Lack of evidence for linkage between low-density lipoprotein subclass phenotypes and the apolipoprotein B locus in familial combined hyperlipidemia.

Low-density lipoprotein (LDL) subclass phenotype B, characterized by a predominance of small, dense LDL particles, appears to be a genetically influenced risk factor for coronary heart disease. Phenotype B, as determined by gradient gel electrophoresis, appears to be inherited in a manner consistent with the presence of a single major genetic locus, based on complex segregation analysis. Familial combined hyperlipidemia (FCHL) is a disorder characterized by elevations in total plasma cholesterol and/or triglyceride levels in probands and family members, variable lipoprotein phenotypes over time, and elevations in apolipoprotein B levels. Because apo B is the primary protein component of LDL particles, the present study was undertaken to determine whether LDL subclass phenotypes are controlled by the APOB locus in FCHL families. The evidence against linkage was very strong based on lod score analyses (total lod = -13.3), under assumptions that LDL subclass phenotypes are influenced by a major genetic locus and that the mode of inheritance and penetrance functions are known. Other methods requiring fewer assumptions also provided evidence against linkage, although the strength of this evidence was weaker. Thus the results demonstrate that the proposed gene responsible for LDL subclass phenotypes is unlikely to be the APOB gene in families with FCHL.     

Linkage analysis of low-density lipoprotein subclass phenotypes and the apolipoprotein B gene.

A common heritable phenotype has recently been identified which is characterized by a relative abundance of small, dense low-density lipoproteins (LDL), and mild elevations of plasma triglycerides and reductions in plasma high-density lipoproteins (HDL) cholesterol. This phenotype, designated LDL subclass phenotype B, has been associated with up to a three-fold increase in coronary disease risk. Complex segregation analysis in two large family studies has demonstrated that LDL subclass phenotype B is influenced by an allele at a single genetic locus with a population frequency of 0.25-0.3, and autosomal dominant inheritance, but with full penetrance only in males age 20 and over and in postmenopausal women. Since apolipoprotein B (apoB) is the principal protein component of LDL, linkage analysis was used to investigate possible linkage between the phenotype B phenotype and the apoB gene, using a variable number of tandem repeats site located 0.5 kb from the 3' end of the apoB gene. In 6 informative families including only family members in the penetrant classes, a total LOD score of -7.49 was found at a recombination fraction of 0.001. Thus, under the assumptions of the single gene model, it is unlikely that the apoB locus controls LDL subclass phenotype B.     

ApoE基因多态性与多因素作用致冠心病研究

目的 探讨冠心病的主要危险因素及载脂蛋白E(ApoE)基因多态性与其它各危险因素之间的交互效应。方法 选择90例冠心病患者(CHD组)及90例非冠心病患者(对照组)，在Logistic回归分析的基础上，分析各因素的比值比以及ApoE基因多态性与其它危险因素之间的交互作用。结果 多因素Logistic回归结果显示，高血压史、高血脂史、肺炎衣原体(Cpn)感染、巨细胞病毒(CMV)感染和ApoE基因多态性为冠心病的危险因素，比值比OR分别为5.04，3.64，2.37，3.51，3.33。ApoE基因多态性与高血压史、高血脂史、Cpn感染、CMV感染间交互作用指数分别为1、73，1.55，1.28，1.20，归因交互百分比分别为40.64％，33.25％，19.01％和15.15％。结论 高血压史、高血脂史、Cpn感染、CMV感染和ApoE基因多态性可能是冠心病的主要危险因素，且ApoE基因多态性与其它危险因素在致冠心病的关系中存在正交互作用。     

Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia

A sample enriched for familial combined hyperlipidemia (FCHL) was examined for evidence of an association between genotype at an apolipoprotein B (apoB) elevating locus defined by complex segregation analysis and FCHL. Complex segregation analysis detected a locus with a large effect on plasma apoB levels and was used to compute the most probable genotype of family members. None of the 35 normolipidemic adults carried a copy of the allele associated with elevated apoB levels, yet 58% of the 109 adults with FCHL carried 1 (29%) or 2 (28%) copies. Two of 28 (7%) normal children had 1 copy of this allele and none had 2 copies, while 88 of 182 (48%) children with FCHL had 1 (26%) or 2 (22%) copies. Further, 4l of 48 (85%) individuals classified as having hyperapobetalipoproteinemia did not carry a copy of this “elevated apoB” allele. Therefore, the presence of the allele associated with elevation of apoB level is highly predictive of FCHL and this association cannot be explained solely by the presence of elevated apoB levels in FCHL, suggesting that the locus controlling apoB levels may play an etiologic role in FCHL. © 1993 Wiley-Liss, Inc.     

