Physiology & Biochemistry 315 Faruque MU et al. Association of GNB3 C825T … Int J Sports Med 2009; 30: 315–319 accepted after revision July 6, 2008 Bibliography DOI 10.1055/s-0029-1202259 Published online: March 19, 2009 Int J Sports Med 2009; 30: 315–319 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0172-4622 Correspondence Dr. M. U. Faruque, MD, PhD National Human Genome Center Howard University 2041 Georgia Avenue N.W. Washington, D.C. 20060 United States Tel.: + 202/806/41 80 Fax: + 202/986/39 72 mfaruque@howard.edu Key words ● ▶ GNB3 ● ▶ cardiorespiratory fitness ● ▶ heart rate variability ● ▶ African-Americans ● ▶ autonomic modulation Association of GNB3 C825T Polymorphism with Peak Oxygen Consumption The C825T SNP has been associated with risk of hypertension [23, 27], obesity [25, 26] and type 2 diabetes [22]. The measurement of peak and maximal oxygen consumption (VO 2peak and VO 2max ) during graded exercise is the gold standard for evaluating car- diorespiratory fitness [9]. Low cardiorespiratory fitness is associated with increased risk for car- diovascular disease, metabolic syndrome and type 2 diabetes [13, 37]. Twin and family studies have shown a significant familial component to VO 2max [3, 4]. Results from the HERITAGE Family Study have shown a maximal heritability esti- mate for VO 2max in the sedentary state of at least 50 % when adjusted for age, sex, body mass and body composition [2, 3]. There are at least two reports of genome-wide scans showing signifi- cant linkage of VO 2max to distinct chromosomal loci [5, 21]. Heart rate variability (HRV), a measure of auto- nomic modulation of the heart, appears to be affected by VO 2max [24] and is associated with the GNB3 C825T polymorphism [20]. In this study, we hypothesized that variation in the GNB3 gene may be a determinant of aerobic capacity and cardiorespiratory fitness. This study was designed Introduction & Guanine nucleotide-binding proteins (G-pro- teins) are heterotrimeric molecules that trans- duce signals from a superfamily of cell-surface receptors with seven membrane-spanning regions to several distinct intracellular signaling pathways regulating a wide range of cellular processes including transcription, cell growth, motility and secretion [17]. G-proteins are com- posed of three subunits α, β and γ. Human gua- nine nucleotide-binding protein, beta-3 ( GNB3; OMIM 139130) encodes for the beta subunit (G β3) containing 11 exons and maps to 12p13. The GNB3 mRNA is 1923 bp in length, has a ubiq- uitous tissue expression, and encodes for 340 amino acid residues. A C825T (rs5443) single nucleotide polymorphism (SNP) in exon 10 of the GNB3 gene has been reported [27]. The T allele gives rise to a splice variant, GNB3s, in which the nucleotides 498-620 of exon 9 are deleted from the transcript. This in-frame deletion causes the loss of 41 amino acids. Evidence from transient expression experiments suggests that G β3s is a biologically active protein that confers an enhanced signal transduction activity [27, 34]. Authors M. U. Faruque 1 , R. M. Millis 2 , G. M. Dunston 3 , J. Kwagyan 4 , V. Bond Jr. 5 , C. N. Rotimi 6 , T. Davis 7 , R. Christie 5 , A. L. Campbell 8 Affiliations Affiliation addresses are listed at the end of the article Abstract & The C825T single nucleotide polymorphism (SNP) in the guanine nucleotide-binding pro- tein, beta polypeptide 3 ( GNB3) gene gives rise to a splice variant, GNB3s that has enhanced G protein activation and signal transduction activ- ity. This variant has been reported to be associ- ated with cardiovascular disease, diabetes and obesity. We studied this SNP in 95 healthy 18 to 30 year-old African American university stu- dents to determine its association with aerobic capacity and cardiorespiratory fitness as mea- sured by peak oxygen consumption (VO 2 peak). We also tested the effect of heart rate variability (HRV) as an independent predictor of VO 2 peak. We tested the association of the SNP and HRV with VO 2 peak in a multivariate regression analy- sis with appropriate adjustments of covariates, under dominant and recessive models. We found a significant independent association of the 825T allele with VO 2 peak under the dominant model ( β-coef. = − 0.101, P = 0.0442). We also observed that HRV marginally influenced VO 2 peak. This finding suggests that GNB3 C825T polymorphism is associated with VO 2 peak which is influenced by autonomic modulation of heart rate in African Americans.