Environmental mismatch and obesity in humans: The Jerusalem Perinatal Family Follow-Up Study.

BACKGROUND: According to the hypothesis of Gluckman and Hanson, mismatch between the developmental and postdevelopmental environments may lead to detrimental health impacts such as obesity. While several animal studies support the mismatch theory, there is a scarcity of evidence from human-based studies. OBJECTIVES: Our study aims to examine whether a mismatch between the developmental and young-adult environments affect obesity in young adults of the Jerusalem Perinatal Family Follow-Up Study. METHODS: Data from The Jerusalem Perinatal Family Follow-Up Study birth cohort was used to characterize early and late environments using offspring and parental sociodemographic and lifestyle information at birth, age 32 (n = 1140) and 42 (n = 404). Scores characterizing the early and late environments were constructed using factor analysis. To assess associations of mismatch with obesity, regression models were fitted using the first factor of each environment and adiposity measures at age 32 and 42. RESULTS: Having a stable non-beneficial environment at birth and young-adulthood was most strongly associated with increased adiposity, while a stable beneficial environment was most favorable. The transition from a beneficial environment at birth to a less beneficial environment at young-adulthood was associated with higher obesity measures, including higher BMI (ß = 0.979; 95% CI: 0.029, 1.929), waist circumference (ß = 2.729; 95% CI: 0.317, 5.140) and waist-hip ratio (ß = 0.017; 95% CI: 0.004, 0.029) compared with those experiencing a beneficial environment at both time points. Transition from a less beneficial environment at birth to a beneficial environment at adulthood was also associated with higher obesity measurements (BMI -ß = 1.116; 95% CI: 0.085, 2.148; waist circumference -ß = 2.736; 95% CI: 0.215, 5.256). CONCLUSIONS: This study provides some support for the mismatch hypothesis. While there is indication that an accumulation of the effects of the non-beneficial environment has the strongest detrimental impact on obesity outcomes, our results also indicate that a mismatch between the developmental and later environments may result in maladaptation of the individual leading to obesity.

Phenotypic and genetic variation in leptin as determinants of weight regain.

AIMS: Over 75% of obese subjects fail to maintain their weight following weight loss interventions. We aimed to identify phenotypic and genetic markers associated with weight maintenance/regain following a dietary intervention. SUBJECTS AND METHODS: In the 2-year Dietary Intervention Randomized Controlled Trial, we assessed potential predictors for weight changes during the 'weight loss phase' (0-6 months) and the 'weight maintenance/regain phase' (7-24 months). Genetic variation between study participants was studied using single-nucleotide polymorphisms in the leptin gene (LEP). RESULTS: Mean weight reduction was -5.5% after 6 months, with a mean weight regain of 1.2% of baseline weight during the subsequent 7-24 months. In a multivariate regression model, higher baseline high-molecular-weight adiponectin was the only biomarker predictor of greater success in 0- to 6-month weight loss (ß = -0.222, P-value = 0.044). In a multivariate regression model adjusted for 6-month changes in weight and various biomarkers, 6-month plasma leptin reduction exhibited the strongest positive association with 6-month weight loss (ß = 0.505, P-value < 0.001). Conversely, 6-month plasma leptin reduction independently predicted weight regain during the following 18 months (ß = -0.131, P-value < 0.013). Weight regain was higher among participants who had a greater (top tertiles) 6-month decrease in both weight and leptin (+3.4% (95% confidence interval 2.1-4.8)) as compared with those in the lowest combined tertiles (+0.2% (95% confidence interval -1.1 to 1.4)); P-value < 0.001. Weight regain was further significantly and independently associated with genetic variations in LEP (P = 0.006 for both rs4731426 and rs2071045). Adding genetic data to the phenotypic multivariate model increased its predictive value for weight regain by 34%. CONCLUSION: Although greater reduction in leptin concentrations during the initial phase of a dietary intervention is associated with greater weight loss in the short term, plasma leptin reduction, combined with the degree of initial weight loss and with genetic variations in the LEP gene, constitutes a significant predictor of subsequent long-term weight regain.

Predictors of long-term mortality in the elderly: the Dubbo Study.