南宁市儿童ApoB基因Xba I位点多态性分析

目的研究南宁市126名健康体检儿童载脂蛋白B（ApoB）基因Xba I位点各基因型的分布情况,探讨其多态性对儿童生长发育、营养状况、血脂代谢及肾功能的影响。方法应用聚合酶链反应-限制性片段长度多态性（PCR-RFLP）技术检测126例健康体检儿童ApoB基因Xba I位点的基因型,计算体质指数（BMI）,测定血清总蛋白（TP）、白蛋白（AIB）、球蛋白（GLO）、白蛋白/球蛋白（A/G）、脂蛋白a（LPa）、总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）、非高密度脂蛋白胆固醇（non-HDL）、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白A1、（ApoA1）、ApoB、ApoA1/B、尿素氮（BUN）、肌酐（Ccr）及尿酸（UA）。结果（1）Xba I位点各基因型的频率分别为X-/X-：92.06%（116/126）,X＋/X-：7.14%（9/126）,X＋/X＋：0.79%（1/126）;等位基因X-与X＋的频率分别为95.63%和4.37%;（2）等位基因X＋组血清TP、AIB、A/G和ApoA1/B显著低于X-组,而BMI、LPa、TC、TG、non-HDL、LDL-C、ApoB、BUN和Ccr明显高于X-组。结论ApoB基因Xba I位点多态性对儿童生长发育、营养状况、血脂代谢及肾功能有影响。     

Segregation analysis of plasma lipoprotein(a) levels in pedigrees with molecularly defined familial hypercholesterolemia

The role of genetic and environmental factors in determining the variability in plasma lipoprotein(a) [Lp(a)] levels was investigated in 220 members of 14 families with familial hypercholesterolemia (FH) whose plasma Lp(a) levels were previously reported [Leitersdorf et al. (1991) J Lipid Res 32:1513–1519]. One hundred four subjects harbored a mutant low density lipoprotein (LDL) receptor allele as confirmed by the identification of the specific mutations in addition to the haplo-type analysis reported before. Four different mutant alleles were identified, each in a defined genetic group—Druze, Christian-Arabs, Ashkenazi, and Sephardic Jews. Sex- and age-adjusted mean plasma Lp(a) levels were significantly higher in FH family members (34.0 mg/dl) than in non-FH family members (21.1 mg/dl). Lp(a) levels were further adjusted for lipid levels and apo(a) isoforms. A mixture of two normal distributions fitted the adjusted Lp(a) levels better than did a single normal distribution. Segregation analysis indicated that a major effect of a non-transmitted environmental factor explained the mixture of distributions in addition to polygenic loci which influenced Lp(a) levels within each distribution. The major environmental factor and the polygenic loci accounted for 45% and 20% of the adjusted Lp(a) variation, respectively. Furthermore, sex, age, lipid levels, apo(a) isoform, the major environmental effect, and the unmeasured polygenes could account for 80% of the unadjusted variation of plasma Lp(a) in these families. © 1995 Wiley-Liss, Inc.     

Dementia among elderly apolipoprotein E type 4/4 homozygotes: A prospective study

The E*4 allele of the apolipoprotein E (APOE) gene on chromosome 19 has been shown to be an age- and dose-related risk factor for Alzheimer's disease. Of 870 elderly women participating in an osteoporosis study, 13 were previously found to be homozygous for the APOE*4 allele; 1 was deceased and the rest were assessed for dementia in a “piggyback” study of dementia. One had moderate [clinical dementia rating (CDR) = 2], 2 had mild dementia (CDR = 1), and 2 had possible dementia (CDR = 0.5). All 3 women over 80 years were definitely demented (CDR ? 1). Typically, genetic studies of Alzheimer's and other dementias require the identification and diagnosis of large numbers of demented subjects, at considerable expense, followed by genotyping or phenotyping with a relatively low yield of individuals with rare alleles. We demonstrate a more cost-effective approach in which the population is first phenotyped and then stratified by phenotype, so that diagnostic evaluation can be restricted to individuals with the phenotype of interest. ©1995 Wiley-Liss, Inc.     

