Biomedical subjects

D C Rao

Publications and source records attributed to D C Rao.

At least 19 recordsLinked to original sources

PubMed2007

Effect of exercise training on in vitro LDL oxidation and free radical-induced hemolysis: the HERITAGE Family Study.

Oxidant stress and overproduction of reactive oxygen species (ROS) contribute to the development of cardiovascular disease. Oxidative modifications of low-density lipoproteins (LDL) are thought to play an early and critical role in atherogenesis. LDL oxidation can be reproduced in vitro, but results usually show a large interindividual variation not entirely explained by the environment. Free radical-induced hemolysis is also proposed to reveal the overall antioxidant capacity. The roles of genetic factors and exercise on the variability of both measures were investigated. The study was conducted in 146 healthy individuals from 28 families participating in a 20-week exercise-training program. In addition to important biological and environmental influences on variation, significant familial aggregation was detected in all oxidation measures. Exercise did not significantly modify the LDL oxidation parameters, but significantly increased resistance was observed in the free radical-induced hemolysis, especially in women, this effect was not observed in smokers. In total, the findings suggest the presence of familial effects in the response to ex vivo oxidation. Further, smoking negates the beneficial effect of exercise training on erythrocyte resistance to free radical-induced hemolysis. These observations emphasize the importance of context in the evaluation of exercise and oxidant stress.

Adolescent↗

PubMed2006

Effect of regular exercise on homocysteine concentrations: the HERITAGE Family Study.

We investigated whether regular aerobic exercise could affect plasma total homocysteine (tHcy), and whether there were sex-related or racial differences in tHcy changes. Data were available for 816 black and white men and women, aged 17-65 years, 711 of whom completed a 20 week aerobic exercise training program. The tHcy concentration was measured in frozen plasma samples by an HPLC method. In Blacks, tHcy did not change with exercise training [men -0.5 (SD 3.7) micromol/l, women 0.0 (2.2) micromol/l) but increased significantly in Whites (men +0.3 (1.7) micromol/l, women +0.2 (1.6) micromol/l). No sex-related differences were found in either racial group. Changes in tHcy correlated negatively with baseline homocysteine (r = -0.40, P < 0.0001). Homocysteine levels of the "High" (hyperhomocysteinemia) (>or=15 micromol/l) group (n = 30) decreased significantly with regular aerobic exercise from 23.1 (12.1) to 19.6 (7.6) micromol/l. Homocysteine levels of the "Normal" group increased slightly from 8.2 +/- 2.2 to 8.5 +/- 2.4 micromol/l. Men exhibit racial differences for tHcy responses to exercise training. Regular aerobic exercise has favorable effects on individuals with hyperhomocysteinemia, but tHcy slightly increased in individuals within the normal range.

Adolescent↗

PubMed2006

Genome-wide linkage scans for loci affecting total cholesterol, HDL-C, and triglycerides: the Family Blood Pressure Program.

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD=3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD=3.0 at 182 cM) and 12 (LOD=3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD >or= 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.

Adult↗

PubMed2006

Quantitative trait locus on chromosome 20q13 for plasma levels of C-reactive protein in healthy whites: the HERITAGE Family Study.

C-reactive protein (CRP) is a sensitive marker of systemic low-grade inflammation. Increased plasma levels of CRP predict the risk of cardiovascular and metabolic diseases. Although genetic factors account for 30-40% of individual differences in plasma CRP levels, genomic regions contributing to CRP levels remain unknown. We performed a genome-wide linkage scan for plasma CRP levels in healthy whites from the HERITAGE Family Study. CRP was measured with a high-sensitivity assay. Multipoint linkage analyses were performed in 280 sibling pairs with 654 markers using regression and variance components-based methods. Data were adjusted for independent correlates of plasma CRP. We showed the strongest evidence of linkage for plasma CRP levels on chromosome 20q13. Markers which gave suggestive linkages in this region were D20S52 [logarithm of odds (LOD) score 3.18, P = 0.00006], D20S857 (LOD score 2.87, P = 0.00014), D20S869 (LOD score 2.75, P = 0.0002), D20S480 (LOD score 2.59, P = 0.0003), D20S501 (LOD score 2.55, P = 0.0003), D20S840 (LOD score 2.18, P = 0.0008), and D20S876 (LOD score 2.07, P = 0.001). We also detected suggestive linkage on chromosome 5p13 for marker D5S1470 (LOD score 2.23, P = 0.0007). Chromosome 20q13 may contribute to plasma CRP levels in healthy whites. This region contains genes that are important in the inflammatory process and may play a role in the development of chronic inflammatory diseases. The present findings may be useful in the ongoing effort to search for genes contributing to inflammation and to identify individuals at an increased risk of chronic inflammatory diseases.

