Correlates of infection with Helicobacter pylori positive and negative cytotoxin-associated gene A phenotypes among Arab and Jewish residents of Jerusalem.

We examined the prevalence and correlates of Helicobacter pylori (H. pylori) infection according to cytotoxin-associated gene A (CagA) phenotype, a main virulence antigen, among the ethnically diverse population groups of Jerusalem. A cross-sectional study was undertaken in Arab (N = 959) and Jewish (N = 692) adults, randomly selected from Israel's national population registry in age-sex and population strata. Sera were tested for H. pylori immunoglobulin G (IgG) antibodies. Positive samples were tested for virulence IgG antibodies to recombinant CagA protein, by enzyme-linked immunosorbent assay. Multinomial regression models were fitted to examine associations of sociodemographic factors with H. pylori phenotypes. H. pylori IgG antibody sero-prevalence was 83.3% (95% confidence interval (CI) 80.0%-85.5%) and 61.4% (95% CI 57.7%-65.0%) among Arabs and Jews, respectively. Among H. pylori positives, the respective CagA IgG antibody sero-positivity was 42.3% (95% CI 38.9%-45.8%) and 32.5% (95% CI 28.2%-37.1%). Among Jews, being born in the Former Soviet Union, the Middle East and North Africa, vs. Israel and the Americas, was positively associated with CagA sero-positivity. In both populations, sibship size was positively associated with both CagA positive and negative phenotypes; and education was inversely associated. In conclusion, CagA positive and negative infection had similar correlates, suggesting shared sources of these two H. pylori phenotypes.

Body mass index and infectious disease mortality in midlife in a cohort of 2.3 million adolescents.

BACKGROUND: Obesity was linked to altered immunity, but also to favorable outcomes among patients with infectious disease (ID) in some settings. We assessed the association between adolescent body mass index (BMI) and ID mortality. METHODS: BMI of 2 294 139 Israeli adolescents (60% men; age 17.4±0.3 years) was measured between 1967 and 2010. The outcome, obtained by linkage with official national records, was death due to ID as the underlying cause. Multivariable Cox proportional hazards models were applied. RESULTS: During 42 297 007 person-years of follow-up (median 18.4 years), there were 689 deaths from ID (mean age 44.1±10.5 years). Adjusted hazard ratios (HR) were 1.039 (1.011-1.068) and 1.146 (1.099-1.194) among men and women, respectively, per unit increment in BMI (P for sex interaction=4.4 × 10-5). Adjusted hazard ratios among men were 1.2 (1.0-1.5), 1.9 (1.4-2.5) and 2.5 (1.5-4.2) for those with high-normal BMI (22.0-24.9 kg m-2), overweight and obese, respectively, compared with the 18.5⩽BMI<22 kg m-2 reference group, and 1.7 (1.1-2.6), 2.6 (1.6-4.3) and 6.6 (3.3-13.1) among women, respectively. The increased risk among underweight (<18.5 kg m-2) boys was attenuated when the study sample was restricted to those with unimpaired health at baseline. A multivariable spline model indicated a minimum risk for total ID mortality at 20.7 and 18.0 kg m-2 for men and women, respectively, with significantly increased risk seen above adolescent BMI values of 23.6 and 24.0 kg m-2, respectively. The association with BMI was particularly evident for bacterial infections (predominantly sepsis), airways and central nervous system infections (63% of the ID deaths). CONCLUSIONS: Adolescent overweight and obesity were strongly associated with ID mortality, especially of bacterial origin and among women.

Paternal Age and Transgenerational Telomere Length Maintenance: A Simulation Model.

Telomere length (TL) in offspring is positively correlated with paternal age at the time of the offspring conception. The paternal-age-at-conception (PAC) effect on TL is puzzling, and its biological implication at the population level is unknown. Using a probabilistic model of transgenerational TL and population dynamics, we simulated the effect of PAC on TL in individuals over the course of 1,000 years. Findings suggest a key role for an isometric PAC midpoint (PACmp) in modulating TL across generations, such that offspring conceived by males younger than the isometric PACmp have comparatively short telomeres, while offspring conceived by males older than the isometric PACmp have comparatively long telomeres. We further show that when cancer incidence escalates, the average PAC drops below the isometric PACmp and transgenerational adaptation to cancer ensues through TL shortening. We propose that PAC serves to maintain an optimal TL across generations.