Estimation of the frequency of isoform-genotype discrepancies at the apolipoprotein E locus in heterozygotes for the isoforms.

Estimates of the impact of apolipoprotein E (apo E) alleles coding for the three common isoforms on plasma lipid levels assume genetic homogeneity among the genotype classes. To test this assumption, we have determined the apo E genotype at the two common polymorphic sites (amino acids 112 and 158) by DNA amplification and hybridisation with allele-specific oligoprobes, in 195 unrelated Caucasian participants of the Rochester Family Heart Study previously classified as heterozygotes by isoelectric focusing (IEF). Fourteen discordant samples were initially detected. Repeat typing of these samples by both methods resolved nine discrepancies and analysis of additional blood samples from the remaining five individuals eliminated a further four discrepancies. The only truly discordant allele was found in a female subject who had an E3 isoform with the common E2 (Cys112, Cys158) genotype. Transmission of this allele from the mother was demonstrated. From these results, we estimate the frequency of discrepancies between isoforms and common genotypes to be 0.25% in this population. Allele misclassification was caused by poor amplification of the DNA in six samples and superimposition of glycosylated and nonglycosylated apo E isoforms on isoelectric focusing gels in five samples. We conclude that the assumption of genetic homogeneity among genotype classes is valid and that misclassification due to technical difficulties is more frequent than true discordancies.     

Investigating Effects of Plasma Apolipoprotein E on Ischemic Heart Disease Using Mendelian Randomization Study

Background: Observationally plasma apolipoprotein E (apoE) is positively associated with ischemic heart disease (IHD). A Mendelian randomization (MR) study suggesting apoE is unrelated to cardiovascular mortality did not consider specific isoforms. We used MR to obtain estimates of plasma apoE2, apoE3 and apoE4 on IHD, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, triglycerides and apolipoprotein B (apoB). Methods: We obtained independent genetic instruments from proteome genome-wide association studies (GWAS) and applied them to large outcome GWAS. We used univariable MR to assess the role of each isoform and multivariable MR to assess direct effects. Results: In univariable MR, apoE4 was positively associated with IHD (odds ratio (OR) 1.05, 95% confidence interval (CI) 1.01 to 1.09), but apoE2 and apoE3 were less clearly associated. Using multivariable MR an association of apoE2 with IHD (OR 1.16, 95% CI 0.98 to 1.38) could not be excluded, and associations of apoE3 and apoE4 with IHD were not obvious. In univariable MR, apoE2 and apoE4 were positively associated with apoB, and a positive association of apoE2 with LDL cholesterol could not be excluded. Using multivariable MR apoE2 was positively associated with LDL cholesterol, and associations with apoB could not be excluded. After adjusting for apoB, no direct effects of apoE isoforms on IHD were evident. Conclusions: Plasma apoE2 and apoE4 may play a role in lipid modulation and IHD. Whether apoE could be a potential therapeutic target requires further clarification when larger genetic studies of apoE isoforms are available.     

单纯性肥胖症儿童血脂、载脂蛋白A1、B100的研究

通过对单纯性肥胖儿童血脂,载脂蛋白Ａ１,Ｂ１００的研究,以初步了解其脂质代谢紊乱的状况,并探讨其动脉粥样硬硬化危险性增加的可能机制。对筛选出的肥胖儿童及其正常儿童各４９名,测定其血清甘油三酯（ＴＧ）,总胆固醇（ＴＣ）,高密度脂蛋胆固醇（ＨＤＬ－ｃｈ）,低密度脂蛋白胆固醇（ＬＤＬ－ｃｈ）,极低密度脂蛋白胆固醇（ＶＬＤＬ－ｃｈ）,载脂蛋白Ａｌ（ａｐｏＡ１）;载脂蛋白Ｂ１００（ａｐｏＢ１００）。     

冠心病合并焦虑、抑郁的研究进展[*基金项目： 首都全科医学研究专项(17QK19)；首都医科大学“本科生科研创新”项目（XSKY2018）。①首都医科大学2015级临床医学专业 北京 100069②首都医科大学附属北京安贞医院 北京 100029# 通讯作者]*

