Insulin clearance: confirmation as a highly heritable trait, and genome-wide linkage analysis

Aims/hypothesis

We have previously documented a high heritability of insulin clearance in a Hispanic cohort. Here, our goal was to confirm the high heritability in a second cohort and search for genetic loci contributing to insulin clearance.

Methods

Hyperinsulinaemic–euglycaemic clamps were performed in 513 participants from 140 Hispanic families. Heritability was estimated for clamp-derived insulin clearance and a two-phase genome-wide linkage scan was conducted using a variance components approach. Linkage peaks were further investigated by candidate gene association analysis in two cohorts.

Results

The covariate-adjusted heritability of insulin clearance was 73%, indicating that the majority of the phenotypic variance is due to genetic factors. In the Phase 1 linkage scan, no signals with a logarithm of odds (LOD) score >2 were detected. In the Phase 2 scan, two linkage peaks with an LOD >2 for insulin clearance were identified on chromosomes 15 (LOD 3.62) and 20 (LOD 2.43). These loci harbour several promising candidate genes for insulin clearance, with 12 single nucleotide polymorphisms (SNPs) on chromosome 15 and six SNPs on chromosome 20 being associated with insulin clearance in both Hispanic cohorts.

Conclusions/interpretation

In a second Hispanic cohort, we confirmed that insulin clearance is a highly heritable trait and identified chromosomal loci that harbour genes regulating insulin clearance. The identification of such genes may improve our understanding of how the body clears insulin, thus leading to improved risk assessment, diagnosis, prevention and therapy of diabetes, as well as of other hyperinsulinaemic disorders, such as the metabolic syndrome and polycystic ovary syndrome.     

Genomewide linkage analysis of weight change in the Framingham Heart Study

BACKGROUND: Weight gain adversely affects blood pressure, lipids, and glycemia. The genetic contribution to weight change is unknown. METHODS: Variance components linkage analysis using microsatellites was performed on 336 families from the Framingham Heart Study offspring cohort, using a 10-cM genome-wide linkage analysis. We evaluated linkage to two traits: short-term (8-yr) weight change and long-term (up to 24-yr) weight change. Models were adjusted for age, age squared, baseline weight, smoking status, and menopausal status. RESULTS: Mean short-term weight change ranged from 1.4-3.8 kg, and mean long-term weight change was 7.7 kg. The heritability of long-term weight change was 0.24; weight change was minimally heritable among younger individuals and over shorter follow-up intervals. We found significant evidence for linkage for long-term weight change, with a peak LOD score of 3.10 on chromosome 20 at 63.7 cM (nearest marker, D20S481). We also found suggestive evidence for linkage on chromosome 1 at 239.7 cM (LOD score, 2.28; nearest marker, D1S1644). CONCLUSION: Long-term weight change is heritable, and evidence for linkage exists on chromosomes 1 and 20. Potential candidate genes include MC3R, ASIP, AGT, and HSD11B1. Additional research is necessary to uncover the genetic underpinnings of weight change that might contribute to associated adverse metabolic profiles.     

Evidence for linkage of red blood cell size and count: genome-wide scans in the Framingham Heart Study

Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count (RBCC) and size, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), studies have indicated that each of these measures has a substantial genetic component. So far, no linkage analysis or genome scan has been reported. We carried out 10 cM genome-wide scans on RBCC, MCV, and MCH in a community-based Caucasian cohort, the Framingham Heart Study, using 325 pedigrees with 1,144 individuals genotyped and phenotyped. Using variance-component linkage methods, heritabilities were estimated as 56, 52, and 52% after covariate adjusted for RBCC, MCV, and MCH, respectively. For RBCC, we found a maximum LOD score of 3.2 on chromosome 19, 24 cM (7.0 Mbp). Near this region, there lie a few important candidate genes, including erythropoietin receptor and erythroid Krüppel-like factor. For linkage analyses for MCV and MCH, there were coinciding maximized LOD scores on chromosome 11, 9 cM (5.2 Mbp) with values of 3.8 and 3.6, respectively. Under the peak resides the hemoglobin beta cluster - several beta-like genes, which are important candidates for RBC size. In subsequent analyses, we excluded individuals with low MCV to assess the possible influence of beta-thalassemia carriers, and there continued to be evidence for linkage in the same region on chromosome 11p15 (LOD scores of 2.6 and 2.7 for MCV and MCH, respectively). For MCV, we also identified a new region on chromosome 6q24 with a LOD score of 2.9. These findings suggest that further studies are warranted to identify potential causal genetic variants for RBC size and count and related erythrocyte indices.     

