Meta-analysis on anxiety and depression in adult celiac disease.

OBJECTIVE: We used meta-analysis to test hypotheses concerning whether adult celiac disease is reliably linked with anxiety and/or depression. METHOD: We examined published reports on anxiety and depression in adult celiac disease. RESULTS: Eighteen studies on depression and eleven studies on anxiety in adult celiac disease met selection criteria. They show that depression is reliably more common and/or more severe in adults with celiac disease than in healthy adults (overall meta-analysis effect size: 0.97). The fail-safe margin of unpublished reports that would be required to negate the finding exceeds 8000. Adults with celiac disease do not, however, differ reliably in terms of depression from adults with other physical illnesses, nor do they differ reliably from healthy adults or adults with other physical illnesses in terms of anxiety. CONCLUSION: Depression is common in adult celiac disease and resembles the condition in other physical illnesses. We view the findings as support for the notion that non-specific mechanisms mediate emotional disorders in adult celiac disease.

Trends in lifestyle coronary risk factors in the Danish MONICA population 1982-1992.

Myocardial infarction incidence rate declined 3-5% per year during 1982-1992 in the Danish study population of the WHO MONICA Project. We examined whether smoking habits, alcohol intake, dietary habits and physical activity levels changed in the population during the same period. Data from 6695 men and women of ages 30, 40, 50 and 60 y, examined in 1982-4, in 1986-7, and in 1991-2, were analysed to estimate trends. A summary healthy eating index and six scores derived by factor analysis were used to analyse food frequency data. The percentage of smokers declined 1.6% per year in men, and 1.0% per year in 30-, 40- and 50-y-old women, but increased 0.9% per year in 60-y-old women. The percentages of heavy cigarette smoking men and women nevertheless remained constant and close to 30%. Total alcohol intake declined among 30-y-olds, but appeared constant in other age groups. However, among 60-y-old men and among women over 30, the percentage of wine-drinkers rose from 6-11% in 1982-4 to 9-18% in 1991-2. Only 60-y-old men became more physically active at work and only 30-y-old women more so in leisure times. The percentage of individuals with a low healthy eating index decreased and the percentage with a high index increased. More importantly, dietary factor scores showed trends suggesting that very profound and potentially beneficial changes in dietary habits occurred. Lifestyle in the DAN-MONICA population changed in several ways that may have contributed to the declining incidence of myocardial infarction during the 1980s.

Survival and cause of death after myocardial infarction: the Danish MONICA study.

As part of the Danish WHO MONICA study, a register of patients with myocardial infarction was established in 1982, covering 11 municipalities in the western part of Copenhagen County, Denmark. During the period 1982-91, all cases of myocardial infarction among citizens aged 25-74 years were registered and validated according to the criteria set up for the WHO MONICA project. Short-term (28 days) and long-term (up to 15 years) survival in three periods were compared. The rate of mortality after a non-fatal myocardial infarction was compared with that of the general population, and causes of death were analyzed. Short-term survival did not change during the study period, whereas long-term survival improved for men but did not change for women. The excess mortality rate among female patients over that of the general population was due to ischemic heart disease, other cardiovascular diseases, cancer and other diseases. The excess mortality among male patients was due only to cardiovascular diseases.

Regional and hormone-dependent effects of apolipoprotein E genotype on changes in bone mineral in perimenopausal women.