BACKGROUND: This study examines the predictors of long-term all-causes mortality (ACM) in Australian senior citizens. METHODS: We have analysed ACM in a cohort of 2805 citizens, 1233 men and 1572 women aged ≥60 years, first examined in 1988 and followed for 20 years. Hazard ratios and 95% confidence intervals for ACM were obtained from Cox models employing conventional predictors. RESULTS: Over 20 years 66% of men (815/1233) and 53% of women (833/1572) died. Constant proportional hazard over the 20 years was demonstrated for all predictors, indicating similar relative hazard of ACM during long-term or short-term follow up. There was significant prediction of ACM by current smoking (hazard ratio 1.96, 95% confidence interval 1.57-2.43 in men; 1.67, 1.32-2.10 in women), high blood pressure (1.37, 1.03-1.81; 1.41, 1.07-1.86), diabetes (1.46, 1.17-1.82; 1.83, 1.43-2.34), impaired peak expiratory flow (1.39, 1.15-1.69; 1.80, 1.47-2.21), coronary heart disease at study entry in men (1.33, 1.13-1.57), physical disability (1.38, 1.13-1.68; 1.45, 1.17-1.79) and alcohol intake (0.82, 0.69-0.97; 0.77, 0.66-0.89 respectively). ACM was not significantly predicted by standard lipid parameters. Over the 20-year period smoking was associated with reduced survival of 41 months in men and 25 months in women, hypertension with reduced survival of 20 and 17 months, and diabetes with reduced survival of 24 and 30 months respectively. CONCLUSIONS: The findings confirm the contribution of cigarette smoking, hypertension and diabetes to ACM in senior citizens, conditions that are potentially amenable to intervention.

Cancer risk after exposure to treatments for ovulation induction.

Uncertainty continues as to whether treatments for ovulation induction are associated with increased risk of cancer. The authors conducted a long-term population-based historical cohort study of parous women. A total of 15,030 women in the Jerusalem Perinatal Study who gave birth in 1974-1976 participated in a postpartum survey. Cancer incidence through 2004 was analyzed using Cox's proportional hazards models, controlling for age and other covariates. Women who used drugs to induce ovulation (n = 567) had increased risks of cancer at any site (multivariate hazard ratio (HR) = 1.36, 95% confidence interval (CI): 1.06, 1.74). An increased risk of uterine cancer was found among women treated with ovulation-inducing agents (HR = 3.39, 95% CI: 1.28, 8.97), specifically clomiphene (HR = 4.56, 95% CI: 1.56, 13.34). No association was noted between use of ovulation-inducing agents and ovarian cancer (age-adjusted HR = 0.61, 95% CI: 0.08, 4.42). Ovulation induction was associated with a borderline-significant increased risk of breast cancer (multivariate HR = 1.42, 95% CI: 0.99, 2.05). Increased risks were also observed for malignant melanoma and non-Hodgkin lymphoma. These associations appeared stronger among women who waited more than 1 year to conceive. Additional follow-up studies assessing these associations by drug type, dosage, and duration are needed.

Consanguinity and birth defects in the jerusalem perinatal study cohort.

BACKGROUND: While parental consanguinity is known to increase the risk of birth defects in offspring, it is hard to quantify this risk in populations where consanguinity is prevalent. METHODS: To support ongoing studies of cancer and of psychiatric disease, we studied relationships of consanguinity to 1,053 major birth defects in 29,815 offspring, born in 1964-1976. To adjust for confounding variables (geographic origin, social class and hospital), we constructed logistic regression models, using GEE to take into account correlations between sibs. Odds ratios (ORs) and 95% confidence limits were estimated in comparison to a reference group of offspring with grandfathers born in different countries. RESULTS: With 10.1% of offspring having consanguineous parents, the adjusted OR for major birth defect was 1.41 (1.12-1.74). Offspring of marriages between uncles-nieces, first cousins and more distant relatives showed adjusted ORs of 2.36 (0.98-5.68), 1.59 (1.22-2.07) and 1.20 (0.89-1.59) respectively. For descendents of grandfathers born in the same country, but not known to be related, the OR was 1.05 (0.91-1.21); these showed increased risk associated with ancestries in Western Asia (1.27, 1.04-1.55, p < 0.02) or Europe (1.13, 0.79-1.80). CONCLUSIONS: A strong association of consanguinity with poverty and low education points to the need to avoid exposure to environmental hazards in these families.

Cholesteryl ester transfer protein (CETP) genetic variation and early onset of non-fatal myocardial infarction.

Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP -2708 G/A, -971 A/G, -629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (-2708 G, -971 G, -629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (-2708 G, -971 A, -629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4-14.8] and haplotype B (-2708 G, -971 G, -629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 - 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations.

Twin pregnancy and the risk of schizophrenia.

BACKGROUND: Twins are exposed to intrauterine environments that differ significantly from those of singletons. These diverse environments might alter the risk for schizophrenia in twins and make it difficult to generalize from findings in twins when studying the risk of schizophrenia in the general population. Previous studies report contradictory findings on the risk for schizophrenia in twins. METHODS: We studied the incidence of schizophrenia spectrum disorders, ascertained from Israel's National Psychiatric Registry, in a cohort of 2124 twins and 87,955 singletons. These offspring were followed from their birth in 1964-76 in the Jerusalem Perinatal study. Cox proportional hazards methods were used to compare outcomes over 28-41 years, adjusting for ages of parents. RESULTS: Twins showed a relative risk [RR] of .84 relative to singletons, with a 95% confidence interval [CI] of (.51-1.4). RRs and CIs for males and females were .68 [.34-1.4] and 1.1 [.55-2.2] respectively. Twins in male-male, female-female or opposite-sex sets showed no significant variation in RRs; furthermore, first- or second-born twins did not differ significantly from each other. Siblings of twins had the same risk of schizophrenia as siblings of singletons. CONCLUSION: Twins have the same risk for schizophrenia as the general population.

Acute maternal stress in pregnancy and schizophrenia in offspring: a cohort prospective study.

UNLABELLED: Schizophrenia has been linked with intrauterine exposure to maternal stress due to bereavement, famine and major disasters. Recent evidence suggests that human vulnerability may be greatest in the first trimester of gestation and rodent experiments suggest sex specificity. We aimed to describe the consequence of an acute maternal stress, through a follow-up of offspring whose mothers were pregnant during the Arab-Israeli war of 1967. A priori, we focused on gestational month and offspring's sex. METHOD: In a pilot study linking birth records to Israel's Psychiatric Registry, we analyzed data from a cohort of 88,829 born in Jerusalem in 1964-76. Proportional hazards models were used to estimate the relative risk (RR) of schizophrenia, according to month of birth, gender and other variables, while controlling for father's age and other potential confounders. Other causes of hospitalized psychiatric morbidity (grouped together) were analyzed for comparison. RESULTS: There was a raised incidence of schizophrenia for those who were in the second month of fetal life in June 1967 (RR = 2.3, 1.1-4.7), seen more in females (4.3, 1.7-10.7) than in males (1.2, 0.4-3.8). Results were not explained by secular or seasonal variations, altered birth weight or gestational age. For other conditions, RRs were increased in offspring who had been in the third month of fetal life in June 1967 (2.5, 1.2-5.2), also seen more in females (3.6, 1.3-9.7) than males (1.8, 0.6-5.2). CONCLUSION: These findings add to a growing literature, in experimental animals and humans, attributing long term consequences for offspring of maternal gestational stress. They suggest both a sex-specificity and a relatively short gestational time-window for gestational effects on vulnerability to schizophrenia.

Gestational diabetes as a risk factor for pancreatic cancer: a prospective cohort study.

BACKGROUND: Diabetes is known to be associated with cancer of the pancreas, though there is some debate as to whether it is a cause or a consequence of the disease. We investigated the incidence of pancreatic cancer in a cohort of 37926 Israeli women followed for 28-40 years for whom information on diabetes had been collected at the time they gave birth, in 1964-1976, in Jerusalem. There were 54 cases of pancreatic cancer ascertained from the Israel Cancer Registry during follow-up. METHODS: We used Cox proportional hazards models to adjust for age at baseline and explore effects of other risk factors, including ethnic groups, preeclampsia, birth order and birth weight of offspring. RESULTS: We observed no cases of pancreatic cancer in the women with insulin dependent diabetes; however, there were five cases in the women with gestational diabetes. The interval between the record of diabetes in pregnancy and the diagnosis of pancreatic cancer ranged from 14-35 years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1 (95% confidence interval, 2.8-18.0). CONCLUSION: We conclude that gestational diabetes is strongly related to the risk of cancer of the pancreas in women in this population, and that gestational diabetes can precede cancer diagnosis by many years.

Associations of socioeconomic position in childhood and young adulthood with cardiometabolic risk factors: the Jerusalem Perinatal Family Follow-Up Study.