心血管疾病严重威胁人类身心健康,近年来,冠心病死亡率仍呈现上升趋势。越来越多的专家认识到焦虑、抑郁与冠心病关系密切。焦虑、抑郁可引起心肌供血不足,从而产生相应躯体症状,是冠心病的独立危险因素。就冠心病合并焦虑、抑郁的流行病学现状、发病机制、早期诊断和评价等方面的相互影响予以综述。     

Cost-effectiveness of dietary treatment of hypercholesterolemia in Spain

Background: Dietary treatment of hypercholesterolemia is one of the most frequently proposed measures to prevent cardiovascular disease. In this study cost-effectiveness of dietary treatment in Spain was assessed.Methods: Cost-effectiveness ratio was measured in terms of cost per life years gained, comparing net programme cost to its effectiveness. Effectiveness was estimated using a model that incorporates the Framingham multiple logistic equation to obtain the number of coronary events prevented and life years gained according to age, sex and initial cholesterol concentration. In this study it was assumed that dietary treatment could reduce cholesterol concentration by 5% in the group of participants. Net programme cost was estimated as total programme cost less averted cardiovascular disease treatment costs due to disease prevention. Costs and benefits were estimated for 1990 using a 5% discount rate.Results: Cost per life year gained ranged from $6,270 to 61,439 in men and $28,067 to 171, 459 in women, according to age and initial cholesterol concentration. The lowest cost-effectiveness ratio was obtained in individuals with a cholesterol concentration of 9.7 mmol/l (380 mg/dl) aged 45–49 years in men and 50–54 years in women, and the highest one was obtained in those men and women with a cholesterol concentration of 5.7 mmol/l (220 mg/dl) aged 60–65 years. Cost per life year gained was lower than $25,000 in men aged 35 to 64 years with a cholesterol concentration higher than 6.2 mmol/l (240 mg/dl) and it was lower than $35,000 in women aged 35 to 64 years with a cholesterol concentration higher than 9.3 mmol/l (360 mg/dl).Conclusion: Individual dietary treatment of hypercholesterolemia could be considered an efficient use of health resources. Programmes for dietary treatment of hypercholesterolemia should be recommended in men aged 35–64 years with hypercholesterolemia (>6.2 mmol/1) and in women aged 35–64 years with very high cholesterol concentrations.     

Obesity, Hypertension, Hypercholesterolemia and Diabetes Mellitus in Women Aged 20-69, Living in a Highland Community of Crete

Risk factors for coronary heart disease were studied in a femalepopulation aged 20 to 69 years living in a highland communityof Crete. 375 women participated in the study. Mean value oftotal cholesterol was 6.23 mmol/l, of HDL-cholesterol 1.41 mmol/l,of serum triglycerides 1.58 mmol/l, of serum glucose 5.36 mmol/l,of systolic blood pressure 130.64 mmHg and of diastolic bloodpressure 78.07 mmHg. 46% of the study population had a bodymass index higher than 27. Upon multiple regression analysis,the body mass index correlated positively and independentlyof age with serum lipid level and the systolic and diastolicblood pressure. The results of this study agree with data fromother studies suggesting an increase in frequency of coronaryheart disease risk factors in Crete over the past 20 years.     

Homocysteine, folate, vitamin B12, and cardiovascular risk in Indians, Malays, and Chinese in Singapore

OBJECTIVE: To examine the hypothesis that the higher rates of coronary heart disease (CHD) in Indians (South Asians) compared with Malays and Chinese is partly attributable to differences in blood concentrations of homocysteine, and related blood concentrations of folate and vitamin B12. DESIGN: Cross sectional study of the general population. SETTING: Singapore. PARTICIPANTS: Random sample of 726 fasting subjects aged 30 to 69 years. MAIN RESULTS: Mean plasma total homocysteine concentrations did not show significant ethnic differences; values were Indians (men 16.2 and women 11.5 mumol/l), Malays (men 15.0 and women 12.5 mumol/l), and Chinese (men 15.3 and women 12.2 mumol/l). Similarly, the proportions with high plasma homocysteine (> 14.0 mumol/l) showed no important ethnic differences being, Indians (men 60.0 and women 21.9%), Malays (men 53.9 and women 37.8%), and Chinese (men 56.6 and women 30.6%). Mean plasma folate concentrations were lower in Indians (men 8.7 and women 10.9 nmol/l) and Malays (men 8.5 and women 10.8 nmol/l), than Chinese (men 9.7 and women 13.8 nmol/l). Similarly, the proportions with low plasma folate (< 6.8 nmol/l) were higher in Indians (men 44.9 and women 36.6%) and Malays (men 45.3 and women 24.5%) than Chinese (men 31.4 and women 12.6%). Mean plasma vitamin B12 concentrations were lowest in Indians (men 352.5 and women 350.7 pmol/l), then Chinese (men 371.1 and women 373.7 pmol/l), and then Malays (men 430.5 and women 486.0 pmol/l). CONCLUSION: While there were ethnic differences for plasma folate and vitamin B12 (in particular lower levels in Indians), there was no evidence that homocysteine plays any part in the differential ethnic risk from CHD in Singapore and in particular the increased susceptibility of Indians to the disease.     