A modified ambulatory arterial stiffness index is independently associated with all-cause mortality.

Dependence of the ambulatory arterial stiffness index (AASI) on data scattering interferes with its potential clinical relevance. We assessed the correlates and all-cause mortality associations of a modified AASI (s-AASI). AASI was derived from the 24-h diastolic vs. systolic blood pressure linear regression line, whereas s-AASI was derived by symmetric regression (bisecting the line of diastolic vs systolic and systolic vs. diastolic). Of 2918 patients 55% were women; age was 56 +/- 16 years and body mass index was 27.3 +/- 4.5 kg/m(2). Average 24-h ambulatory blood pressure was 138 +/- 16/78 +/- 10 mm Hg. Applying the modified method for calculating AASI yielded a different measure: the negative correlation between AASI and blood pressure dipping (r = -0.304, P < 0.0001) was abolished (r = +0.223, P < 0.0001), s-AASI was more dependent on age (r = 0.266 vs. r = 0.089 for AASI), and prediction of all-cause mortality was enhanced; hazard ratio (95% confidence intervals) 1.17 (1.00-1.36) per 1 s.d. increase in s-AASI in the fully adjusted model as compared with 1.15 (0.97-1.36) for AASI.

Pyridoxal phosphate as an antisickling agent in vitro.

Although pyridoxal phosphate is known to inhibit gelation of purified hemoglobin S, antisickling activity has never been demonstrated for intact erythrocytes. We incubated washed erythrocytes at 37 degrees C either in buffer alone, or with added pyridoxal phosphate or pyridoxal, washed these cells, suspended them in untreated buffer, and compared the percent modified hemoglobin, the oxygen affinity, and the extent of sickling under hypoxia. Pyridoxal phosphate modified intracellular hemoglobin more slowly than pyridoxal. Pyridoxal phosphate lowered the oxygen affinity of normal cells, but had no effect on oxygen binding by sickle cells. Pyridoxal increased the oxygen affinity of normal and sickle erythrocytes equally. Pyridoxal phosphate significantly inhibited sickling of sickle or sickle trait erythrocytes (P less than 0.001). Inhibition of sickling by pyridoxal phosphate was largely independent of oxygen binding; whereas inhibition of sickling by pyridoxal was almost entirely dependent on increased oxygen binding. Although pyridoxal phosphate and pyridoxal both inhibit sickling by modification of hemoglobin S, they differ in the kinetics of whole cell modification, the effect on oxygen affinity of intact cells, and the mechanism of action of the antisickling activity.

Inhibition of erythrocyte sickling in vitro by pyridoxal.

To test the antisickling activity of pyridoxal, we compared the oxygen affinity and the percent sickling at low PO2 of untreated erythrocytes with values for cells from the same blood sample incubated with pyridoxal, glyceraldehyde, or pyridoxine. Pyridoxal increased oxygen affinity much more than glyceraldehyde. 20 mM pyridoxal and glyceraldehyde had equivalent antisickling activity. At PO2 levels above 20 mm Hg, both agents reduced sickling to less than 2%. In samples examined by electron microscopy, pyridoxal reduced the percent sickled cells and the percent cells that contain hemoglobin S fibers by the same amount (from 74 to 3%). Pyridoxine had no effect on oxygen affinity or sockling. Pyridoxal reacts with intracellular hemoglobin to increase oxygen affinity, which inhibits hemoglobin S polymerization and sickling.

Paternal age and risk of testicular germ cell tumors: a cohort study of 1,000,000 men.

Testicular germ cell tumors (TGCT) are the most frequent cancer among young men, with increasing incidence worldwide. Advanced paternal age has been linked to adverse health outcomes in offspring, but reports on the association of paternal age with TGCT are few and inconsistent. We aimed to examine the relationship of paternal age (PAB) at birth with the risk of TGCT and by histologic type: seminoma and non-seminoma. A population-based cohort of 1,056,058 males, examined at ages 16-19 between the years 1980-2011, was linked to the Israel National Cancer Registry to obtain incident TGCT through 2012. We applied multivariable Cox regression. During 16.5 million person-years of follow-up, 1247 incident cases (604 seminomas and 643 non-seminomas) were detected. Increasing PAB was linearly associated with lower risk of TGCT (HRper year  = 0.983, 95% CI: 0.974-0.993, p = 0.001), after adjustment for year of birth, years of education, height, cryptorchidism history and origin, and also with additional adjustment for maternal age at birth (MAB) (HRper year  = 0.980: 0.965-0.995, p = 0.008). The association was stronger for seminoma (HRper year  = 0.968: 0.946-0.989, p = 0.004) and persisted in a subset adjusted for sibship size (HRper year  = 0.950: 0.917-0.983, p = 0.003). In the fully adjusted model, young PAB (15-24 vs. ≥30) was a risk factor for seminoma (HR = 1.41: 1.07-1.85, p = 0.014). In models adjusted for PAB, MAB was not associated with risk of TGCT. In conclusion, our findings suggest that young paternal age is a risk factor of TGCT, especially seminoma. The findings warrant further investigation into the possible impact of young paternal age on their offsprings' testes.

