Genomics: Insight

Research Question: How significantly does the TCF7L2 locus increase the risk of developing Type 2 Diabetes, what other genetic loci are involved in developing Type 2 Diabetes, and how do environmental factors such as diet and lifestyle mitigate or intensify the risk presented by TCF7L2?  

Introduction

Caused by elevated levels of blood glucose, Type 2 Diabetes (T2D) is the most common form of diabetes and affects nearly 40 million people in America and 462 million people worldwide.¹ However, T2D is a complex disease that is influenced by multiple factors such as genetic predisposition and environmental conditions. The strongest genetic locus associated with the development of T2D is TCF7L2, specifically the rs7903146 allele, a variant of the TCF7L2 locus. TCF7L2 is a transcription factor involved in the Wnt signaling pathway, which helps regulate the expression of genes that are critical for insulin secretion and glucose homeostasis.² However, the rs7903146 allele of TCF7L2 increases the likelihood of developing T2D because it both impairs insulin secretion from pancreatic beta cells and increases insulin resistance, leading to higher circulating blood glucose levels.² This paper explores the intersection of genetic loci and environmental factors, with a focus on the prevalence of the rs7903146 allele of TCF7L2, to examine their combined impact on the development of Type 2 Diabetes.

"Type 2 Diabetes is the most common form of diabetes and affects nearly 40 million people in America"

TCF7L2 is a genetic locus for Type 2 Diabetes

In a Danish sample that included 1,149 affected individuals and 2,400 controls, the rs7903146 T allele was determined to have a relative risk of 1.49 (confidence interval 95%) and a Population Attributable Risk of 21%.^2,3 Another study was conducted in a West African group consisting of 621 affected individuals and 448 controls. The study yielded similar results with a relative risk of 1.45 and a Population Attributable Risk of 20%.^3,4 Both studies also examined the DG10S478 X and rs12255372 alleles in the TCF7L2 but identified no significant correlation, ruling them out as causal variants. The Danish and West African samples both convey that the rs7903146 T allele, a variant of the TCF7L2 locus, is a primary and reliable indicator of Type 2 Diabetes.

Other Genetic Loci and the Prominence of TCF7L2

Though TCF7L2 is one of the most well-established loci associated with Type 2 Diabetes, 400 other genetic loci are linked to T2D risk. Notable examples include SLC30A8, KCNJ11, and FTO. Each of these contributes to different pathways related to insulin secretion, beta-cell function, or insulin sensitivity. Variants in SLC30A8 disrupt zinc transport in beta cells, impairing insulin storage and secretion.⁸ Mutations in KCNJ11 reduce ATP sensitivity, keeping beta cells polarized and blocking insulin secretion.⁹ Lastly, FTO variants have been associated with obesity, an indirect risk factor for T2D.¹⁰

Despite the broad landscape of genetic contributors, TCF7L2 remains the most significant in terms of effect size and consistency across ethnicities. Its rs7903146 variant has shown the strongest and most reproducible association with T2D across multiple populations, including European, African, and Asian ancestries.¹¹ While many other loci contribute modestly to risk, the rs7903146 T allele typically confers a stronger genetic effect. For example, individuals with the rs7903146 variant of the TCF7L2 gene had a 1.91 times higher risk of developing Type 2 Diabetes than those with the other genotypes in Caucasian populations, and a 1.48 times higher risk in West African populations.¹¹ Moreover, TCF7L2 influences T2D both through genetic variation and epigenetic mechanisms—further amplifying its importance. Therefore, TCF7L2 stands out not only because of the strength of its association but also due to its multidimensional effect on T2D.

Environmental Factors

In addition to the 20% Population Attributable Risk for Danish and West African samples mentioned above, environmental factors, particularly diet and lifestyle, play a critical role in diabetes development through the TCF7L2 locus. In a 2022 study that conducted seven randomized trials on obese adults worldwide, researchers discovered that diet and physical activity interventions lowered fasting glucose levels by -3.06 mg/dL in comparison to control groups for each rs7903146 risk allele.⁵ This research demonstrates that while the rs7903146 allele does cause an increased risk of developing T2D, environmental factors such as a moderated diet and physical activity can combat this risk by reducing the insulin resistance that the rs7903146 allele produces. A 2022 systematic review of observational studies reached similar conclusions, determining that people who had the rs7903146 allele faced disproportionately high insulin resistance as a result of fat intake compared to non-risk allele carriers.⁶ Evidently, these findings underscore the importance of integrating environmental factors like dietary adjustments as effective strategies to mitigate the heightened risk of Type 2 Diabetes associated with the rs7903146 allele.

Furthermore, the TCF7L2 locus can also increase T2D risk through the methylation of nearby CpG sites (a cytosine nucleotide followed by a guanine nucleotide). A 2021 case-control study among rural Chinese adults found significant positive associations between the methylation of CpG5 of TCF7L2 and CpG78 of TCF7L2: for each 1% increase in DNA methylation at these two sites, the risk of developing Type 2 Diabetes Mellitus, the variant of T2D that accounts for 90% of all cases, increases by 12% and 32% respectively.⁷ Several environmental factors can contribute to the increased methylation of these CpG sites through several mechanisms; for example, an increased consumption of B vitamins and nutrients like folate can influence the availability of substrates necessary for DNA methylation. Additionally, exposure to environmental toxins like heavy metals or physical inactivity can disrupt methylation patterns, further elevating the risk of T2D through the methylation of the TCF7L2 locus. These findings highlight the complex connections between environmental factors and DNA methylation at the TCF7L2 locus, suggesting that lifestyle choices alongside exposure to environmental influences can significantly elevate the risk of developing Type 2 Diabetes Mellitus.

Conclusion

This paper explored how the TCF7L2 Locus increases the chance of developing Type 2 diabetes, how environmental factors influence the increased risk, and why this locus is most prominent in causing Type 2 Diabetes. For individuals who contain the at-risk allele at the TCF7L2 locus, it is important to adjust lifestyle choices accordingly by maintaining a healthy diet and engaging in physical activity to mitigate the heightened risk. While there is still much to research about Type 2 Diabetes, a lack of sufficient funding remains a significant barrier. In 2021, diabetes caused 399,000 deaths.¹² On the other hand, AIDS caused fewer than 20,000 deaths in 2022.  However, according to a 2024 study, only $2.4 billion in government funding was allocated to diabetes research compared to $3.2 billion for AIDS research.¹³ Given the stark difference in the number of deaths attributed to diabetes and AIDS, it is clear that diabetes should receive more attention and funding for research. 

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