We studied 479 perimenopausal Danish women aged 45-58 years to examine differences between APOE genotypes with respect to (1) baseline total body bone mineral density (BMD) and densities measured in five different regions (ultradistal forearm, proximal forearm, lumbar spine, femoral neck, and total hip region); (2) serum levels of alkaline phosphatase, bone isoenzyme alkaline phosphatase, osteocalcin, parathyroid hormone (PTH), 25-hydroxyvitamin D, and urine hydroxyproline/creatinine excretion ratio; and (3) changes in bone mineral during 5 years of follow-up. Baseline BMDs were identical, whereas serum levels of alkaline phosphatase and its bone isoenzyme were higher in women with APOE 2-2 and APOE 2-3 than in women with APOE 3-3 and APOE 3-4 and lower in women with APOE 4-4. Among women not receiving hormonal-replacement therapy (HRT; n = 262), those with APOE 2-2 and APOE 2-3 had 30-40% lower rates of femoral neck and total hip bone mineral loss than women with APOE 3-3 and APOE 3-4, whereas the rates of mineral loss in other skeletal regions did not differ between these APOE genotypes. Women with APOE 4-4 appeared to have lower rates of bone mineral loss in all regions. Women treated with hormones throughout the follow-up period (n = 113) gained bone mineral, and women with APOE 3-4 and APOE 4-4 gained relatively more mineral than other women. A comparison of untreated and treated women with APOE 2-3, APOE 3-3, and APOE 3-4 suggests a possible modification of the effect of APOE genotype by HRT. In conclusion, the common APOE polymorphism has a complex effect on bone metabolism in perimenopausal Danish women including possible modification by hormone use: (1) among women not receiving HRT, those with APOE*2 have lower bone mineral losses in the femoral neck and hip region than other women, and (2) among women receiving HRT, those with APOE*4 gain more bone mineral than other women.

Dietary patterns and mortality in Danish men and women: a prospective observational study.

The analysis of dietary patterns emerged recently as a possible approach to examining diet-disease relation. We analysed the risk of all-cause and cardiovascular mortality associated with dietary patterns in men and women, while taking a number of potential confounding variables into account. Data were from a prospective cohort study with follow-up of total and cause-specific mortality. A random sample of 3698 men and 3618 women aged 30-70 years and living in Copenhagen County, Denmark, were followed from 1982 to 1998 (median 15 years). Three dietary patterns were identified from a twenty-eight item food frequency questionnaire, collected at baseline: (1) a predefined healthy food index, which reflected daily intakes of fruits, vegetables and wholemeal bread, (2) a prudent and (3) a Western dietary pattern derived by principal component analysis. The prudent pattern was positively associated with frequent intake of wholemeal bread, fruits and vegetables, whereas the Western was characterized by frequent intakes of meat products, potatoes, white bread, butter and lard. Among participants with complete information on all variables, 398 men and 231 women died during follow-up. The healthy food index was associated with reduced all-cause mortality in both men and women, but the relations were attenuated after adjustment for smoking, physical activity, educational level, BMI, and alcohol intake. The prudent pattern was inversely associated with all-cause and cardiovascular mortality after controlling for confounding variables. The Western pattern was not significantly associated with mortality. This study partly supports the assumption that overall dietary patterns can predict mortality, and that the dietary pattern associated with the lowest risk is the one which is in accordance with the current recommendations for a prudent diet.

Trends in incidence, case-fatality and recurrence of myocardial infarction in the Danish MONICA population 1982-1991.

BACKGROUND: Growing awareness of risk factors for myocardial infarction (MI), continuous mass campaigns on lifestyle factors, increasing use of heart rehabilitation and improved treatment should imply decreases in the incidence, case-fatality and recurrence rates of MI. The purpose of the study was to assess trends in the incidence, case-fatality and recurrence rate of MI and to analyse whether any changes seen were due to a period or a cohort effect. METHODS: The Danish MONICA population comprises all men and women aged 25-74 years in the period 1982-1991 living in a suburban area of Copenhagen, Denmark. Fatal and non-fatal attacks classified as definite MI and non-fatal attacks classified as possible MI were included. The incidence rate was analysed by Poisson regression, the case-fatality rate by logistic regression, and the rate of recurrence by Cox regression. Age-period-cohort analyses were carried out according to a method described by Clayton and Schifflers. RESULTS: During the 10-year period a significant decrease in the incidence rate of MI was seen for men and women and for the rate of recurrent MI. The decrease in incidence and recurrence could not unambiguously be ascribed to a period or cohort effect. The rate of case-fatality after a first MI was not changed significantly during the period, whereas men and women had different trends in case-fatality after recurrent MI. CONCLUSIONS: In accordance with results from other Western countries we found a decline in the incidence and recurrence rate of MI. Contrary, the lack of a decrease in the case-fatality rate after a first MI was unexpected and difficult to explain.