Serum vitamin A (retinol) and cancer incidence in Evans County, Georgia.

A total community sample of 3,102 individuals from Evans County, Georgia, was followed for 12-14 years. During this period, 129 documented new cases of cancer were ascertained from medical records and death certificates. Cases were considered for inclusion only if documented at least 12 months after subjects were inducted into the cohort study. Cases were classified as definite, probable, and possible by strict criteria. Blood samples were drawn at the beginning of the study in 1960-62 and sera were frozen. Serum vitamin A (retinol) levels were measured in 1976 on the stored sera of 85 cancer patients and for 174 age-, race-, and sex-matched controls. Retinol estimations were performed by a fluorometric method after alumina column separation. Experiments conducted to simulate the exposure to light, thawing, and refreezing that sera may have undergone during the 14-16 years of storage showed retinol to be quite stable in response to these possible insults. As compared to controls, persons that eventually developed cancer had significantly lower mean serum retinol levels at least 12 months before the cancer diagnosis. The association was in the same direction for all 4 race-sex groups, although stronger overall for males than females, and was consistent for the various cancer sites and cell types. Both matched and regression residual analyses were used to control for the confounding variables considered: age, race, sex, obesity, social class, and smoking.

Plasma homocysteine and parental myocardial infarction in young adults in Jerusalem.

BACKGROUND: A causal role for mildly elevated plasma homocysteine (tHcy) in cardiovascular disease remains undetermined. To address the unresolved issue of the antecedent-consequent directionality of the relationship, we assessed the familial association of tHcy with parental myocardial infarction (MI) in young Israeli men and women. We also compared tHcy concentrations in Jerusalem, where rates of coronary heart disease (CHD) are high, with the United States Third National Health and Examination Survey (NHANES III). METHODS AND RESULTS: A total of 8646 17-year-olds and 6952 parents were examined from 1976 to 1979 in Jerusalem. At ages 28 to 32 years, offspring of parents who experienced a documented MI during a 10-year follow-up (n=133 men, 62 women; 72% response) and offspring of CHD-free parents (n=389 men, 208 women; 71% response) were reexamined. tHcy levels were determined by the same laboratory for the NHANES non-Hispanic white population aged 25 to 34 years (n=379) and the Jerusalem population sample (n=858). Men from Jerusalem, but not women, had clearly higher tHcy levels than the sample from the United States (90th percentile, 23 versus 14 micromol/L). This difference was largely attributable to lower plasma vitamin B12 levels in the Israeli population. Male case offspring had higher adjusted tHcy than did controls (1.9 micromol/L, P=0.002). Logistic modeling revealed a graded increase in risk of parental MI across quintiles of offspring tHcy, with an adjusted odds ratio of 2.7 in the 5th quintile (P=0.0026 for trend). CONCLUSIONS: The higher tHcy in young male offspring of parents with CHD suggests that elevated tHcy precedes manifestation of CHD. The elevated population tHcy in men may contribute to the high incidence of CHD in Israel.

Are lean smokers at increased risk of lung cancer? The Israel Civil Servant Cancer Study.