Age Factors↗

PubMed2006

Scaling submaximal exercise cardiac output and stroke volume: the HERITAGE Family Study.

This study investigated different methods of scaling submaximal cardiac output (Q) and stroke volume (SV) to best normalize for body size (body surface area [BSA], height [Ht], weight [Wt], and fat-free mass [FFM]). Q and SV were measured at both an absolute (50 W) and a relative power output (60 % of VO2max) in 337 men and 422 women, 17 to 65 years of age. Traditional ratio scaling was examined in addition to allometric scaling, where scaling exponents ( B) were determined for each body size variable (x) that best normalized the physiological outcome variables (y) for body size (y = ax(b)). With ratio scaling, regardless of the body size variable (x = BSA, Ht, Wt, FFM), there was no evidence of a linear relationship between x and y (y = Q or SV). A linear relationship is a necessary condition for appropriate normalization. Further, when ratio-scaled variables (e.g., Q/BSA) were correlated to the body size variable (e.g., BSA) by which they were scaled, significant (p <or= 0.05) relationships still existed for BSA, Ht, Wt, and FFM. Thus, ratio scaling did not meet either criteria for normalizing Q and SV for body size. In contrast, when allometrically-derived scaling exponents were used to normalize Q and SV (e.g., Q/BSA(b)), the resulting scaled values were uncorrelated (i.e., size-independent) with BSA, Ht, Wt, or FFM. These results were independent of age, sex or race. In summary, ratio scaling did not appropriately normalize Q and SV for differences in body size, while allometric scaling did result in size-independent values. Thus, individually-derived allometric exponents should be applied to body size variables to most appropriately adjust Q and SV for body size.

Adolescent↗

PubMed2006

Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans.

Admixed populations such as African Americans and Hispanic Americans present both challenges and opportunities in genetic epidemiologic research. Because of variation in admixture levels among individuals, case-control association studies may be subject to stratification bias. On the other hand, admixed populations also present special opportunities both for examining the role of genetic and environmental factors for observed racial/ethnic differences, and for possibly mapping alleles that contribute to such differences. Here we examined the distribution and relationship of individual admixture (IA) estimates with BMI and three measures of blood pressure in two admixed populations in the NHLBI Family Blood Pressure Program (FBPP): African Americans and Mexican Americans. For the African Americans, we observed modest but significant differences in average African IA among four recruitment sites. We observed a slight excess of African IA among hypertensives compared to normotensives, and a positive (non-significant) regression of African IA on blood pressure in untreated participants. Within Mexican Americans, we found no difference in average IA between hypertensives and normotensives, but a positive (marginally significant) regression of African IA on diastolic blood pressure. We also observed a significant positive regression of Caucasian IA (and negative regression of Native American IA) on BMI. Our results are suggestive of genetic differences between Africans and non-Africans that influence blood pressure, but such effects are likely to be modest compared to environmental ones. Excess obesity among Native Americans compared to whites is not consistent with a simple genetic explanation.

Adult↗

PubMed2006

The TNF-alpha G-308A polymorphism is associated with C-reactive protein levels: the HERITAGE Family Study.

