Ronit Sinnreich

Taq1B CETP polymorphism, plasma CETP, lipoproteins, apolipoproteins and sex differences in a Jewish population sample characterized by low HDL-cholesterol

Mean high-density lipoprotein cholesterol (HDL-C) concentrations are low in the Jewish population of Israel. With this in mind we assessed the association of the Taq1B CETP polymorphism, plasma CETP mass and plasma lipid, lipoprotein and apolipoprotein concentrations in a sample of 884 Jerusalem residents aged 28-32. The allele frequency (0.435 +/- 0.017(S.E.)) is similar to that reported elsewhere. There was a strong (apparently codominant) association of the Taq1 B allele with plasma CETP in both sexes, and an inverse association with HDL-C and apo A-1, significant in women and undiminished upon adjustment for plasma CETP. There was evidence in this population for an admixture of two plasma CETP distributions, with 9% belonging to a distribution with the higher mean, pointing to a possible major gene effect. Mean plasma CETP was higher in women than men. Plasma CETP was inversely associated with HDL-C in men but not in women (P< 0.05 for the sex difference, multivariate analysis), inversely related to the HDL-C/apo A-1 ratio in men and positively related in women (P < 0.005 for the sex difference), and was positively associated with total cholesterol (TC) and low-density lipoprotein cholesterol in both sexes, and with the TC/HDL-C ratio and apo B in men alone. The sex differences may reflect dissimilarities in the regulatory function of CETP in lipid exchange. The absence of an unusual allele frequency of the Taq1B CETP polymorphism and its relatively modest association with HDL-C argue against an important role for this or strongly linked sites in determining the low population levels of HDL-C in Israel.

Energy intake and leukocyte telomere length in young adults

BACKGROUND Dietary energy restriction in mammals, particularly at a young age, extends the life span. Leukocyte telomere length (LTL) is thought to be a bioindicator of aging in humans. High n-6 (omega-6) PUFA intake may accelerate LTL attrition. OBJECTIVE We determined whether lower energy and higher PUFA intakes in young adulthood are associated with shorter LTL in cross-sectional and longitudinal analyses. DESIGN In a longitudinal observational study (405 men, 204 women), diet was determined at baseline by a semiquantitative food-frequency questionnaire, and LTL was determined by Southern blots at mean ages of 30.1 y (baseline) and 43.2 y (follow-up). Spearman correlations and multivariable linear regression were used. RESULTS Baseline energy intake was inversely associated with follow-up LTL in men (standardized β = -0.171, P = 0.0005) but not in women (P = 0.039 for sex interaction). The difference in men between the highest and lowest quintiles of energy was 244 base pairs (bp) (95% CI: 59, 429 bp) and between extreme quintiles of LTL was 440 kcal (95% CI: 180, 700 kcal). Multivariable adjustment modestly attenuated the association (β = -0.157, P = 0.002). Inverse associations, which were noted for all macronutrients, were strongest for the unsaturated fatty acids. In multivariable models including energy and the macronutrients (as percentage of energy), the significant inverse energy-LTL association (but not the PUFA-LTL association) persisted. The energy-LTL association was restricted to never smokers (standardized β = -0.259, P = 0.0008; P = 0.050 for the smoking × calorie interaction). CONCLUSIONS The inverse calorie intake-LTL association is consistent with trial data showing beneficial effects of calorie restriction on aging biomarkers. Further exploration of energy intake and LTL dynamics in the young is needed.

Adiponectin and Lipoprotein Particle Size

OBJECTIVE Adiponectin has been postulated to affect lipid and insulin signal transduction pathways. We evaluated the relationships of plasma adiponectin with lipoprotein mean particle size and subclass concentrations, independent of obesity and insulin sensitivity. RESEARCH DESIGN AND METHODS A cross-sectional analysis of 884 young Israeli adults who participated in the population-based Jerusalem Lipid Research Clinic (LRC) study was conducted. Lipoprotein particle size was assessed using proton nuclear magnetic resonance. RESULTS In multivariable linear regression models that included sex, BMI, waist circumference, homeostasis model assessment of insulin resistance, and leptin, adiponectin was associated with mean LDL size (standardized regression coefficient B = 0.20; P < 0.001), VLDL size (B = −0.12; P < 0.001), and HDL size (B = 0.06; P = 0.013). Adiponectin was inversely related to large VLDL (P < 0.001) but positively to small VLDL (P = 0.02), inversely related to small LDL (P < 0.006) but positively to large LDL (P < 0.001), and positively related to large HDL (P < 0.001) subclass concentrations. CONCLUSIONS Adiponectin is favorably associated with lipoprotein particle size and subclass distribution independent of adiposity and insulin sensitivity.

Genetic and environmental sources of QT interval variability in Israeli families: the kibbutz settlements family study.