BACKGROUND: Whether leanness is related to an increased risk of lung cancer is controversial. OBJECTIVE: To examine the association of leanness with lung cancer incidence in a sample of Israeli men. METHODS: The 23-year lung cancer incidence (1963 through 1986) was determined by linkage to the Israel Cancer Registry in 9975 male civil servants aged 40 through 69 years at initial examination in 1963. In 198,298 person-years of follow-up, 153 cases of lung cancer were identified. In 1963, body mass index (BMI) and cigarette smoking status were determined; in the 1968 reexamination, lung function tests were performed and BMI was reassessed. RESULTS: Adjusted for age, smoking, and city by Cox regression, BMI was exponentially inversely related to lung cancer incidence, with a relative risk of 2.3 (95% confidence interval [CI], 1.4 to 3.8) comparing the lowest fifth of BMI (< 22.93 kg/m2) with the highest. The association was evident in light, moderate, and heavy smokers. Among smokers, the adjusted relative risk was 3.7 (95% CI, 1.9 to 7.3) for the lowest fifth of BMI. The associations were stronger for men in the lowest 10th of the BMI distribution (< 21.38 kg/m2). Controlling for lung function did not materially change the results. The adjusted population-attributable fraction associated with the lowest fifth of BMI among smokers was 20.4% (95% CI, 10.1% to 29.9%). Survival analysis showed that the association of BMI with lung cancer persisted throughout follow-up. CONCLUSIONS: The association shown between thinness and lung cancer incidence, particularly in smokers, was not attributable to the confounding factors studied, preclinical weight loss, or competing risks. Thinness in smokers may lead to, or may reflect, enhanced host susceptibility.

Low protective PON1 lactonase activity in an Arab population with high rates of coronary heart disease and diabetes.

BACKGROUND: Recent studies showing that high density lipoproteins (HDL) can effect plaque regression indicate that recent trial failures do not exclude an atheroprotective role of HDL. Instead, they highlight differences between HDL function and measured HDL-cholesterol (HDL-C). PON1 is one key functional activity of HDL. Urban Palestinians have lower HDL-C and a higher incidence and mortality of coronary heart disease than those of Israelis. We hypothesized that the cardioprotective PON1 lactonase and arylesterase activities and PON1 functional genotype may differ between Palestinians and Israelis. METHODS: We measured PON1 activities in a cross-sectional population-based study of Palestinian (n=960) and Israeli (n=694) residents in Jerusalem, 1654 participants in all. RESULTS: Palestinians had high prevalences of obesity and diabetes and low mean concentrations of HDL-cholesterol (0.97 mmol/l in men and 1.19 mmol/l in women). Lactonase and arylesterase activities were lower by 10.8% (p=1.2∗10(-14)) and 2.7% (p<0.0005), respectively, in Palestinians as compared to Israelis. The functional genotype distribution, demonstrated by plotting paraoxonase vs lactonase activities, showed a modest between-group difference (p=0.024), with 12.1% RR in Palestinian Arabs vs 8.4% in Israeli Jews, but no overall difference in allele frequencies. Lactonase correlated inversely with age (Spearman's rho=-.156), weakly with BMI (-.059), positively with HDL-C (.173) and non-HDL-C (.103), but was not associated with triglycerides or fasting glucose. Palestinians showed consistently lower lactonase activity in logistic regression models adjusted for multiple covariates and for functional genotype (odds ratios of 1.81 and 1.98, respectively, for the lower fifth vs the upper 4 fifths of lactonase activity p<0.0001). CONCLUSION: We showed a lower physiologically-significant lactonase PON1 activity in an Arab population, a finding consistent with the high cardiovascular and diabetes risk of Palestinians.

An ultrastructural study of subacute combined degeneration of the spinal cord in vitamin B12-deficient rhesus monkeys.

Prolonged deprivation of vitamin B12 in rhesus monkeys produced changes in the central nervous system that were indistinguishable topographically and histologically from those of human subacute combined degeneration. Ultrastructural studies of early lesions of the spinal cord disclosed a degeneration of myelin characterized by separation of myelin lamellae and formation of intramyelinic vacuoles, leading eventually to complete destruction of myelin sheaths. At a later stage, there was degeneration and loss of axons, and marked gliosis. The theories of pathogenesis of subacute combined degeneration are reviewed in the light of these observations.

The effects of pyridoxine on pituitary hormone secretion in amenorrhea-galactorrhea syndromes.

