Association of Neutrophil-to-Lymphocyte Ratio With Mortality and Cardiovascular Disease in the Jackson Heart Study and Modification by the Duffy Antigen Variant

Importance The neutrophil-to-lymphocyte ratio (NLR) is associated with mortality and cardiovascular disease at the time of incident disease, but it is not known whether this is true in prospective studies. Further, a common genetic variant of African origin associated with a relative neutropenia, the Duffy antigen variant, is a candidate to modify associations between NLR and outcomes. Objective To investigate the association between NLR and mortality and cardiovascular-related outcomes in the Jackson Heart Study (JHS) and validated our findings in the Normative Aging Study (NAS). We also evaluated whether the Duffy antigen variant modifies these associations in the JHS. Design, Setting, and Participants The JHS is a large prospective cohort study designed to examine risk factors and cardiovascular disease among African American individuals residing in Jackson, Mississippi. The NAS is a longitudinal cohort established by the United States Department of Veterans Affairs in 1963. The JHS is a population-based longitudinal study. The NAS is an interdisciplinary longitudinal study located in the Veterans Affairs Outpatient Clinic in Boston, Massachusetts. A total of 5301 participants were recruited for the JHS at baseline. Genotype data on the Duffy antigen variant were available in the JHS. The participants in the NAS were white men only and free of chronic disease at the time of recruitment and were invited for in-person examinations every 3 years since 1986. Data were analyzed between November 2016 and January 2018. Main Outcomes and Measures All-cause mortality, coronary heart disease (CHD), stroke, and heart failure (HF). Two NLR cutoff values (≥2.15 for overall and ≥1.77 for African American participants) were used as the exposure measurements. Results The participants were African American men and women, aged 21 to 93 years, residing in Jackson, Mississippi. For NLR <2.15, the mean age was 54.2 (12.5); for NLR >2.15, the mean age was 56.5 (13.8); for NLR <1.77, the mean age is 54.1 (12.4); and for NLR >1.77, the mean age was 55.8 (13.6). Adjusting for potential confounders, elevated NLR (≥2.15) was significantly associated with an increased risk for all-cause mortality (hazard ratio, 1.40; 95% CI, 1.14-1.70) and CHD (hazard ratio, 1.69; 95% CI, 1.23-2.34) in JHS. Using a lower NLR cutoff (≥1.77) for African American participants did not alter the significant associations. In the NAS, elevated NLR was associated with an increased risk of mortality (hazard ratio, 1.32; 95% CI, 0.99-1.76), with no statistical significance. In both prospective studies, NLR was less of a robust predictor when the time of event was more distant. The Duffy antigen variant was associated with neutrophil count, and NLR (≥1.77) was significantly associated with mortality, CHD, stroke, and HF in the Duffy antigen–negative group. Conclusions and Relevance Neutrophil-to-lymphocyte ratio was prospectively associated with all-cause mortality, CHD, and HF, with closer median time to event diagnoses in the JHS. Furthermore, the Duffy antigen variant locus was associated with a lower baseline NLR and modified the mortality, CHD, stroke, and HF associations.