QT interval prolongation not attributed to long QT syndromes is reported to be associated with increased risk of sudden and nonsudden cardiac death. Genetic and environmental determinants of QTc interval were investigated in an unselected free living population sample of 80 kindreds residing in kibbutz settlements in Israel.The sample included 214 males and 227 females aged 15–97 years. There was a significant familial aggregation of adjusted QT interval levels, as indicated by inter‐ and intraclass correlation coefficients significantly different from zero. Complex segregation analysis applied to the sex‐ and age‐adjusted data was not conclusive and heterogeneous etiologies for individual differences were suggested. There was evidence for a single recessive locus (q=0.173) with a major effect in addition to polygenic effects (h2=0.41) that explained the mixture of distributions. In parallel, a nontransmitted environmental major factor in addition to polygenic effects that explained the adjusted variation in QTc could not be rejected. Similar results were obtained upon the adjustment for sex, age, and environmental covariables. The major factor, either genetic or environmental, and polygenic‐loci accounted for about 20 and 33% of the adjusted QTc variation, respectively. Furthermore, sex, age, measured environmental covariables, the unmeasured major factor, and the unmeasured polygenes could account for 63% of the variation of QTc in these families.Our data provide evidence for a major factor, either genetic or environmental, in addition to a polygenic background, influencing QT interval levels in a population‐based sample of pedigrees.

Possible Association of the Human KCNE1 (minK) Gene and QT Interval in Healthy Subjects: Evidence from Association and Linkage Analyses in Israeli Families

QT interval prolongation is associated with increased risk of sudden and non‐sudden cardiac death. Potassium channel gene variants are associated with inherited long QT syndromes. Using linkage and association analyses, we investigated whether variants in the potassium channel subunit KCNE1 are associated with QTc intervals in an unselected population sample of 80 kindreds living in kibbutz settlements in Israel. Variance‐component linkage analysis revealed weak evidence of linkage of KCNE1 polymorphisms with QTc intervals. Family‐based association analysis showed a significant association between the G38S polymorphism and QTc interval. Further quantitative trait association analysis demonstrated a significant residual heritability component (h2= 0.33), and that the effect of the G38S variant allele is modified by gender. Estimated maximum likelihood parameters from these models indicated that male gender, age, hypertension, diabetes, hypercholesterolemia, fibrinogen and BMI were positively associated with QTc interval; level of education and cigarette smoking showed an inverse association. Both erythrocyte membrane n‐6 and n‐3 fatty acids showed a significant inverse association with QTc interval. While more than 15.8% of QTc variability was contributed by covariates, another 4.7% was explained by dietary factors, the G38S polymorphism explained 2.2%, and approximately 36% was explained by polygenes. An in silico analysis showed also that the novel V80 SNP, another KCNE1 synonymous variant, abolishes the recognition for a splicing enhancer, which may lead to an increased effect of the G38S mutation.

The triglyceride to high-density lipoprotein-cholesterol ratio in adolescence and subsequent weight gain predict nuclear magnetic resonance-measured lipoprotein subclasses in adulthood.

OBJECTIVE To assess whether the fasting triglyceride-to-high-density lipoprotein (HDL)-cholesterol (TG/HDL) ratio in adolescence is predictive of a proatherogenic lipid profile in adulthood. STUDY DESIGN A longitudinal follow-up of 770 Israeli adolescents 16 to 17 years of age who participated in the Jerusalem Lipid Research Clinic study and were reevaluated 13 years later. Lipoprotein particle size was assessed at the follow-up with proton nuclear magnetic resonance. RESULTS The TG/HDL ratio measured in adolescence was strongly associated with low-density lipoprotein, very low-density lipoprotein (VLDL), and HDL mean particle size in young adulthood in both sexes, even after adjustment for baseline body mass index and body mass index change. The TG/HDL ratio measured in adolescence and subsequent weight gain independently predicted atherogenic small low-density lipoprotein and large VLDL particle concentrations (P < .001 in both sexes). Baseline TG/HDL and weight gain interacted to increase large VLDL concentration in men (P < .001). CONCLUSIONS Adolescents with an elevated TG/HDL ratio are prone to express a proatherogenic lipid profile in adulthood. This profile is additionally worsened by weight gain.

Combined Segregation and Linkage Analysis of Fibrinogen Variability in Israeli Families: Evidence for Two Quantitative‐trait Loci, One of Which is Linked to a Functional Variant (−58G > A) in the Promoter of the α‐fibrinogen Gene

The association of α‐ and β‐fibrinogen polymorphisms with plasma fibrinogen levels was examined in a sample of 452 family members from 80 Israeli kindreds. The measured genotype analysis indicated that the β‐fibrinogen −455G > A polymorphism was not associated with fibrinogen levels, while the α‐fibrinogen −58G > A locus showed a significant association with fibrinogen levels (χ2= 17.7; df = 3; p < 0.001), with the −58A allele being associated with higher levels. Segregation analysis in this sample suggested a recessive quantitative‐trait locus (QTL) with a major effect that controlled the sex‐ and age‐adjusted fibrinogen levels. Results from a combined segregation/linkage analysis indicated that a single QTL influencing plasma fibrinogen is in gametic equilibrium with the β‐fibrinogen −455G > A and α‐fibrinogen −58G > A polymorphisms. An extended analysis with a two‐QTL model significantly improved the fit of the model (p ≤ 0.001), and gave support for linkage between the fibrinogen QTL and the α‐fibrinogen polymorphism. In vitro analysis with a DNA fragment containing this variant, linked to a reporter gene, showed 2‐fold higher expression of the A allele compared to the G allele in the liver cell line HepG2, both under basal conditions and after stimulation with interleukin 6. These results demonstrate that two QTLs are jointly involved in determining plasma fibrinogen levels in this sample of families, one of which is located close to a functional variant in the α‐fibrinogen locus.