OBJECTIVE: Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha), stimulate the release of C-reactive protein (CRP). We investigated the association between the TNF-alpha G-308A polymorphism and plasma CRP levels. METHODS: Subjects were 456 White (225 men, 231 women) and 232 Black (83 men, 149 women) healthy adults who underwent a 20-week standardized exercise program in the HERITAGE Family Study. The TNF-alpha gene promoter polymorphism was determined using PCR amplification followed by NcoI digestion. Plasma CRP was measured using a high-sensitivity assay. RESULTS: Genotype frequencies were in Hardy-Weinberg equilibrium. After adjustment for age, smoking, alcohol consumption, maximal oxygen uptake and, in women, hormone use, the AA homozygotes for the G-308A polymorphism had higher baseline CRP levels than other genotypes in White and Black men (P<0.001 and P = 0.044, respectively) and in Black women (P = 0.032). Body mass index partly explained these associations in Blacks. The exercise program results provided further evidence for an association with the polymorphism. Among those with high CRP at baseline (> or = 3.0 mg/L), regular exercise decreased CRP less in AA homozygotes than in other genotypes (P = 0.043). CONCLUSION: The AA genotype of the TNF-alpha G-308A polymorphism is associated with higher plasma CRP levels and less favorable CRP response to regular exercise.

Adult↗

PubMed2006

Blood pressure stress reactivity and left ventricular mass in a random community sample of African-American and caucasian men and women.

Exaggerated blood pressure (BP) reactivity to stress may contribute to left ventricular (LV) hypertrophy, a major risk factor for cardiovascular morbidity. This study examined the extent to which BP responses to acute stress are associated with LV mass and relative wall thickness in a community sample of African-American and white men and women. BP was measured at rest and in response to 2 acute challenges (mental arithmetic and handgrip). Systolic BP at rest was positively associated with LV mass and relative wall thickness (p < 0.001). The associations between the responses to the stressors and LV mass were not significant. African-American and white men who exhibited high BP responses to the arithmetic stressor had greater relative wall thickness than those with low reactivity (p < 0.05). In conclusion, BP reactivity is not related to LV mass, but may be related to concentric remodeling.

Black or African American↗

PubMed2006

An updated meta-analysis of genome scans for hypertension and blood pressure in the NHLBI Family Blood Pressure Program (FBPP).

A meta-analysis of the results from a multicenter genome-wide linkage study for hypertension and blood pressure (BP) based on an initial sample of 6,245 individuals was published in 2003. We report here a combined linkage analysis of hypertension and BP using the complete Family Blood Pressure Program (FBPP) dataset, which includes a total of 12,028 genotyped individuals. Genome-wide linkage analyses for hypertension and BP were first performed in each of the studied ethnic group within each network and the results were combined with a meta-analysis using a modified Fisher's method of combining P values. Our meta-analysis of genome scans for the latest FBPP dataset reveals suggestive linkage for hypertension and BP at several regions on the human genome. Strong evidence for linkage at two of these regions, 2p14 and 3p14.1, have also been published in previous meta-analyses, making them good candidate locations for susceptibility variants.

Adult↗

PubMed2006

Meta-analysis of genome-wide scans for blood pressure in African American and Nigerian samples. The National Heart, Lung, and Blood Institute GeneLink Project.

BACKGROUND: In many genetic studies of complex traits, sample sizes are often too small to detect linkages of low-to-moderate effects. However, the combined linkage evidence across several studies can be synthesized using meta-analysis with the aim of providing more definitive support of linkage. METHODS: In the current study using the National Heart, Lung, and Blood Institute (NHLBI) GeneLink Project, a meta-analysis based on a modification of Fisher's method of pooling P values was used to investigate linkage for systolic blood pressure (SBP) and diastolic blood pressure (DBP) values across three studies involving African American and Nigerian families (HyperGEN, Health, Risk Factors, Exercise Training and Genetics [HERITAGE], and Genetics of Hypertension in Blacks). RESULTS: The meta results suggest two regions (2p and 7p) provide enhanced linkage evidence compared with the individual study results. The maximal meta Lod score of 2.9 on 2p14-p13.1 (64-78 cM) represented approximately 1-Lod unit increase over the respective individual study scores. This general region has been implicated previously involving primarily families of white ethnicity and provides confirmatory evidence that this QTL is common across ethnic groups. The second finding at 7p21.3-p15.3 (8-25 cM) provided a meta Lod of 3.5. Although region was implicated primarily in the Nigerian subjects the low-level but consistent support involving the African American families (individual Lod score of 1.0) suggests a novel QTL with respect to BP variation in individuals of black ethnicity. CONCLUSIONS: Follow-up studies involving positional cloning efforts of the combined families showing linkage evidence in these regions (particularly 2p) may be warranted to verify these findings and identify the genes and causative variants.