Duration of the QT interval and total and cardiovascular mortality in healthy persons (The Framingham Heart Study experience)

The baseline electrocardiograms of 5,125 original subjects of the Framingham Heart Study were measured to examine the relation of the QT interval corrected for heart rate (QTc) to risk of total mortality, sudden cardiac death, and death due to coronary artery disease over a 30-year follow-up period. Quintiles of QTc (seconds) less than or equal to 0.36, 0.36 to 0.38, 0.39 to 0.40, 0.41 to 0.43 and greater than or equal to 0.44 were studied in relation to these outcomes. There were no significant differences in the risk of total mortality, sudden cardiac death or death due to coronary artery disease according to QTc. A similar lack of significant association between QTc and these 3 outcomes was observed among all persons studied and in the 2 sexes after using a multiple regression analysis to control for several potentially confounding characteristics including age, gender, cigarette smoking, serum total cholesterol, systolic systemic blood pressure and Framingham relative weight. The results of this study fail to demonstrate an association between baseline QTc and overall mortality, and deaths due to sudden cardiac events or coronary artery disease in a large population-based cohort of essentially healthy persons in whom pathologic forms of QTc prolongation are uncommon.     

Meta-analysis of five genome-wide linkage studies for body mass index reveals significant evidence for linkage to chromosome 8p

OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).     

Heart rate-corrected QT interval duration is significantly associated with blood pressure in Chinese hypertensives

INTRODUCTION: Many studies demonstrated that a prolonged heart rate-corrected QT interval (QTc) increases the risk of malignant ventricular arrhythmias and sudden death. METHODS: We measured the electrocardiogram and blood pressure of 1480 hypertensive patients and assessed the relationship between the length of QTc and blood pressure. RESULTS: The mean QTc is longer in female than in male participants. There was a positive association between QTc and blood pressure in both men and women. The estimated increase in systolic and diastolic blood pressure for each 100-millisecond increase in QTc was 6.4 and 5.0 mm Hg in men and 3.7 and 2.5 mm Hg in women, respectively. CONCLUSION: Our study demonstrated a significant positive relationship between the QTc interval and baseline blood pressure in a Chinese hypertensive population.     

QRS interval fails to predict coronary disease incidence. The Framingham Study

The Framingham Study cohort of 5209 white men and women was examined to determine the long-term incidence of manifestations of new coronary heart disease as a function of QRS interval on subjects' baseline electrocardiograms (recorded at the 9th biennial examination). Over 18 years of follow-up, age-adjusted incidence of myocardial infarction, angina pectoris, and coronary death appeared unrelated to baseline QRS prolongation in both sexes, by Cox regression. Subjects with left bundle-branch block fared no worse than those with right pattern. These relations held whether or not subjects with baseline electrocardiographic abnormalities other than intraventricular block were excluded from consideration. In sum, QRS duration is an unimportant predictor of coronary disease in this Framingham population.     

Fine linkage mapping of the blood pressure quantitative trait locus region on rat chromosome 1.

To narrow the area known to contain the blood pressure quantitative trait locus (QTL) on rat chromosome 1, we constructed a fine linkage map covering the blood pressure OTL region on the chromosome using 22 genetic markers informative for stroke-prone spontaneously hypertensive rats of the Izumo colony (SHRSP/Izm) and Wistar-Kyoto rats of the Izumo colony (WKY/Izm). Linkage mapping was done by genotyping 626 backcrossed rats from matings between SHRSP/Izm and WKY/Izm. Nineteen genetic markers informative for the two strains were selected from public databases. Two markers were newly isolated by screening a rat genomic library. One marker was mapped using a restriction endonuclease polymorphism. The region between DlWox29 and D1Smu11 was covered with 22 informative markers placed every 0.6 cM on average. In addition, 6 physiological candidates for a hypertension gene were mapped in this region either by linkage or by radiation hybrid (RH) mapping. This information should be essential for the construction and analysis of congenic strains for this QTL region.     