Familial aggregation of heart rate variability based on short recordings – the kibbutzim family study

The objective of this study was to assess the familial aggregation of heart rate variability (HRV), a readily measurable noninvasive reflection of cardiac autonomic function. Familial correlations were analyzed in 451 kibbutz members aged 15–97 years belonging to 80 kindreds. Five-minute duration Holter recordings made during silent supine spontaneous breathing and metronomic breathing were analyzed in the time and frequency domains. The present analysis considers the familial correlations and the heritability estimates of two time-domain indices, the standard deviation (SD) of the R-R interval (RR), reflecting total variability, and the root mean square of successive differences in RR intervals (RMSSD), reflecting vagal (parasympathetic) tone. During free breathing, age- and sex-adjusted correlations between parents and their children (r=0.24 for both indices) and between adult siblings above 30 years of age (r=0.24 and r=0.34 for SD and RMSSD, respectively) were statistically significant, whereas spouse correlations (r=–0.04, r=–0.02 for SD and RMSSD, respectively) and correlations in younger siblings (r=–0.22 and r=0.01, respectively) were not. Significant heritability estimates were demonstrated for the two indices (h2=0.41 for SD and h2=0.39 for RMSSD). These findings suggest that familial aggregation of HRV characteristics is determined mostly by genetic factors and less so by environmental factors and provide a basis for continuing the investigation into the underlying genetic influences on HRV.

Premature aging of leukocyte DNA methylation is associated with type 2 diabetes prevalence.

BackgroundType 2 diabetes mellitus (T2D) is highly prevalent in Middle-Eastern and North African Arab populations, but the molecular basis for this susceptibility is unknown. Altered DNA methylation levels were reported in insulin-secreting and responding tissues, but whether methylation in accessible tissues such as peripheral blood is associated with T2D risk remains an open question. Age-related alteration of DNA methylation level was reported in certain methylation sites, but no association with T2D has been shown. Here we report on a population-based study of 929 men and women representing the East Jerusalem Palestinian (EJP) Arab population and compare with the findings among Israeli Ashkenazi Jews. This is the first reported epigenetic study of an Arab population with a characteristic high prevalence of T2D.ResultsWe found that DNA methylation of a prespecified regulatory site in peripheral blood leukocytes (PBLs) is associated with impaired glucose metabolism and T2D independent of sex, body mass index, and white blood cell composition. This CpG site (Chr16: 53,809,231-2; hg19) is located in a region within an intron of the FTO gene, suspected to serve as a tissue-specific enhancer. The association between PBL hypomethylation and T2D varied by age, revealing differential patterns of methylation aging in healthy and diabetic individuals and between ethnic groups: T2D patients displayed prematurely low methylation levels, and this hypomethylation was greater and occurred earlier in life among Palestinian Arabs than Ashkenazi Jews.ConclusionsOur study suggests that premature DNA methylation aging is associated with increased risk of T2D. These findings should stimulate the search for more such sites and may pave the way to improved T2D risk prediction within and between human populations.

Leukocyte telomere length and coronary artery calcification in Palestinians

OBJECTIVE Shorter leukocyte telomere length (LTL) is associated with higher incidence of coronary heart disease (CHD) and increased mortality. We examined the association of LTL with coronary artery calcification (CAC), which reflects the cumulative burden of coronary atherosclerosis, in an urban Arab sample of Palestinians, a population at high risk of CHD. METHODS Using a cross-sectional design, a random sample of East Jerusalem residents, comprising 250 men aged 45-77 and women aged 55-76 and free of CHD or past stroke, was drawn from the Israel national population register. LTL was measured by Southern blots. CAC was determined by 16-slice multidetector helical CT scanning using Agatston scoring. We applied multivariable logistic modeling to examine the association between sex-specific tertiles of LTL and CAC (comparing scores >100 vs. <100, and the upper third vs. the lower 2 thirds), controlling for age, sex, education and coronary risk factors. RESULTS CAC, evident in 65% of men and 52% of women, was strongly associated with age (sex-adjusted Spearmans rho 0.495). The multivariable-adjusted odds ratios for CAC >100 (found in 30% of men and 29% of women) were 2.92 (95% CI 1.28-6.68) and 2.29 (0.99-5.30) for the lower and mid-tertiles of LTL vs. the upper tertile, respectively (Ptrend = 0.008). Findings were similar for CAC scores in the upper tertile (Ptrend = 0.006), and persisted after the exclusion of patients with diabetes or receiving statins. CONCLUSIONS Shorter LTL was associated with a greater prevalence of asymptomatic coronary atherosclerosis in an urban Arab population-based sample. Mechanisms underlying this association should be sought.