BACKGROUND: Several stages in the life course have been identified as important to the development of cardiovascular disease. This study aimed to assess the associations of childhood and adulthood socioeconomic position (SEP) and social mobility with cardiometabolic risk factors (CMRs) later in life. METHODS: We conducted follow-up examinations of 1132 offspring, aged 32, within a population-based cohort of all births in Jerusalem from 1974 to 1976. SEP was indicated by parents' occupation and education, and adulthood SEP was based on offspring's occupation and education recorded at age 32. Linear regression models were used to investigate the associations of SEP and social mobility with CMRs. RESULTS: Childhood-occupational SEP was negatively associated with body mass index (BMI; ß=-0.29, p=0.031), fat percentage (fat%; ß=-0.58, p=0.005), insulin (ß=-0.01, p=0.031), triglycerides (ß=-0.02, p=0.024) and low-density lipoprotein cholesterol (LDL-C; ß=-1.91, p=0.015), independent of adulthood SEP. Adulthood-occupational SEP was negatively associated with waist-to-hip ratio (WHR; ß=-0.01, p=0.002), and positively with high-density lipoprotein cholesterol (HDL-C; ß=0.87, p=0.030). Results remained similar after adjustment for smoking and inactivity. Childhood-educational SEP was associated with decreased WHR and LDL-C level (p=0.0002), and adulthood-educational SEP was inversely associated with BMI (p=0.001), waist circumference (p=0.008), WHR (p=0.001) and fat% (p=0.0002) and positively associated with HDL-C (p=0.030). Additionally, social mobility (mainly upward) was shown to have adverse cardiometabolic outcomes. CONCLUSIONS: Both childhood and adulthood SEP contribute independently to CMR. The match-mismatch hypothesis may explain the elevated CMRs among participants experiencing social mobility. Identification of life-course SEP-related aspects that translate into social inequality in cardiovascular risk may facilitate efforts for improving health and for reducing disparities in cardiovascular disease.

The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.

BACKGROUND AND AIM: Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. CONCLUSIONS: These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.

Paternal age and spontaneous abortion.

OBJECTIVE: To evaluate the influence of paternal age upon spontaneous abortion. METHODS: This case-control study of 13,865 women draws on data from women's antenatal or postpartum interviews in the Jerusalem Perinatal Study, a population-based cohort derived from 92,408 births in 1964-1976. Case women (n=1,506) reported spontaneous abortion in the pregnancy preceding the interview; they were compared with women reporting live births in their previous pregnancy (n=12,359). Logistic regression was used to adjust for maternal age, maternal diabetes, maternal smoking, history of spontaneous abortions before the index pregnancy, parity at interview, and interval between the index pregnancy and the interview. RESULTS: The adjusted odds ratio for spontaneous abortion was 0.59 (95% confidence interval 0.45-0.76, P< .0001) for pregnancies conceived from fathers aged younger than 25 years compared with those from fathers aged 25-29 years. For fathers age 40 years or older the odds ratio for spontaneous abortion was 1.6 (95% confidence interval 1.2-2.0, P=.0003) when compared with the same reference group. CONCLUSION: Increasing paternal age is significantly associated with spontaneous abortion, independent of maternal age and multiple other factors.

Coronary heart disease risk factors among religious groupings in a Jewish population sample in Jerusalem.

The hypothesis that plasma lipids, blood pressure, smoking and dietary intake differed according to degree of religiosity was examined in a sample of Jewish residents of Jerusalem. Religiosity was classified according to the subject's self-ranking of his perceived degree of religiosity. Prevalence of smoking, and plasma levels of cholesterol, triglycerides, and low-density lipoprotein cholesterol were higher in secular participants than in the orthodox group. No differences in blood pressure and in high-density lipoprotein cholesterol were observed. Secular subjects consumed more total fat, more saturated fatty acids and less carbohydrate than religious subjects. These differences in nutrient intake among the religious groups reflected differences in their food selection, notably consumption of dairy products. These findings of parallel differences in plasma lipids and in dietary intake are consistent with the differing incidence of myocardial infarction in the religious groups which has been shown in the Israeli population.

Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins--the Jerusalem Nutrition Study: high MUFAs vs high PUFAs.