Adolescent↗

PubMed2006

Genome-wide scan to identify quantitative trait loci for baseline resting heart rate and its response to endurance exercise training: the HERITAGE Family Study.

Evidence of a genetic component for resting heart rate (RHR) has been found. Quantitative trait loci (QTLs) for baseline RHR have been reported, but not for RHR training response. It is of interest to identify QTLs that may harbor genes influencing RHR variation at baseline and in response to regular exercise training. Here, a multipoint variance components linkage scan using 654 markers was performed to search for QTLs that influence RHR adjusted for several covariates at baseline and in response to 20 weeks of endurance training (post-training minus baseline) in 99 White and 127 Black families in the HERITAGE Family Study. Potentially interesting linkages were revealed on 4 q and 11 p for baseline RHR, and on 1 q and 21 q for RHR training response in Whites. The QTLs on 2 q, 6 q, 7 q, 12 q, 14 q, and 15 q for baseline RHR, and on 3 p, 20 p and 21 q for RHR training response were found in Blacks. Promising linkages (lod scores >or= 1.75, p or= 135/80 mm Hg) subset of 40 White families suggesting a pleiotropic gene for BP and RHR with interactions. In conclusion, among QTLs on 1 q, 2 p, 3 p, 4 q, and 11 p that replicated across subsamples and studies, 11 p is most promising for dense mapping and association studies in HERITAGE and other cohorts.

Black People↗

PubMed2006

Pleiotropic QTL on chromosome 12q23-q24 influences triglyceride and high-density lipoprotein cholesterol levels: the HERITAGE family study.

To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p = 0.00010) was found on chromosome 12q23-q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD = 2.07, p = 0.00108; for HDL-C, LOD = 2.04, p = 0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p = 0.04). In conclusion, these results suggest that a QTL on chromosome 12q23-q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.

Adolescent↗

PubMed2006

Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study.

Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.

Black People↗

PubMed2005

Haplotype association analysis of AGT variants with hypertension-related traits: the HyperGEN study.

OBJECTIVE: Function of the renin-angiotensin system is important to human hypertension, but its genetic etiology remains elusive. We set out to examine a hypothesis that multiple genetic variants in the system act together in blood pressure regulation, via intermediate phenotypes such as blood pressure reactivity. METHODS: A sample of 531 hypertensive cases and 417 controls was selected from the HyperGEN study. Hypertension-related traits including blood pressure responses to challenges to math test, handgrip and postural change (mathBP, gripBP, and postBP), and body mass index (BMI) were analyzed for association with 10 single nucleotide polymorphisms (SNPs) in the angiotensinogen (AGT) gene. Single-marker and haplotype analyses were performed to examine the effects of both individual and multiple variants. Multiple-trait profiling was used to assess interaction of latent intermediate factors with susceptible haplotypes. RESULTS: In Blacks, two SNPs in exon 5 and 3'UTR showed significant association with gripBP, and two promoter SNPs were strongly associated with postBP. In Whites, only borderline association was found for 2 promoter SNPs with mathBP. Haplotype analyses in Blacks confirmed association with gripBP, and detected significant association of a haplotype to BMI (p=0.029). With the interactions modeled, haplotype associations found in Blacks remain significant, while significant associations to BMI (p=0.009) and gripSBP emerged in Whites. CONCLUSION: Genetic variants in regulatory regions of AGT showed strong association with blood pressure reactivity. Interaction of promoter and genic SNPs in AGT revealed collective action of multiple variants on blood pressure reactivity and BMI both in Blacks and in Whites, possibly following different pathways.

Black or African American↗

PubMed2005

An evaluation of the metabolic syndrome in a large multi-ethnic study: the Family Blood Pressure Program.

