Abstract 662: Association Analysis of Raptor Gene Variants with Overweight and Hypertension in American Men of Japanese Ancestry

Abstract

The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth and has been implicated in aging, cardiovascular disease, obesity, diabetes and cancer. mTOR signaling is involved in cardiac leptin-mediated cardiac hypertrophy and fibrosis associated with obesity. mTOR is a key component of two multiprotein complexes, mTOR complex 1 and mTOR complex 2. The former is pro-growth and contains a unique protein, raptor. The present study tested for the first time whether genetic variation across the raptor gene ( RPTOR ) is associated with overweight/obesity, essential hypertension (EHT) and isolated systolic hypertension (ISH). We genotyped 61 common (allele frequency ≥ 0.1) tagging single nucleotide polymorphisms (SNPs) that captured most of the genetic variation across RPTOR in 374 subjects of normal lifespan and 439 subjects with a lifespan exceeding 95 years. Subjects were drawn from the Honolulu Heart Program, a homogeneous population of American men of Japanese ancestry, well characterized for phenotypes relevant to conditions of aging. Hypertension status was ascertained when subjects were 45–68 years old. Statistical evaluation was performed by contingency table analysis, logistic regression and recursive partitioning (RP), which is regarded as amongst the most powerful methods for statistical analysis of large complex sets of genetic information. After analysis of RPTOR genotypes by each statistical approach we found no significant association between genetic variation in RPTOR and either EHT or ISH. For EHT, RP revealed that even the most predictive SNPs ( rs4969322 and rs4890052 ) provided little contribution to correctly assigning individuals to EHT or NT ( P =0.22 by Z test). In the case of ISH, RP revealed that only one SNP ( rs2589118 ) made a noticeable contribution, and that this was no better than the contribution from the weakest laboratory/examination variable (overweight/obesity). In contrast, for overweight/obesity, the RP model revealed that RPTOR SNPs significantly enhanced the predictive capacity of the model ( P =0.008 by one-tailed Z test). In conclusion, genetic variation across RPTOR is associated with overweight/obesity, but not EHT or ISH in the populations of normal lifespan and of long-lived subjects studied.