[Trends in selected biological risk factors of cardiovascular diseases in the Danish MONICA population 1982-1992]. / Udviklingen i udvalgte biologiske risikofaktorer for kardiovaskulaere sygdomme i den danske MONICA-population 1982-1992.

INTRODUCTION: The incidence rate of a first myocardial infarction declined 3-5% annually in the Danish WHO MONICA population in the period from 1982 to 1991. The aim of this study was to investigate whether levels of the most commonly considered biological traits associated with cardiovascular risk have changed in the Danish MONICA population during this period. METHOD: Data from 6,695 men and women of 30, 40, 50 and 60 years of age, examined in the Danish WHO MONICA surveys in 1982-1984, 1986-1987, and 1991-1992, were analysed to estimate temporal trends in body height and weight, blood pressure, and serum total, HDL, and LDL cholesterol, and triglyceride. RESULTS: Body height increased by 0.1% per year and the body mass index by 0.4% per year in women. The diastolic blood pressure increased 0.4% per year in women and 0.6% per year in 60-year-old men. HDL cholesterol declined 0.4% per year. Body mass indices in men, diastolic blood pressures in men < 60 years of age, systolic blood pressures, total and LDL cholesterol and triglyceride did not change. DISCUSSION: The levels of biological risk factors in the Danish WHO MONICA study population did not show trends during the 1980s that contribute to explain the declining incidence of myocardial infarction in the population.

Estimation of apolipoprotein E genotype-specific relative mortality risks from the distribution of genotypes in centenarians and middle-aged men: apolipoprotein E gene is a "frailty gene," not a "longevity gene".

We developed a method to estimate genotype-specific average relative mortality risk, R, from genotype distributions in cross-sectional studies of people belonging to different age-groups, and applied the method to new data from a study of apolipoprotein E genotypes (apoE) in 177 Danish centenarians and data from a study of 40-year-old Danish men. Twenty-one percent of the centenarians were epsilon 2-carriers (genotypes epsilon 2 epsilon 2 and epsilon 3 epsilon 2) and 15% were epsilon 4-carriers (genotypes epsilon 4 epsilon 4 and epsilon 4 epsilon 3) compared to 13 and 29%, respectively, of the young men. The R-values were 0.95 (95% CI 0.88 to 1.02) for epsilon 2-carriers and 1.13 (95% CI 1.05 to 1.22) for epsilon 4-carriers, using epsilon 3 epsilon 3- and epsilon 4 epsilon 2 genotypes as reference. Corresponding values for epsilon 4-carriers were obtained by using published data from a French and a Finnish study of centenarians, whereas the values for epsilon 2-carriers were about 0.90 with these data. The method to estimate mortality risk and the results associate with the view that the apoE gene is a "frailty gene." On the other hand, if odds ratios are used to summarize data from studies of this kind, they are more impressive and may propagate the misconception that apoE is a "longevity gene".

Apolipoprotein E genotype is associated with differential expansion rates of small abdominal aortic aneurysms.