Six patients with amenorrhea, five of whom had galactorrhea and elevated PRL levels, were evaluated on a metabolic ward. All had normal sella tomograms, normal thyroid functions, and routine laboratory evaluations. None of the patients had taken any medication in the previous 6 months. On alternate days, five patients received 500 microgram of TRH iv with the measurement of PRL, TSH, FSh, LH, and hGH; 500 mg L-dopa orally with the measurement of PRL, FSH, and LH; a bolus infusion of 300 mg pyridoxine (B6) with measurement of PRL, hGH, TSH, FSH, and LH; and 25 mg chlorpromazine (CPZ) im with the measurement of PRL, LH, and FSH. The patients were then discharged on 600 mg oral pyridoxine/day and were readmitted for a repeat of the complete protocol 21 days later. The patients were continued on 600 mg oral pyridoxine for 3-4 months with monthly evaluations of serum PRL, LH, and FSH levels. These evaluations continued for 3 months after discontinuing pyridoxine. There was no demonstrable change in serum PRL after acute or chronic B6 therapy, mor was there a significant change in the response of PRL to CPZ, L-dopa, or TRH. The mean basal PRL was 97.5 +/- 9.7 ng/ml and after 3-4 months of oral pyridoxine was 97.1 +/- 14.8. In addition, there was no significant change in LH or FSH levels in response to acute or chronic B6, TRH, L-dopa, or CPZ. Neither acute B6 infusion nor chronic B6 therapy had any effect on TSH or the TSH response to TRH. Finally, acute B6 infusion had no effect on hGH levels and there were no paradoxical hGH responses to TRH. Two patients began having regular menses while on chronic pyridoxine. Their hormonal responses did not differ from those of the group, however.

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.

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.

Neuropathology of experimental vitamin B12 deficiency in monkeys.

We have produced severe vitamin B12 deficiency in rhesus monkeys by feeding them a defined experimental diet under controlled conditions. Five years after institution of the deficient diet, the morphology and counts of peripheral blood and bone marrow are normal. Gross visual impairment appeared in five of the monkeys between 33 and 45 months after the institution of the vitamin B12 deficient diet. Subsequently, in three of the visually impaired animals, a gradually progressive spastic paralysis of their hind limbs developed. Autopsies of six deficient animals showed degeneration of the peripheral visual pathway in all and of white matter in the spinal cord in four. Degeneration of several cranial nerve roots was found in four monkeys and a mild diffuse degeneration of cerebral white matter in four. The lesions in all affected parts of the central nervous system were bilaterally symmetrical and were indistinguishable from those due to B12 deficiency in the human. No abnormalities were found in one B12 supplemented control animal.

Plasma Lp(a), apolipoprotein(a) isoforms and acute myocardial infarction in men and women: a case-control study in the Jerusalem population.

The relationship of Lp(a) with manifestations of coronary heart disease (CHD) has not been studied extensively in women. There is little information as to the association of the unique Lp(a) apolipoprotein moiety (apo(a)) with CHD in either men or women. We therefore assessed the association of the apo(a) polymorphism and of Lp(a) with first acute myocardial infarction (MI) in a population-based case-control study in Jewish residents of Jerusalem between the ages of 25 and 64. The patients consisted of 238 men and 47 women hospitalized for a first acute MI in the 4 hospitals of Jerusalem serving the population (70% response rate among all first MI patients). The control subjects comprised 318 men and 159 women sampled from the national population registry and who were free of CHD (75% response). Lp(a) and apo(a) were measured in plasma stored at -20 degrees C for 6-24 months. Among men, plasma Lp(a) concentrations were higher in cases than controls in both univariate and multivariate analyses. The elevated risk was limited to the upper fifth of the Lp(a) distribution (unadjusted odds ratio = 1.65, P < 0.01 vs. the lower four quintiles, multivariable odds ratio = 1.82, P < 0.01). Among women, Lp(a) was not elevated in acute MI patients. Apo(a) isoforms with a B, S1 or S2 band (associated with higher Lp(a) values and having lower molecular weights) were more prevalent in female MI cases than controls (unadjusted odds ratio = 2.5, P = 0.016). This association could not be attributed to the higher Lp(a) concentrations associated with these isoforms and was not seen in men. In conclusion, our study points to an association of the apo(a) isoforms with acute MI in women, not evident in this population sample in men. Previously described associations of elevated Lp(a) with acute MI were confirmed in men but not in women. While the role of chance and inadequate statistical power cannot be excluded, the suggestion of a sex difference in the strength of these associations deserves further investigation, as does the question of whether apo(a) phenotype contributes to risk independently of Lp(a) level.

Aggregation of plasma lipids and lipoproteins in families with and without coronary heart disease.