Assessment of QT interval and QT dispersion for prediction of all-cause and cardiovascular mortality in American Indians: The Strong Heart Study

BACKGROUND: Both a prolonged QT interval and increased QT interval dispersion (QTD) have been proposed as surface ECG markers of vulnerability to ventricular arrhythmias and potential predictors of mortality. METHODS AND RESULTS: The predictive values of QT prolongation and QTD were assessed in 1839 participants in the Strong Heart Study, a prospective study of cardiovascular disease in American Indians. ECGs were acquired at 250 Hz; QT intervals were measured by computer in all 12 leads and corrected for heart rate (QTc) by use of Bazett's formula. QTD was calculated as the difference between the maximum and minimum QTc. After a mean follow-up of 3.7+/-0.9 years, there were 188 deaths from all causes, including 55 cardiovascular deaths. In univariate Cox analyses, prolonged QTc and increased QTD were significant predictors of all-cause mortality (chi(2)=53.0, P<0.0001; chi(2)=11.3, P=0.0008) and cardiovascular mortality (chi(2)=14.7, P=0.0001; chi(2)=26.5, P<0.0001). In multivariate Cox regression analyses controlling for risk factors, QTc remained a strong predictor of all-cause mortality (chi(2)=16.5, P<0.0001) and a weaker predictor of cardiovascular mortality (chi(2)=5.8, P=0.016); QTD remained a significant predictor of cardiovascular mortality only (chi(2)=12.5, P=0.0004). CONCLUSIONS: These findings support the value of computerized measurements of QTc and QTD in noninvasive risk stratification and suggest that these surface ECG variables may reflect different underlying abnormalities of ventricular repolarization.     

Genetic loci influencing lung function: a genome-wide scan in the Framingham Study

Prior studies have found cross-sectional lung function to be highly heritable. In the present study, we used a 10-cM genome-wide scan of 1,578 members of 330 families participating in the Framingham Study to test for linkage of genetic markers to level of lung function as determined by spirometry during middle age. At this age, lung function measures may reflect the effects of genes influencing lung growth and development, as well as of those influencing decline in lung function during adulthood. We performed spirometry on 345 members of the Original Cohort and 1,233 members of the Offspring Cohort of the Framingham Study. The effects of age, height, body mass index, and smoking status on spirometric measures were adjusted through linear regression models created separately for men and women in each cohort. Standardized residuals for FEV1, FVC, and the ratio of FEV1 to FVC were obtained from these models. The residual spirometric measures were analyzed for linkage to the genome scan markers through the use of variance component models in the Sequential Oligogenic Linkage Analysis Routines software program. The loci most strongly influencing FEV1 and FVC colocalized on chromosomes 4, 6, and 21. FEV1 was most influenced by the locus on chromosome 6 (logarithm of the odds favoring genetic linkage [LOD] = 2.4), whereas chromosome 21 contained markers with the strongest linkage to FVC (LOD = 2.6).     