BACKGROUND: The common polymorphism of the apolipoprotein E (APOE) gene is associated with differential risk of atherosclerosis; the gene could be a candidate gene in abdominal aortic aneurysms (AAA). METHODS: APOE genotypes were determined in 57 men aged 65-73 years with a small AAA (30-50 mm). The patients were included in a population ultrasonographic screening programme and were followed with at least two examinations during an interval of 2-4.5 years. The AAA expansion rates in patients with four different APOE genotypes were studied, with adjustment for initial AAA size and smoking. RESULTS: APOE genotype was a significant determinant of AAA expansion rate (P = 0.001). The adjusted mean (95 per cent confidence interval) rate was 2.1 (1.7-2.6) mm/year in 31 men with genotype E3E3, 1.3 (0.7-1.9) mm/year in 17 men with E3E4, 3.1 (2.0-4. 1) mm/year in six men with E2E3 and 4.2 (2.7-5.6) mm/year in three men with E2E4. The mean expansion rate was 2.2 (1.5-2.8) mm/year in non-smokers and 3.0 (2.5-3.6) mm/year in smokers (P = 0.014). CONCLUSION: APOE genotype seems to influence AAA expansion rate, but the effects of the individual genotypes, in particular E3E3 and E3E4, are contradictory when compared with the effects of the genotypes on risk of atherosclerosis.

Association of coronary heart disease with age-adjusted aortocoronary calcification in patients with familial hypercholesterolaemia.

OBJECTIVES: Existing algorithms of risk of coronary heart disease (CHD) do not pertain to patients with familial hypercholesterolaemia (FH), whose arteries have been exposed to hypercholesterolaemia since birth. We studied a cohort of FH patients to compare four diagnostic models of CHD: traditional risk factors of CHD (age, sex, cholesterol, hypertension, smoking and body mass index), cholesterol year score, and aortic as well as coronary calcium measured by spiral computed tomography (CT). SUBJECTS: We invited 88 individuals with molecularly defined FH of whom 80 (91%) decided to participate. RESULTS: Analysis of receiver operating characteristic curves showed that the age-adjusted coronary calcium score was more strongly associated with clinical manifestations of CHD than were traditional risk factors (P < 0.002), cholesterol year score (P << 0.0001), and the age-adjusted aortic calcium score (P < 0.0004). CONCLUSIONS: Age-adjusted coronary calcium score shows promise as an indicator of CHD in FH patients.

The marker of cobalamin deficiency, plasma methylmalonic acid, correlates to plasma creatinine.

OBJECTIVE: To examine the relationship between the two diagnostic tests, plasma methylmalonic acid and plasma cobalamins, and their association with plasma creatinine, age and sex. DESIGN: Cross-sectional study of simultaneous laboratory measurements. SETTING: County of Aarhus, Denmark. SUBJECTS: Records on 1689 patients who had their first plasma methylmalonic acid measurement during 1995 and 1996, and who had a simultaneous measurement of plasma cobalamins. Plasma creatinine values measured within a week of measurements of plasma methylmalonic acid and plasma cobalamins were available for 1255 of the patients. MAIN OUTCOME MEASURES: Predictors of variation in plasma methylmalonic acid; plasma cobalamins, plasma creatinine, age and sex. RESULTS: Plasma methylmalonic acid was positively correlated with plasma creatinine, even for plasma creatinine within the normal range. These associations remained in a multiple regression analysis. For plasma cobalamins below 200 pmol L-1, there was a strong negative correlation between plasma methylmalonic acid and plasma cobalamins, whilst the association was weak for higher plasma cobalamin levels. Plasma methylmalonic acid increased and plasma cobalamins decreased with age. CONCLUSIONS: The strong correlation between plasma methylmalonic acid and plasma creatinine suggests that plasma creatinine - also within the normal range - must be taken into consideration when interpreting plasma methylmalonic acid.

Physicians' use of plasma methylmalonic acid as a diagnostic tool.