Meta-analysis of Egg Consumption and Risk of Coronary Heart Disease and Stroke

The possible relationship between dietary cholesterol and cardiac outcomes has been scrutinized for decades. However, recent reviews of the literature have suggested that dietary cholesterol is not a nutrient of concern. Thus, we conducted a meta-analysis of egg intake (a significant contributor to dietary cholesterol) and risk of coronary heart disease (CHD) and stroke. A comprehensive literature search was conducted through August 2015 to identify prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke. Random-effects meta-analysis was used to generate summary relative risk estimates (SRREs) for high vs low intake and stratified intake dose–response analyses. Heterogeneity was examined in subgroups where sensitivity and meta regression analyses were conducted based on increasing egg intake. A 12% decreased risk (SRRE = 0.88, 95% confidence interval [CI], 0.81–0.97) of stroke was observed in the meta-analysis of 7 studies of egg intake (high vs low; generally 1/d vs <2/wk), with little heterogeneity (p-H = 0.37, I² = 7.50). A nonstatistically significant SRRE of 0.97 (95% CI, 0.88–1.07, p-H = 0.67, I² = 0.00) was observed in the meta-analysis of 7 studies of egg consumption and CHD. No clear dose–response trends were apparent in the stratified intake meta-analyses or the meta regression analyses. Based on the results of this meta-analysis, consumption of up to one egg daily may contribute to a decreased risk of total stroke, and daily egg intake does not appear to be associated with risk of CHD.

Key Teaching Points:

? The role of egg consumption in the risk of stroke and coronary heart disease has come under scrutiny over many years.

? A comprehensive meta-analysis of prospective cohort studies that reported risk estimates for egg consumption in association with CHD or stroke was performed on the peer-reviewed epidemiologic literature through August 2015.

? Overall, summary associations indicate that intake of up to 1 egg daily may be associated with reduced risk of total stroke.

? Overall, summary associations show no clear association between egg intake and increased or decreased risk of CHD.

? Eggs are a relatively low-cost and nutrient-dense whole food that provides a valuable source of protein, essential fatty acids, antioxidants, choline, vitamins, and minerals.     

Influence of apolipoprotein E genotypes on plasma lipid and lipoprotein concentrations: Results from a segregation analysis in pedigrees with molecularly defined familial hypercholesterolemia

Familial hypercholesterolemia (FH) is a monogenic disorder caused by mutations in the low-density lipoprotein (LDL) receptor gene. Large variations in plasma lipids and lipoprotein levels have been observed in FH families. These may be caused by other environmental and genetic factors of which apolipoprotein E (apo E) is a candidate. The possible influence of apo E polymorphism on components of variation in plasma LDL-C, triglycerides, high-density lipoprotein cholesterol (HDL-C), and lipoprotein(a) (Lp(a)) levels was investigated in 235 members of 14 families with FH. Sex- and age-adjusted mean LDL-C was influenced significantly by the apo E genotype in non-FH subjects (P ≤ .01), and a similar trend was observed in FH cases. Mean plasma levels of triglyceride, HDL-C, and Lp(a) were not significantly different across the apo E genotypes in FH and in non-FH family members. Complex segregation analysis was first applied to these sex- and age-adjusted data. In addition to the major gene involved in LDL-C levels (i.e., the LDL receptor gene), there was evidence for a nontransmitted environmental major factor in addition to polygenic effect that explained the mixture of distributions in TG and a major effect in addition to polygenic loci which influenced Lp(a) levels. There was no evidence for a single major factor controlling HDL-C levels in these pedigrees. When the segregation models allowed apo E regression coefficients to be ousiotype (class) specific, the results suggested that apo E genotypes have a significant effect on LDL-C, TG, and Lp(a) levels. In conclusion, the analysis presented here supports the concept that the apo E gene has an important role in the regulation of plasma lipid and lipoproteins in FH. © 1996 Wiley-Liss, Inc.     

