Clinical and Genetic Profiles of the Aging Sickle Cell Patient.
Authors: Ashley-Koch Allison E. , De Castro Laura M. , Lennon-Graham Felicia , Jonassaint Jude , Jackson Terry L. , Price Jennifer , Galloway Jason , Jones Susan , Randall Eldrida , Packman Charles , Knupp Charles , Eckman James R. , Orringer Eugene P. , Vance Jeffery M. , Telen Marilyn J. 
Published: April 2020

Abstract
The life expectancy of many patients with sickle cell disease (SCD) is well into the 5th and 6th decade, but this remains extremely variable. Little is known about the biological factors that protect certain SCD patients from early demise while others never reach mid-adulthood. Recently, McKerrell and colleagues (2004) compared the clinical and laboratory profiles of SCD patients aged 40 years and over with SCD patients who were between 21 and 30 years of age. Similarly, we have compared clinical and genetic correlates of older SCD patients (50 years and over) with those of younger patients (18–30 years). Among 514 patients in our total study population, 49 (10%) were categorized as “older” and 194 (38%) were categorized as “younger.” Older SCD patients had lower hemoglobin (older: 7.8 ± 1.1 vs. younger: 8.5 ± 1.2, p=0.004), platelet count (older: 372 ± 126 vs. younger: 460 ± 225, p=0.02), MCV (older: 92 ± 12 vs. younger: 89 ± 9, p=0.08), MCHC (older: 33.6 ± 1.4 vs. younger: 34.3 ± 1.8, p=0.05), and WBC (older: 10.2 ± 2.7 vs. younger: 13.1 ± 4.1, p&lt;0.001). Older patients also had lower total bilirubin (p=0.01), and increased alkaline phosphatase (p=0.0002) and creatinine (p=0.0002), which was associated with poorer creatinine clearance (p&lt;0.0001). The older SCD patients also had increased systolic (p&lt;0.0001) and diastolic (p=0.008) blood pressure, decreased O2 saturation (p=0.03), and a history of fewer pain episodes per year requiring medical treatment (p&lt;0.0001). Many of our findings are consistent with those of McKerrell et al. (2004). In order to identify genetic factors associated with longevity in SCD, we examined 155 SNPs in a total of 41 genes, primarily involved in red blood cell adhesion and inflammation pathways. Chi Square tests of association were constructed for the genotypes of each SNP with the two clinical categories: “older” and “younger.” When the number of rare homozygotes was less than 5 individuals, we combined those individuals with the heterozygote individuals for analysis. All p-values are uncorrected for multiple testing. We found putative associations with 5 SNPs in 3 genes. Three non-coding SNPs in Klotho, not in linkage disequilibrium, exhibited different genotype frequencies in the older versus younger SCD patients (p=0.007, p=0.01 and p=0.01). Similarly, a single non-coding SNP in NOS2A (p=0.02) and TGFBR2 (p=0.02) also exhibited significantly different genotype frequencies in the older versus younger patients. These data support the clinical findings in aging SCD patients reported by McKerrell and colleagues (2004), and they also suggest that genetic factors contribute to variability in longevity in SCD. Interestingly, multiple SNPs in Klotho exhibited differing genotype frequencies in older versus younger patients. Mutations in Klotho have been previously associated with aging-related phenotypes in mice. A better understanding of the biological mechanisms associated with longevity in SCD may help identify those at risk for early demise and in need of more specialized medical care.