OBJECTIVES: To investigate physicians' reasons for requesting plasma methylmalonic acid and their reactions to an increased concentration of plasma methylmalonic acid. DESIGN: Study of medical records. SETTING: Three somatic district hospitals in Denmark. SUBJECTS: Medical records of 198 patients with a plasma methylmalonic acid measurement above the reference interval. Information on diagnostic decisions was available for 177 patients. MAIN OUTCOME MEASURES: Reasons for requesting plasma methylmalonic acid and the reactions to the finding of elevated plasma methylmalonic acid. RESULTS: An explicit reason for requesting plasma methylmalonic acid was stated in 57% of 198 examined medical records, known or suspected anaemia being the most frequent reason. No further action was taken in 109 (62%) of the 177 cases available for follow-up. Amongst the remaining 68 patients, the finding of an increased plasma methylmalonic acid led to diagnosis of cobalamin deficiency in 46 patients. Six patients with a markedly increased plasma methylmalonic acid (above 0.99 micromol L-1) and clearly decreased plasma cobalamins (below 200 pmol L-1) were not recognized as having cobalamin deficiency. CONCLUSIONS: This lack of response to an increased plasma methylmalonic acid raises an important question. Is the clinical response inadequate, or is the connection between an increased level of plasma methylmalonic acid and signs of clinical significant cobalamin deficiency less clear?

Trends in selected biological risk factors for cardiovascular diseases in the Danish MONICA population, 1982-1992.

Data from 6695 men and women of ages 30, 40, 50, and 60 years, examined in the Danish WHO MONICA surveys in 1982-84, in 1986-87, and in 1991-92, were analyzed to estimate secular trends in body height and weight, blood pressure, and serum total, HDL-, and LDL-cholesterol, and triglyceride. Body height increased 0.1% per year, and body mass index increased 0.4% per year in women. Diastolic blood pressure increased 0.4% per year in women and 0.6% per year in 60-year-old men. HDL cholesterol declined 0.4% per year. Body mass indices in men, diastolic blood pressures in men <60 years of age, systolic blood pressures, total- and LDL cholesterol and triglyceride did not change. The levels of biological risk factors in the Danish WHO MONICA study population did not show trends during the 1980s that help explain the declining incidence of myocardial infarction in the population.

The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study.

BACKGROUND: Carriers of the epsilon4 allele of the apolipoprotein E gene are at a higher risk of coronary heart disease than individuals with other genotypes. We examined whether the risk of death or a major coronary event in survivors of myocardial infarction depended on apolipoprotein E genotype and whether the benefits of treatment with simvastatin differed between genotypes. METHODS AND RESULTS: Cox proportional hazards models were used to analyze 5.5 years of follow-up data from 966 Danish and Finnish myocardial infarction survivors enrolled in the Scandinavian Simvastatin Survival Study. A total of 16% of the 166 epsilon4 carriers in the placebo group died compared with 9% of the 312 patients without the allele, which corresponds to a mortality risk ratio of 1.8 (95% confidence interval, 1.1 to 3.1). The risk ratio was unaffected by considerations of sex, age, concurrent angina, diabetes, smoking, and serum lipids in multivariate analyses. Simvastatin treatment reduced the mortality risk to 0.33 (95% confidence interval, 0.16 to 0.69) in epsilon4 carriers and to 0.66 (95% confidence interval, 0. 35 to 1.24) in other patients (P=0.23 for treatment by genotype interaction). Apolipoprotein E genotype did not predict the risk of a major coronary event. Baseline serum levels of lipoprotein(a) also predicted mortality risk and could be combined with epsilon4-carrier status to define 3 groups of patients with different prognoses and benefits from treatment. CONCLUSIONS: Myocardial infarction survivors with the epsilon4 allele have a nearly 2-fold increased risk of dying compared with other patients, and the excess mortality can be abolished by treatment with simvastatin.

Socioeconomic status and trends in risk factors for cardiovascular diseases in the Danish MONICA population, 1982-1992.