Twenty-six Yeshiva students were randomly assigned to a 24-wk crossover study of monounsaturated fatty acid (MUFA) vs polyunsaturated fatty acid (PUFA) diets (50% carbohydrate, 32% fat, 18% protein) fed alternately during two 12-wk periods. Total plasma cholesterol (TC) decreased significantly by approximately 10% and approximately 16% on the MUFA and PUFA diets, respectively. Plasma triglyceride response was variable. Low-density-lipoprotein cholesterol (LDL-C) decreased in both groups with an additional significant effect between periods. Concentrations of high-density-lipoprotein cholesterol did not change significantly. LDL-receptor status in fresh monocytes, affinity of LDL towards the LDL receptor in cultured fibroblasts, zonal-centrifugation profiles, and lipoprotein composition were not significantly different between the diets. There was a significantly higher tendency toward lipid peroxidation on the PUFA diet, as ascertained by more thiobarbituric acid-reactive-substances formation on that diet. Dietary PUFA results in somewhat lower TC and LDL-C concentrations whereas with MUFA the susceptibility of LDL to oxidative stress is lower.

Comparison of nutrient intakes of selected populations in the United States and Israel: the Lipid Research Clinics prevalence study.

Nutrient intakes of 2,772 US and 2,680 Jerusalem participants of the Lipid Research Clinics Program were assessed by 24-h dietary recall in men aged 15-19 and 40-59 yr and women aged 15-19 and 35-59 yr. Energy intake was higher in the US than in Jerusalem. In Jerusalem intake of total fat ranged between 32.2-33.7% of kcal, of saturated fatty acids (SFA) between 9.8-10.9%, of polyunsaturated fatty acids (PFA) between 7.9-8.6%, of carbohydrates between 50.5-53.9%, and of starch between 24.0-30.5%. The P:S ratio ranged between 0.80 and 1.01. The corresponding ranges for the US were 38.8-40.8% for fat, 14.3-15.9% for SFA, 5.9-6.8% for PFA, 38.9-46.2% for carbohydrates, 17.0-17.9% for starch, and 0.40-0.53 for the P:S ratio. Intake of cholesterol (mg/1000 kcal) was higher in Jerusalem than in the US. These data address the feasibility of reducing fat in diets of free-living, Western populations.

Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins--the Jerusalem Nutrition Study. II. Monounsaturated fatty acids vs carbohydrates.

Seventeen male Yeshiva students were randomly allocated to a crossover study with two 12-wk dietary periods of monounsaturated fatty acids (MUFAs) vs a carbohydrate (CHO)-rich diet while concentrations of saturated (SFAs) and polyunsaturated (PUFAs) fatty acids were kept similar. Total plasma cholesterol (TC) decreased significantly by approximately 7.7% and low-density-lipoprotein cholesterol (LDL-C) by 14.4% on the MUFA diet, whereas on the CHO diet no significant change in cholesterol concentrations occurred, in contrast to that predicted by the equations of Keys and Hegsted. Concentrations of high-density-lipoprotein cholesterol (HDL-C) did not change significantly on either diet. On the MUFA diet there was a significantly lower proneness to peroxidation of plasma and LDL lipids and less extensive metabolism of conditioned LDL by peritoneal macrophages. We conclude that dietary MUFAs lower TC and LDL-C concentrations, independently of other dietary fatty acids and in addition may reduce the susceptibility of LDL to oxidative stress.

Apolipoprotein B gene polymorphisms and serum lipids: meta-analysis of the role of genetic variation in responsiveness to diet.

BACKGROUND: The genetic variance determining plasma lipid and lipoprotein concentrations may modify individual responsiveness to alterations in dietary fat and cholesterol content. OBJECTIVE: The aim was to examine the role of apolipoprotein (apo) B DNA polymorphisms in responsiveness of plasma lipids and lipoproteins to diet. DESIGN: A controlled dietary intervention study was conducted in 44 healthy, middle-aged subjects with a 3-mo baseline, a 1-mo fat-controlled, a 1-mo high-fat, and a 1-mo habitual diet period. We also conducted a meta-analysis of all published dietary trials, including our own. RESULTS: In our own dietary study, the apo B XbaI restriction-site polymorphism affected the responsiveness to diet of the plasma LDL-cholesterol concentration (P < 0.05, repeated-measures analysis of variance). Especially during the high-fat diet, homozygous absence of the XbaI restriction site (X(-)/X(-)) was associated with a greater increase in LDL cholesterol (44 +/- 5%) than was X(+)/X(+) (27 +/- 7%) or X(+)/X(-) (40 +/- 5%). The high-fat diet also induced a larger increase in plasma LDL cholesterol in subjects with the R(-)/R(-) genotype (homozygous absence of the EcoRI restriction site) (59 +/- 10%) than in those with the R(+)/R(-) (39 +/- 6%) or R(+)/R(+) (36 +/- 4%) genotype. The M(+)/M(+) genotype (homozygous presence of the MspI restriction site) was also more responsive (41 +/- 3% increase in LDL cholesterol) than the M(+)/M(-) genotype (27 +/- 10% increase). The meta-analysis supported the finding of the significant role of the EcoRI and MspI polymorphisms, but not that of the XbaI polymorphism. CONCLUSIONS: The present study indicated that the apo B EcoRI and MspI polymorphisms are associated with responsiveness to diet.

