Gene-Environment Interactions Among Black Adults With Kidney Failure – Not A Straight Forward Relationship

See Clinical Research on Page 1476

Black Americans have a disproportionaly higher burden of chronic kidney disease and kidney failure relative to White Americans.¹ In addition to socioeconomic and health system factors, these disparities have been linked to 2 sequence variants (G1 and G2) in the APOL1 gene. The high-risk APOL1 genotype (2 copies of variant) has been shown to be associated with an increased risk for chronic kidney disease and is present in approximately 12% to 14% of individuals of African ancestry and not present in individuals of European ancestry.² However, only a minority of those with the high-risk genotype go on to develop kidney disease,^2,3 suggesting that the presence of modifiers or “second hits” are needed for disease penetrance, such as other genetic variants, pathogens, autoimmunity, as well as social and environmental factors. Gene-environment interactions represent an important subset of potential second hits.

In this month’s issue of Kidney International Reports, Takkavatakarn et al.⁴ examine the interaction between the APOL1 gene and neighborhood socioeconomic status (SES) on the risk of kidney disease progression. Specifically, they leverage BioMe biobank data from more than 4000 Black adults nonselectively enrolled from outpatient primary care clinics throughout the Mount Sinai Health System between 2007 and 2015. Participants were included if they were aged ≥ 18 years old and had ≥ 3 creatinine measures. The primary composite kidney outcome was defined as a sustained 30% decline in estimated glomerular filtration rate or incidence of kidney failure (defined as the need for dialysis or transplant) within 8 years of follow-up. Neighborhood-level SES was defined as median income and poverty levels based on American Community Survey estimates mapped to individuals’ residential ZIP-code.

The key findings are somewhat counterintuitive. If neighborhood SES is indeed the “second hit” needed for high-risk APOL1 individuals to progress to kidney disease, you would expect that as poverty increases, or income decreases, the likelihood of kidney progression would be higher. However, Takkavatakarn et al.⁴ found that among those with the high-risk APOL1 genotype, lower SES (i.e., more poverty and lower income) appeared to be associated with a lower risk of the composite end point. It should be noted that these trends were not statistically significant. In contrast, among those with the low-risk APOL1 genotype, the relationship between neighborhood SES and kidney progression was as expected; lower SES was associated with higher risk.⁴

Reasons for these discordant findings are unclear, though the authors postulate 2 theories. First, it is possible that individuals with APOL1 high-risk variants may have increased access to specialized health care services with earlier institution of lifestyle modification that could potentially mitigate the detrimental effects of low neighborhood SES. However, it is unclear if the participants in this study knew what their APOL1 genotype was to support such a theory. The second theory is that APOL1 high-risk genotypes may override or diminish the influence of external environmental factors, because their kidney outcomes are predominantly driven by inherent genetic risk rather than environmental or social determinants.

It is possible that in this study from 1 center among individuals self-identifying as Black, there was not sufficient variation in neighborhood poverty or income to examine this impact meaningfully. For example, in those who did and did not develop the composite end point, median neighborhood income was $34,433 (interquartile range: $30,551–$39,939] and $34,696 ($31,238–$46,061), respectively; whereas the proportion with high neighborhood poverty was 29% (24%–32%) and 28% (20%–32%), respectively; demonstrating a relatively homogenous group with respect to neighborhood level SES.⁴ A $263 difference in annual income and a 1% difference in poverty may be statistically significant but the absolute differences are quite small and may not be clinically significant. It is possible that looking at the effects of income and neighborhood poverty in a larger and more representative group of patients may reveal an association of APOL1 with worsening of kidney outcomes in patients of low SES.

Interestingly, this same research group has previously reported on the interaction between APOL1 and neighborhood-level air pollution as another possible environmental “second hit” that may increase the risk of kidney disease.⁵ In that study, findings were more intuitive: among self-identified Black individuals with the high-risk APOL1 genotype, there was a 54% increased risk of the same composite kidney outcome for every 10 μg/m³ increase in fine particulate matter (defined as < 2.5 μm [PM2.5]), compared with 11% among those with the low-risk APOL1 genotype, suggesting that although air pollution is bad for both groups, the effect is more pronounced for those with the higher risk genotype.⁵

Why neighborhood-level air pollution is associated with a modified risk for kidney progression in high-risk APOL1 whereas neighborhood-level income and poverty are not is interesting and suggests a complex interplay between genes and environments. It is possible that air pollution is a stronger “second hit” than income or poverty, though curiously the authors did not adjust for air pollution in the current study, possibly because of collinearity with other neighborhood-level SES, thus limiting the opportunity to identify independent associations.

Certainly, the current study is limited by a lack of individual-level SES data including education, income, family history of chronic kidney disease, and health behaviors (e.g., diet and physical activity) that would be helpful to delineate the role of individual versus neighborhood level SES factors contributing to these associations. Importantly, associations at the neighborhood-level do not infer associations at the individual-level and the precise biological pathways underlying these interactions remain unclear.

The APOL1 Long-Term Kidney Transplantation Outcomes Network study is a prospective multicenter initiative that has amassed a comprehensive biobank comprising data from over 2600 transplant recipient-donor pairs of Black or African ancestry from transplant programs nationwide.⁶ This extensive study primarily aims to elucidate the impact of APOL1 gene variants on kidney transplantation outcomes but the scope of the APOL1 Long-Term Kidney Transplantation Outcomes Network study extends beyond genetic factors, and will allow individual and neighborhood-level SES data to be analyzed.⁶ Although focused on individuals with kidney failure who have undergone transplantation, this rich dataset will likely offer additional opportunities to unravel the complex mechanisms underlying gene-environment interactions in kidney disease.

The findings from Takkavatakarn et al.⁴ regarding a possible interaction between APOL1 and neighborhood SES, though nonsignificant, are hypothesis-generating. More robust studies will be needed to definitively assess the effects of SES on modifying APOL1-related kidney disease. As we continue to unravel the intricacies of APOL1-related kidney disease, it becomes increasingly clear that a multifaceted approach, considering both genetic and environmental factors, will be crucial in addressing the disproportionate burden of kidney disease among individuals of African ancestry.

Disclosure

All the authors declared no competing interests.