Genetic variation in the raptor gene is associated with overweight but not hypertension in American men of Japanese ancestry

Abstract

Background: The mechanistic target of rapamycin (mTOR) pathway is pivotal for cell growth. Regulatory associated protein of mTOR complex I (Raptor) is a unique component of this pro-growth complex. The present study tested whether variation across the raptor gene (RPTOR) is associated with overweight and hypertension.

Methods: We tested 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 for association with overweight/obesity, essential hypertension, and isolated systolic hypertension. 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 involved contingency table analysis, logistic regression, and the powerful method of recursive partitioning.

Results: After analysis of RPTOR genotypes by each statistical approach, we found no significant association between genetic variation in RPTOR and either essential hypertension or isolated systolic hypertension. Models generated by recursive partitioning analysis showed that RPTOR SNPs significantly enhanced the ability of the model to accurately assign individuals to either the overweight/obese or the non-overweight/obese groups (P = 0.008 by 1-tailed Z test).

Conclusion: Common genetic variation in RPTOR is associated with overweight/obesity but does not discernibly contribute to either essential hypertension or isolated systolic hypertension in the population studied.

Keywords: blood pressure; body weight; essential hypertension; genetic association analysis; hypertension; isolated systolic hypertension; mechanistic target of rapamycin (mTOR); raptor gene (RPTOR); recursive partitioning analysis..

Figure 1.

LD plot showing the 61 tagging SNPs in RPTOR on chromosome 17p25.3. Shown is the region spanning nucleotides 76122143–76565844 (from HapMap data release 27, phase II + III, February 2009, on NCBI B36 assembly, dbSNP b126). It is estimated that 406 alleles with a mean r ² of 0.92 are captured using the tagSNPs in the present study. The figure was plotted using Haploview. In the figure, red squares denote blocks that have a Hedrick’s multiallelic D′ = 1, whereas pink or white denote blocks that have a D′ value < 1. Abbreviations: LD, linkage disequilibrium; SNP, single nucleotide polymorphism.

Figure 2.

Results from recursive partitioning analysis for (A) overweight/obesity, (B) essential hypertension, and (C) isolated systolic hypertension. Shown is contribution to fit for each of the variables in the full model generated from RP analysis. In (A), 19 SNPs failed to improve assignment efficiency; in (B), 6 SNPs failed to improve assignment efficiency; and in (C), 4 SNPs failed to improve assignment efficiency. In (A), (B), and (C), all SNP contributions were less than laboratory/examination variables. The most promising of the 61 SNPs genotyped are shown: 19 for overweight/obesity, 6 for EHT, and 4 for ISH. Abbreviations: BMI_1, body mass index at examination 1 (1965–1968); BMI_4, BMI at examination 4 (1991–1993); Overweight/obese, overweight or obese at examination 1 (1965–1968); CASI, Cognitive Abilities Screening Instrument (score range: 0–100) at examination 4 (1991–1993); CHOL_4, fasting plasma total cholesterol at examination 4 (1991–1993); GLUC_4, fasting glucose at examination 4 (1991–1993); EHT, essential hypertension; GRIP_4, grip strength at examination 4 (1991–1993); HDL_4, fasting plasma high density lipoprotein cholesterol at examination 4 (1991–1993); Height_4, height at examination 4 (1991–1993); INS_4, fasting insulin at examination 4 (1991–1993); ISH, isolated systolic hypertension; log INS_4, logarithm of fasting insulin at examination 4 (1991–1993); RP, recursive partitioning; SNP, single nucleotide polymorphism; Waist:Hip, waist:hip ratio at examination 4 (1991–1993); Weight_1, body weight at examination 1 (1965–1968).

Figure 3.

Receiver operating characteristic curves showing sensitivity and specificity for training data (left panel) and validation data (right panel) that formed the final output of recursive partitioning analysis testing for influence of the variables on (A) overweight/obesity, (B) essential hypertension, and (C) isolated systolic hypertension.