Ageing and the mismatch repair system.

Age-related accumulation of mutations has been extensively documented, and it has been proposed as one of the prominent causes of malignancies in old age. The present review is focused on the particular case of DNA mismatch repair system (MMR), that has drawn increased attention for its possible relevance to malignancy. We also report on our own observations on an age-associated genomic instability that develops with age in the MMR system. Our study was performed on DNA samples that were prepared from peripheral blood cells, obtained at a 10-year interval from young and old human subjects. The two DNA samples from each individual were examined comparatively. The older individuals showed a significantly higher rate of microsatellite instability (MSI) in several loci examined, whereas no difference was found between the paired samples of any of the young subjects. We suggest that this increase in MSI with age may indicate an overall genomic instability in the elderly.

Sibling correlations of coronary heart disease risk factors in a sample of Israeli offspring with parental history of myocardial infarction.

Sibling correlations for coronary heart disease risk factors were analyzed in 731 pairs of siblings whose parents experienced a first myocardial infarction. Sibling correlations for lipids, lipoproteins and apolipoproteins ranged from 0.29 to 0.48, with limited changes on adjustment for sex, age, education and body mass index. For most lipid variables brother-brother correlation coefficients were highest and sister-brother correlation coefficients were lowest. Sib-sib correlation coefficients for lipids, lipoproteins, blood pressure and body mass index were similar to those estimated from a random sample of Jewish families. The sibling correlations were relatively low for waist to hip ratio, triceps and suprailiac skinfolds, moderate for subscapular skinfolds and body circumference measurements and high for number of cigarettes smoked by the siblings. The sibling correlations for lipid variables showed a moderate dependency on the apolipoprotein B XbaI genotypes. Siblings living in the same household tended to have higher correlation coefficients for HDL-C, apolipoprotein B and apolipoprotein AI than those living apart. The correlation coefficients for number of cigarettes and anthropometric variables tended to be heterogeneous due to the higher correlations among siblings living apart. A clear trend of decline in sib-sib correlations for apolipoprotein AI, glucose, cigarette smoking, body mass index and circumference measurements with increased spacing between sibling's ages was indicated. This temporal trend in sibling correlations for coronary heart disease risk factors suggests that genetic and/or environmental factors may have different influences at different ages.

Lipoprotein(a) is not associated with coronary heart disease in the elderly: cross-sectional data from the Dubbo study.

Lipoprotein(a) (Lp(a)) may be an independent risk factor for cardiovascular disease. We have examined Lp(a) concentration in 1202 males and 1512 females, aged 60 years and older, who were participants in an ongoing prospective study of cardiovascular disease in the elderly. This report relates to cross-sectional data at study entry. Median Lp(a) concentration was significantly higher in females than in males (P < 0.001), but did not vary with age. Lp(a) concentration rank was significantly correlated with total (r = 0.16, P < 0.001) and LDL cholesterol (r = 0.19, P < 0.001), but this relationship disappeared after adjustment of LDL cholesterol for Lp(a) cholesterol content. Twenty-four percent of males and 17% of females had prevalent coronary heart disease (CHD) at study entry based on non-invasive criteria. Median Lp(a) concentration was slightly higher in those subjects with CHD, compared with those without CHD, but the difference was not statistically significant (P > 0.20). In a multiple logistic model, the following variables were independent predictors of CHD in this elderly population: age, hypertension (males only), family history of CHD, HDL cholesterol and triglycerides (females only), but not total cholesterol or Lp(a). These relationships were similar whether or not the model included Lp(a) concentration. The findings do require confirmation in the prospective study now in progress.