QT interval analysis in patients with chronic liver disease: a prospective study

In previous studies, it has been shown that QT interval prolongation is related to an increased mortality rate in chronic liver disease (CLD). But QT dispersion (QTd) and its clinical significance in CLD has not been well studied. The objectives of this study were to investigate the relation between QTd and severity of the disease and determine its prognostic value in cirrhotic patients. Thirty-three consecutive patients with cirrhosis and 35 sex- and age-matched healthy subjects were studied. QT intervals and QT dispersions were measured on admission, and all intervals were corrected for heart rate according to Bazett's formula. The authors analyzed the potential relationship between QT parameters and the disease severity according to Child-Pugh classification and compared these values between survivors and nonsurvivors after a 3-year follow-up. Child-Pugh classification is used to assess liver function in cirrhosis. Corrected QT (QTc) prolongations were found in 32% of patients with cirrhosis and 5.7% of the healthy controls (p <0.001). The prevalence of increased (>70 ms) corrected QT dispersion (QTcd) was 45% in patients with cirrhosis. According to Child-Pugh criteria: QTd, maximum QT interval (QTmax), corrected QTmax (QTcmax), and QTcd in class C were significantly higher than those of class A and B (p <0.05, for all comparison). But there was no significant difference between class A and B in QTmax, QTcmax, QTd, and QTcd. There were 10 (30%) deaths from all causes during 3-year follow-up in the study group. Cox regression analysis showed that QTd and QTcd were better mortality indicators than QTmax and QTcmax, and Child's classification was the best predictor for mortality among all variables. In conclusion, QT dispersion and corrected QT dispersion parameters were better mortality indicators than other QT interval parameters and also may give additional prognostic information in patients with chronic liver disease.     

Echocardiographic Left Ventricular Hypertrophy: Clinical Characteristics. The Framingham Heart Study

Recent data suggest that echocardiographic left ventricular (LV) hypertrophy is associated with increased cardiovascular morbidity and mortality. Based upon application of sex-specific echocardiographic criteria for LV hypertrophy, the clinical characteristics of 863 subjects with and 4097 subjects without LV hypertrophy are examined. Subjects with LV hypertrophy are older, more obese, have higher blood pressure, and are more likely to have pre-existing coronary artery disease. In addition subjects with LV hypertrophy have a higher prevalence of reduced echocardiographic fractional shortening.

We conclude that subjects with echocardiographic LV hypertrophy are at high risk for cardiovascular disease complications by virtue of their clinical profile. Additional investigation of the benefits of therapeutic interventions directed toward the prevention or regression of LV hypertrophy is warranted.     

Heart rate-corrected QT interval prolongation is associated with decreased heart rate variability in patients with type 2 diabetes

We investigated the association between the heart rate-corrected QT interval (QTc interval) measured by standard electrocardiography and heart rate variability (HRV) in patients with type 2 diabetes mellitus (T2DM). From March 1, 2009, to December 12, 2009, 411 patients with T2DM who underwent resting 12-lead electrocardiography and cardiovascular autonomic function testing concurrently without the exclusion criteria were consecutively recruited in this cross-sectional study. Time- and frequency-domain HRV variables were assessed for 5 minutes by beat-to-beat HRV recording. The QT interval was corrected for the heart rate using Bazett’s formula. QTc interval measurements of >440 ms were considered abnormally prolonged. The mean age and diabetes duration were 56.3 ± 10.6 years and 9.6 ± 7.3 years, respectively. A total of 90 patients had QTc interval prolongation (21.9%). The participants with a prolonged QTc interval were older (59.4 ± 10.1 years vs 55.5 ± 10.6 years, P = .002), were more likely to be a woman (72.2% vs 51.7%, P = .001), had a higher prevalence of hypertension (46.7% vs 33.4%, P = .022), had a higher hemoglobin A1c level (8.8% ± 2.2% vs 8.2% ± 1.8%, P = .045), and had decreased values for the variables measuring HRV, except for the low frequency (LF)/high frequency (HF) ratio (total power [TP], 147.7 [74.1–335.9] ms vs 328.7 [185.7–721.7] ms, P = .002). After adjusting for multiple confounders, QTc interval prolongation was associated with the lowest quartile of the HRV parameters of TP (odds ratio [OR] = 3.99; 95% confidence interval [CI]: 2.29–6.96), HF (OR = 3.20; 95% CI: 1.84–5.58), LF (OR = 3.68; 95% CI: 2.10–6.43), standard deviation of the normal-to-normal interval (OR = 3.31; 95% CI: 1.89–5.77), and root-mean-square of the successive differences (OR = 1.98; 95% CI: 1.13–3.47) in patients with T2DM. Decreased values for the variables measuring HRV, except for the LF/HF ratio, might be associated with QTc interval prolongation in patients with T2DM.