KIF5B gene sequence variation and response of cardiac stroke volume to regular exercise

Abstract

A genome-wide linkage scan for endurance training-induced changes in stroke volume detected a quantitative trait locus on chromosome 10p11 in white families of the HERITAGE Family Study. Dense microsatellite mapping narrowed down the linkage region to a 7 Mb area containing 16 known and 14 predicted genes. Association analyses with 90 single nucleotide polymorphisms (SNPs) provided suggestive evidence (P values from 0.03 to 0.06) for association in the kinesin heavy chain (KIF5B) gene locus in the whole cohort. The associations at the KIF5B locus were stronger (P values from 0.001 to 0.008) when the analyses were performed on linkage-informative families only (family-specific logarithm of the odds ratio scores Ͼ0.025 at peak linkage location). Resequencing the coding and regulatory regions of KIF5B revealed no new exonic SNPs. However, the putative promoter region was particularly polymorphic, containing eight SNPs with at least 5% minor allele frequency within 1850 bp upstream of the start codon. Functional analyses using promoter haplotype reporter constructs led to the identification of sequence variants that had significant effects on KIF5B promoter activity. Analogous inhibition and overexpression experiments showed that changes in KIF5B expression alter mitochondrial localization and biogenesis in a manner that could affect the ability of the heart to adjust to regular exercise. Our data suggest that KIF5B is a strong candidate gene for the response of stroke volume to regular exercise. Furthermore, training-induced changes in submaximal exercise stroke volume may be due to mitochondrial function and variation in KIF5B expression as determined by functional SNPs in its promoter.genotype; exercise training; functional studies; mitochondria REGULAR EXERCISE HAS BEEN shown to protect against morbidity and mortality from cardiovascular diseases (CVD), whereas sedentariness is associated with increased risk of CVD. Cardioprotective effects of exercise are mediated by several physiological mechanisms, such as improved plasma lipid and lipoprotein profile, lower blood pressure, improved endothelial function, and enhanced insulin sensitivity. Regular exercise also improves cardiac function. Exercise-trained hearts work more efficiently, i.e., physically active individuals have lower heart rates but greater stroke volume at rest and during submaximal exercise than their sedentary counterparts. Exercisetrained hearts can also adjust better to suddenly increased circulatory demands and tolerate better the demands of heavy physical exertion.Although regular physical activity improves cardiac function on average, there are marked interindividual differences in exercise training-induced changes in cardiac phenotypes. For instance, in the HERITAGE Family Study, a 20-wk endurance training program resulted in a mean increase of 3.9 ml/beat in stroke volume measured during steady-state exercise at 50 W (SV50) (29). However, the training responses ranged from a decrease of 41 ml/beat to an increase of 45 ml/beat. The stronge...

Genomics and Genetics in the Biology of Adaptation to Exercise

“…Both traits are characterized by increased incidence of cardiac events during exercise. The positional cloning efforts of the response to exercise QTLs in the HERITAGE Family Study have yielded a number of strong candidates for the changes in submaximal exercise capacity with regular exercise ( CREB1 ) and in SV and Q ( KIF5B ) (16, 253). …”

Personalized Preventive Medicine: Genetics and the Response to Regular Exercise in Preventive Interventions

“…The QTL on 10p11 for the gains in stroke volume was narrowed down to a 7 Mb region. Among the linkage-positive families, the strongest associations were found with single nucleotide polymorphisms (SNPs) in the kinesin family member 5B ( KIF5B ) gene locus (41). Resequencing of KIF5B revealed several sequence variants.…”

“…The SNP with the strongest association modified the KIF5B promoter activity in cell-based systems. Furthermore, inhibition and overexpression studies in C2C12 cells showed that changes in KIF5B expression level altered mitochondrial localization and biogenesis; KIF5B inhibition led to diminished biogenesis and perinuclear accumulation of mitochondria, while overexpression enhanced mitochondrial biogenesis (41). …”

cAMP Responsive Element Binding Protein 1

“…9,10 These previous studies used the same approach as the present study: They first found significant heritability for the phenotype of interest, identified novel loci potentially underlying this phenotype using genome-wide linkage analyses, fine mapped the chromosomal locus with the highest linkage, performed numerous SNP statistical association analyses, and performed cell culture studies to assess the molecular effects of their novel SNPs. In both previous studies, the phenotype of interest was the traininginduced change in submaximal exercise stroke volume, and the novel genes that they identified were titin 10 and kinesin-1 heavy chain.…”

“…In both previous studies, the phenotype of interest was the traininginduced change in submaximal exercise stroke volume, and the novel genes that they identified were titin 10 and kinesin-1 heavy chain. 9 Neither of these 2 genes would have been considered candidate chromosomal loci to underlie this phenotype. Similarly, cAMP responsive element binding protein 1, found to play such an important role in the present study, would not have been on any list as a potential candidate gene affecting the training-induced change in submaximal exercise HR.…”