Genetic Insights into Aging and Age-Related Diseases among Varied Pedigree Structures.

Abstract

Older age is associated with decline in many physiological functions that eventually lead to increased susceptibility to diseases. The rate of aging varies among individuals and may be influenced by genes. This dissertation has three aims: 1) define a measure of aging using physiologic traits and determine its heritability among various pedigree structures, 2) investigate genetic associations with the age trait using genome-wide association study analyses, and 3) focus on decline in kidney function by examining its association with known kidney loci and clinical risk factors within the SardiNIA Study on Aging. Using data from five genetic cohorts (30,000+ individuals) with varying pedigree structure (SardiNIA Study on Aging – large pedigrees, Framingham Heart Study offspring – small pedigrees, Atherosclerotic Risk in Communities Study – unrelated, and two twins studies: Twingene and TwinsUK), two aging traits were developed. Both traits employ three physiologic health measures (kidney function, systolic blood pressure, and waist circumference) to estimate an individual’s biologic age and contrast it with actual age. Linear mixed modeling was employed to estimate a predicted age, while Cox models were used to estimate a risk age equivalent to the age of the census population with the same mortality risk. Using Merlin software (Abecasis, 2002), both age traits were found to be heritable in all cohorts with h2 estimates of 0.25 to 0.68, depending on pedigree structure. Meta-analysis revealed a genome-wide significant association (p < 5 x 10-8) within the LRP1B gene on chromosome 2. LRP1B produces low density lipoprotein receptor-related protein 1B and has been previously associated with tumor suppression, metabolic traits, and successful aging. Association analyses were also conducted using a genetic risk score for CKD, adjusting for clinical factors, with CKD prevalence and change in kidney function. One additional allele in the genetic risk score for CKD was significantly associated with CKD prevalence (OR=1.07, p=0.001), decline in eGFR (β=-0.23, p=0.004), and eGFR decline > 1 SD (OR=1.05, p=0.04). These findings further our understanding of the genetics of aging and the CKD risk score results suggest a possible clinical utility. Putting the findings into clinical use should be evaluated.