STUDY OBJECTIVE: The decline in cardiovascular mortality in Denmark during the 1980s has been greatest in the highest socioeconomic groups of the population. This study examines whether the increased social inequality in cardiovascular mortality has been accompanied by a different trend in cardiovascular risk factors in different educational groups. DESIGN: Data from three cross sectional WHO MONICA surveys conducted in 1982-84, 1987, and 1991-92, were analysed to estimate trends in biological (weight, height, body mass index, blood pressure, and serum lipids) and behavioural (smoking, physical activity during leisure, and eating habits) risk factors in relation to educational status. SETTING: County of Copenhagen, Denmark. PARTICIPANTS: 6695 Danish men and women of ages 30, 40, 50, and 60 years. MAIN RESULTS: The prevalence of smoking and heavy smoking decreased during the study but only in the most educated groups. In fact, the prevalence of heavy smoking increased in the least educated women. There was no significant interaction for the remaining biological and behavioural risk factors between time of examination and educational level, indicating that the trend was the same in the different educational groups. However, a summary index based on seven cardiovascular risk factors improved, and this development was only seen in the most educated men and women. CONCLUSION: The difference between educational groups in prevalence of smoking increased during the 1980s, and this accounted for widening of an existing social difference in the total cardiovascular risk.

C-reactive protein and bacterial meningitis: a meta-analysis.

The aim of the study was to review published articles on the diagnostic accuracy of C-reactive protein (CRP) tests with cerebrospinal fluid and serum in diagnosing bacterial meningitis. The literature from 1980 and onwards was searched using the electronic databases of MEDLINE, and we used summary receiver operating characteristic curve analyses (SROCs) to describe central tendencies and examine possible sources of inter-study variability in the results. We included data from 35 studies of both children and adults: 21 in which CRP had been measured in cerebrospinal fluid, 10 in which CRP had been measured in serum, and 4 in which it had been measured in both cerebrospinal fluid and serum. The odds ratio for bacterial meningitis versus aseptic meningitis for a positive CRP test with cerebrospinal fluid was estimated at 241 (95% confidence interval [CI]: 59-980), and the central tendencies for the true-positive fraction (sensitivity) and the false-positive fraction (1-specificity) were estimated at 0.94 and 0.06, respectively. The corresponding figures for a CRP test with serum were 150 (95% CI: 44-509), 0.92 and 0.08, respectively. Regression analyses including variables coding for study design features, inclusion of neonatal patients, geographical region, or use of a quantitative biochemical method did not indicate statistically significant contributions to inter-study variances in the log odds ratios. For values of the true- and the false-positive fractions of 0.92-0.94 and 0.06-0.08, respectively, the post-test probability of not having bacterial meningitis given a negative test is very high (> or = 97%), in the range of a pre-test probability (prevalence of bacterial meningitis) from 10 to 30%, whereas the post-test probability of bacterial meningitis given a positive test is considerably lower. Hence, only a negative test is highly informative in a typical clinical setting. This, as well as the absence of analyses to show if CRP tests contribute independent diagnostic information, relatively to the information held in the traditionally used clinical and biochemical variables, makes it difficult to conclude on the clinical usefulness of CRP tests in the management of patients suspected of having bacterial meningitis.

Glucose metabolism, lipid metabolism, and cardiovascular risk factors in adult Turner's syndrome. The impact of sex hormone replacement.

