Our analysis of 26,029 healthy women across the United States found significant state to state variation in inflammation, as measured by hsCRP, sICAM-1 and fibrinogen. We found that the three biomarkers of inflammation identified similar patterns of variability. Iowa was most consistently identified as having the lowest median level of inflammation among healthy women. States in the southeast and Appalachia, namely, Arkansas and West Virginia, were most likely to have elevated levels of inflammation. Notably, the range of state-level variation we observed was clinically relevant. For hsCRP in particular, state-level median values ranged from lower risk values (1.3 mg/L in Iowa) to moderately-higher risk values (2.7 mg/L in West Virginia). The southeast was identified as the area of highest risk by each biomarker of inflammation, global risk score, and the total cholesterol:HDL-C ratio. Moreover, none of the clinical and lifestyle measures of overweight and obesity, diabetes, systolic blood pressure, HDL-C, LDL-C, smoking status, exercise patterns, or caloric intake fully accounted for the state-level variation in biomarkers we observed. More variability in sICAM-1 and fibrinogen was accounted for by clinical and lifestyle factors than was seen for hsCRP, though state-level patterns in all three biomarkers were still apparent after adjustment for covariates.
Our data are consistent with findings in women from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study that found elevated hsCRP levels in the “stroke belt” region of the US (Alabama, Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, and Tennessee) 
. Women in the REGARDS study who resided in the stroke-belt region had 20% higher odds of an elevated hsCRP of > 3 mg/L than women in the non-stroke belt regions; this risk was independent of race/ethnicity, smoking status, cholesterol status, overweight/obesity, blood pressure or the presence of diabetes. Similarly, El Saed et al. found geographic variability in stroke incidence in the Cardiovascular Health Study 
. As in our data, these differences in stroke incidence between high and low risk geographies in the US were not explained by differences in traditional CVD risk factors or medication use 
. Our maps show a geographic pattern of inflammation that is generally consistent with CVD mortality maps from the Centers of Disease Control and Prevention (CDC) that show the southeastern US as an area of high CVD mortality risk among women. Our fibrinogen map appeared to match a west to east gradient in risk, consistent with the known geography of CVD mortality.
The causal patterns underlying these regional effects are uncertain. One potential cause is suggested in epidemiologic data that demonstrate an environmental effect of particulate matter exposure and elevated levels of fibrinogen and hsCRP in select populations 
. In other studies, populations in rural and impoverished areas have been found to be at higher risk of mortality than more urban, wealthy areas 
. Our results suggest the need for additional studies that tease out the effects of state-level characteristics or contextual factors that may be associated with geographically distributed risk for elevated inflammation.
Limitations of our study merit attention. One limitation is that WHS participants are chiefly healthy, non-obese, of white non-Hispanic race/ethnicity, and are health care professionals. Thus, while internally valid, studies of other demographic groups are needed prior to generalizing these data. These characteristics of the WHS likely truncate and therefore under-estimate variability that may exist among states that are more diverse than the WHS population. However, the strength of examining geographic variation in this healthy cohort is its applicability to primary prevention. Our data highlight the extent to which inflammation varies geographically among women prior to the development of clinically apparent CVD. Inflammation is known to correlate with future risk of heart disease among women, and biomarkers of inflammation improve risk prediction for future CVD events 
. Our study suggests the need to understand population-level contributors to geographic patterns in the early development of CVD among women, above and beyond differences in the prevalence of known traditional risk factors.
Another limitation, our study is cross-sectional and only measures inflammatory markers at one point in time during middle and older age. With our study design, we cannot draw causal associations between early life state of residence and inflammation among individual women. An emerging literature suggests that those who have lived in the southeastern US in childhood or adolescence have an elevated risk for an incident CVD event, even if they had subsequently left these regions 
. In the WHS cohort, elevated inflammation in women measured at older ages is known to correlate with subsequent CVD events 
. Thus, the extent to which geographic exposures are correlated with risk of elevated inflammation, population-health prevention efforts should address these exposures across the life-course.
In summary, our study contributes to the literature on population health by demonstrating geographic variability in inflammation among healthy women. Even among otherwise healthy, chiefly non-Hispanic white female health professionals, we found that those living in southern and Appalachian states had high levels of inflammation compared to women in other geographies. The geographic variation in inflammation we observed was in excess of traditional clinical risk factors and lifestyle factors – a pattern that has been observed previously in stroke outcomes 
. Our findings suggest a need for additional research to understand why there is geographic variation in risk in these early biomarkers of atherosclerosis to inform primary prevention strategies. Importantly, further research should find novel population-based strategies to address the increased risk observed in the southern and Appalachian US, in ways that complement the control of traditional risk factors.