Cardiovasc Dis. 2022;32(7):1590-1608. doi:1016/j.numecd.2022.03.025
  5. Javed Z, Haisum Maqsood M, Yahya T, et al. Race, racism, and cardiovascular health: applying a social determinants of health framework to racial/ethnic disparities in cardiovascular disease. Circ Cardiovasc Qual Outcomes. 2022;15(1):e007917. doi:1161/CIRCOUTCOMES.121.007917
  6. Ruiz D, Becerra M, Jagai JS, Ard K, Sargis RM. Disparities in environmental exposures to endocrine-disrupting chemicals and diabetes risk in vulnerable populations. Diabetes Care. 2018;41(1):193-205. doi:2337/dc16-2765
  7. Figueroa JF, Frakt AB, Jha AK. Addressing social determinants of health: time for a polysocial risk score. JAMA. 2020;323(16):1553-1554. doi:1001/jama.2020.2436