Familial aggregation of total plasma cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) was analyzed in 37 families with incidence cases of first myocardial infarction (MI), in 154 families of coronary heart disease (CHD) prevalence cases and in control families. Fasting plasma lipid levels were adjusted for age, sex, country of origin and season of year. Mean TC, LDL-C and TG levels were higher among cases, their spouses and among 17-year-old children of incidence cases than among control families. HDL-C was lower among cases and among wives of incidence cases than in their controls. No differences in HDL-C were noted among children. Mid parent-child correlations for TC and LDL-C were higher in 32 families of men who had a MI (r = 0.43 and r = 0.49) than for control families (r = 0.32 and r = 0.29, respectively). When the 5 families of mothers who had a first MI were included in the analysis, the case-child correlations for TC and LDL-C were 0.60 and 0.68, respectively. Father-child correlation for HDL-C was significantly lower (r = -0.17) among the MI incidence case families than among the control families (r = 0.22; P less than 0.05). No substantial differences in familial correlations for lipid variables were noted in the CHD prevalence families and their controls. These findings suggest that total cholesterol and LDL-C levels, but not HDL-C levels, may be a risk marker in adolescents. The associations evident in adolescent children of families with MI incidence cases were not apparent in children whose parents had CHD on entering the study. This could be due to the probably greater misclassification of CHD prevalence cases than MI incidence cases, the awareness in patients with CHD and subsequent behavioural changes, to possible differences in patterns of survival in the two categories, or may reflect a chance finding.

Familial aggregation of coronary heart disease: partial mediation by high density lipoproteins?

The potential explanation of coronary heart disease inheritance by the major coronary risk factors was explored in a random sample of 1044 males, aged 40-70 years, who formed part of the Jerusalem Lipid Research Clinic Prevalence Study. Standardised data were available on personal and family history, coronary risk factors, resting and exercise electrocardiography. Twelve percent of subjects had coronary heart disease (previous myocardial infarction or electrocardiographic changes) and 20% had a family history of heart attack before 60 years in first degree relatives. In the presence of a family history of heart attack, the mean level of high density lipoprotein-cholesterol (HDL-C) was 5 mg/dl lower in cases of coronary heart disease than in controls. No such difference existed in the absence of a family history of heart attack. In multiple logistic regression, HDL-C was a significant negative predictor of coronary heart disease presence, but only in subjects having a positive family history. A 1 standard deviation (10 mg/dl) increment in HDL-C was associated with a two-thirds reduction in heart disease risk. Other risk factors did not predict the occurrence of coronary heart disease to any significant extent in subjects with a positive family history of heart attack. In an overall logistic model combining family history with other risk factors, the significant predictors of heart disease were: age, total plasma cholesterol, hypertension, family history and HDL-C. The interaction term, family history X HDL-C, was also a significant negative predictor of heart disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The contribution of candidate genes to the response of plasma lipids and lipoproteins to dietary challenge.

The possible role of four candidate genes in lipid and lipoprotein response to diet was examined in 214 members of two large kibbutz settlements in Israel. Four site polymorphisms (signal peptide insertion/deletion, XbaI, EcoRI and MspI) of the apo B gene, the common apo E genotypes, three common mutations (T-93G, S447stop and N291S) of the LPL gene and the CETP I405V RFLP were determined. The average reduction induced by diet in participants with the absence of the EcoRI restriction site (L4154) of the apo B gene compared with those found to be homozygotes for the restriction site (G/G4154) were: 16.2 and 8.0 mg/dl for total cholesterol (TC) (P=0. 01); and 15.6 and 6.2 mg/dl for LDL-C (P=0.007), respectively. TC and LDL-C baseline levels were significantly different among the apo-E genotypes, yet there were no significant effects on lipid and lipoprotein dietary response. Triglyceride baseline values were significantly lower (P=0.007) among subjects with the LPL S447stop mutation and HDL-C was significantly lower (P=0.008) among subjects found to be heterozygous for the LPL N291S mutation. A heterogeneous response for triglyceride was observed for individuals with the S291 allele as compared to those individuals who were found to be homozygous for the N291 allele. No differences in dietary responsiveness were observed among the apo E and CETP genotypes. In conclusion, our results suggest that sequence variation(s) in the coding region of the apo B gene linked to the EcoRI polymorphism are associated with total cholesterol and LDL-C responsiveness to dietary manipulation. In our study population, LPL mutations had a significant effect on TG and HDL-C baseline levels and on their response to diet.