OBJECTIVE: To examine glucose metabolism, blood pressure, physical fitness, and lipid metabolism in adult untreated women with Turner's syndrome compared with a group of normal women and to examine the effects of female sex hormone substitution on these factors. RESEARCH DESIGN AND METHODS: A total of 26 patients with Turner's syndrome were examined before and during sex hormone replacement with 17 beta-estradiol and norethisterone, and an age-matched control group (n = 24) was examined once. A frequently sampled intravenous glucose tolerance test was applied with minimal model assessment. We also performed an oral glucose tolerance test, measurement of 24-h ambulatory blood pressure, and assessment of physical fitness and lipid metabolism. RESULTS: Insulin sensitivity (SI) and glucose effectiveness (SG) were similar in Turner's syndrome patients and control subjects, whereas the acute insulin response (P = 0.03) was lower in Turner's syndrome patients, and no change was seen during sex hormone treatment. Abnormal glucose tolerance was found in 50% of Turner's syndrome patients before and 78% during treatment with sex hormones. Fat-free mass (FFM; P = 0.0005) and physical fitness (P = 0.002) were lower in Turner's syndrome subjects compared with control subjects. During treatment, an increase in FFM (P = 0.001) and physical fitness (P = 0.02) was seen in Turner's syndrome patients. Blood pressure was increased in Turner's syndrome, and a decrease was seen in diastolic blood pressure during treatment with sex hormones. CONCLUSIONS: Turner's syndrome is associated with glucose intolerance, diminished first-phase insulin response, elevated blood pressure, reduced FFM, and physical fitness. Sex hormone administration causes a deterioration in glucose tolerance, increases FFM and physical fitness, and has beneficial effects on blood pressure. The deleterious effect on glucose tolerance may be mediated by norethisterone, a gestagen known to have androgenic effects.

Apolipoprotein(a) isoforms and coronary heart disease in men: a nested case-control study.

The objective of the present study was to examine the possible associations between low molecular weight (LMW) apolipoprotein(a) (apo(a)) isoforms (F,B,S1,S2) and coronary heart disease (CHD). We conducted a nested case-control (prospective) study of five cohorts of white men: The 1936 cohort (baseline 1976, n = 548) and four cohorts from MONICA I born in 1923 (n = 463), 1933 (n = 491), 1943 (n = 504) and 1953 (n = 448) studied at baseline in 1983. At follow up in 1991, 52 subjects had developed a first myocardial infarction and 22 had been hospitalized with angina pectoris. Plasma samples obtained at baseline were stored frozen until 1993-94, when case samples (n = 74) were analyzed together with samples from matched (disease free) controls (n = 190). In a statistical model (conditional logistic regression) including all age groups, cholesterol (or apo B) level (P < 0.01), systolic blood pressure (P = 0.05) and smoking (P = 0.02) predicted CHD. In the statistical model Lp(a) interacted significantly with age (OR = 5.7; 95% CI: 1.4-23.6; P = 0.016), and high Lp(a) (over 45 mg/dl) was associated with significantly increased risk in subjects under 60 years (OR = 3.82; 95% CI: 1.47-9.96), but not in older men (OR = 0.67; 95% CI: 0.235-1.89). Therefore, we studied the impact of Lp(a)/apo(a) and other variables in subjects who had been under 60 years when they became cases. Among the younger subjects the presence of LMW apo(a) isoforms significantly predicted the development of CHD (OR = 3.83; 95% CI: 1.18-12.4). The increased risk pertained to high Lp(a) (above versus below 45 mg/dl: OR = 3.68; 95% CI: 1.03-13.10), and to Lp(a) concentrations when entered into the model as a continuous variable (P = 0.04). Cholesterol or apo B (P < 0.01), smoking (P = 0.02), systolic blood pressure (P = 0.05) and low alcohol consumption (under nine drinks/week) (P = 0.04) were also significant predictors of CHD. We conclude that LMW apo(a) isoforms are significantly associated with increased risk of CHD in men under 60 years.

Phenotypic variation in patients heterozygous for familial defective apolipoprotein B (FDB) in three European countries.

A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B- 100 (FDB). In 205 FDB patients from Germany (n = 73). The Netherlands (n = 87), and Denmark (n = 45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene (SfaNI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women (SfaNI: P = .04 and .03 for TC and LDL-C, respectively; Nco I; P = .003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S + A + N + allele had 13% to 20% higher TC than non-S + A + N + subjects (P = .02 [TC, men]; P = .01 [LDL-C, men]; P = .005 [TC, women]; and P = .004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e3e2, e3e3, and e3e4) with cholesterol concentrations was seen in S + A + N + but not in non-S + A + N + subjects and in P-P- but not in P + P + or P + P- subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.