BACKGROUND: The Family Blood Pressure Program is an ongoing, NHLBI-sponsored, multi-center program to study the genetic determinants of high blood pressure. The goal of this particular study was to study patterns of metabolic syndrome (MetS) in four ethnic groups: African Americans, Caucasians, Hispanics, and Asians. METHODS: A major part of participants in three networks GENOA, HyperGEN and SAPPHIRe were recruited mainly through hypertensive probands. MetS was defined as a categorical trait following the National Cholesterol Education Program definition (c-MetS). MetS was also characterized quantitatively through multivariate factor analyses (FA) of 10 risk variables (q-MetS). Logistic regression and frequency tables were used for studying associations among traits. RESULTS: Using the NCEP definition, the Hispanic sample, which by design was enriched for type 2 diabetes (T2D), had a very high prevalence of MetS (73%). In contrast, its prevalence in Chinese was the lowest (17%). In African Americans and Hispanics, c-MetS was more prevalent in women than in men. Association of c-MetS with type 2 diabetes (T2D) was prominent in the Hispanics and African Americans, less pronounced in the Whites and Japanese, (although still significant), and weakest in the Chinese sample. Using FA without rotation, we found that the main factor loaded obesity (OBS) and blood pressure (BP) in African Americans; OBS and insulin (INS) in Hispanics, in Japanese, and in Whites; and OBS alone in Chinese. In Hispanics, Whites, and Japanese, BP loaded as a separate factor. Lipids in combination with INS also loaded in a separate factor. Using FA with Varimax rotation, 4 independent factors were identified: "Obesity-INS," "Blood pressure," "Lipids-INS," and "Central obesity." They explained about 60% of the variance present in the original risk variables. CONCLUSION: MetS ethnic differences were identified. Ascertaining for hypertension or T2D increased the MetS prevalence in networks compared with the one in the US general population. Obesity was the most prominent risk factor contributing to both c-MetS and q-MetS. INS contributed in two important factors (obesity and lipids). The information imbedded into c-MetS trait /q-MetS factors scores can contribute in future research of the MetS, especially its utilization in the genetic analysis.

Journal Article↗

PubMed2005

Pleiotropic QTL on chromosome 19q13 for triglycerides and adiposity: the HERITAGE Family Study.

Motivated by strong correlations between plasma levels of triglycerides (TG) and adiposity traits, we conducted a series of bivariate genome-wide linkage analyses of TG with body mass index (BMI), total fat mass (FAT), percentage of body fat (FATPC), and abdominal subcutaneous fat (ASF). Maximum lod scores of 3.3, 3.0, 2.2 and 2.4, respectively, were found on chromosome 19q13. This linkage region includes the APOE gene, a predictor of variation in lipid-lipoprotein levels, and the hormone-sensitive lipase (LIPE) gene, a key enzyme in the mobilization of fatty acids from triglyceride stores. In addition, the adiposity measures together with the APOE marker showed significant association with TG levels (p = 0.02 to p = 0.03). In summary, these results suggest that one or more QTLs in the 19q13 region jointly influence TG levels and adiposity. Polymorphisms in the APOE gene, and possibly LIPE gene, appear to be strong candidates for the source of this pleiotropic QTL.

Adiposity↗

PubMed2005

Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study.

AIMS: To study the effect of exercise training on plasma C-reactive protein, a marker of inflammation. METHODS AND RESULTS: We performed a 20 week standardized exercise training programme in 652 sedentary healthy white and black men and women. C-reactive protein was measured with a high sensitivity assay. The study sample was stratified according to baseline C-reactive protein levels using a recommended classification (low <1.0 mg/L, n=265; moderate 1.0-3.0 mg/L, n=225; high >3.0 mg/L, n=162). The median C-reactive protein reduction was 1.34 mg/L in the high baseline C-reactive protein group. C-reactive protein levels did not change in the low or moderate baseline C-reactive protein groups. The difference among the C-reactive protein groups was significant adjusting for all correlates of baseline C-reactive protein (P<0.001) and additionally for changes in body weight, glucose, insulin, LDL cholesterol, HDL cholesterol, triglycerides, systolic and diastolic blood pressure, and maximal oxygen uptake (P<0.001). The C-reactive protein reduction in the high baseline C-reactive protein group was consistent across all population groups (P<0.001 for difference among baseline C-reactive protein groups). CONCLUSION: Plasma C-reactive protein levels are reduced in response to exercise training in sedentary healthy adults with high initial C-reactive protein levels. This finding may partly explain the effectiveness of regular physical activity in the prevention and treatment of cardiovascular and metabolic diseases.

Adult↗

PubMed2005

Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study.

AIMS/HYPOTHESIS: Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. METHODS: These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. RESULTS: In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). CONCLUSIONS/INTERPRETATION: Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.

Adolescent↗