Inheritance of plasma apolipoprotein B levels in families of patients undergoing coronary arteriography at an early age

An elevated plasma level of apolipoprotein B (apoB), the major protein of low density lipoproteins, is a risk factor for coronary artery disease. This study tested the hypothesis, suggested by previous studies, that the apoB level is strongly influenced by a major gene. The study population included 832 family members of 116 subjects who had undergone elective coronary arteriography at an early age. The apoB level was adjusted for age, gender, body mass index, alcohol consumption, and cigarette smoking (R² = 20 %). ApoB levels revealed strong familial aggregation with correlations among spouses of 0.23, parent-offspring of 0.16, and siblings of 0.21. Regressive models were used to examine inter-individual variation in adjusted apoB levels. In the total sample, familial aggregation of the apoB level was consistent with two models: (1) a major gene model and (2) a polygenic model with a mixture of non-transmitted “types.” Comparison of these two models in each family showed that 57 families supported the first model over the second. Segregation analysis in these 57 families conclusively favored a major gene model with codominant transmission. Genotypic means were 124, 164, and 208 mg/dl with relative frequencies of 45 %, 44 %, and 11 %. Linkage studies in these families can be used to clarify the molecular basis of apoB regulation. However, in the whole population the genetic control of apoB levels may be quite complex. © 1993 Wiley-Liss, Inc.     

学龄儿童载脂蛋白CⅢ基因变异与血脂谱的关系研究

为了解载脂蛋白CⅢ基因多态性与学龄儿童血脂谱变异的关系 ,对 30 8名在校儿童 (7～ 11岁 )进行血脂水平测定及载脂蛋白CⅢ基因SacⅠ位点多态性检测 (PCR RFLP方法 )。结果表明载脂蛋白CⅢ基因SacⅠ位点杂合突变型 (+ - )检出率为 48 7% ,纯合突变型 (+ +)检出率为 7 5 % ,其等位基因 (+)频率为31 8% ,高于上海 (12 % )及白种人 (6 % ) ,与日本人 (34 % )接近 ,提示遗传变异有人群及种族差异 ;不同基因型儿童血脂水平比较显示 ,纯合突变基因型儿童的TG水平高于野生型 (P <0 0 5 ) ;高甘油三酯组 (+ +)基因型频率为 30 0 % ,高于对照组 6 7% (P <0 0 5 ) ;ApoCⅢ SacⅠ位点 (+)等位基因可使TG水平升高0 0 31mmol L。结果提示 ,载脂蛋白CⅢ基因SacⅠ位点突变与儿童甘油三酯血症水平升高相关     

Risk factors for coronary heart disease among firefighters in Cincinnati

Since 1984, coronary heart disease (CHD) risk, factors have been prospectively assessed among Cincinnuti, firefighters, free of CHD at study entry. In total, 806 firemen with a mean age of 37 years at entry have been, followed for 6.4 years on average, contributing 5,173 person-years. CHD risk, factors were measured every 1-4 years and included weight, blood pressure, cigarette use, fasting glucose, and lipid profile. When, in aggregate, these CHD risk, factors were, found to be in a high risk range, suggestions were made serially to reduce CHD risk. A composite high CHD risk factor score led to an exercise electrocardiogram (ECG) with thallium scan, which was repeated every 1-4 yeurs. Myocardial infarction (MI) occurred in 7 men, with 1.35 Mis/1,000 mean-years; 15 others developed CHD, with 4.25 MI + CHD/1,000 mean-years. The firefighters' MI event rate (1.35 MIS/1,000 man-years) was lower (but not significantly, p > 0.1) than that for employed 30- to 39-year-old men free of CHD at entry (2.07/1,000 man years), who had an average follow-up of 5.4 years in the NHANES I study. At study entry, the 22 men who later developed CHD (vs. the 784 who did not develop CHD) were older (p=.0001), smoked more (p=.001), and were more likely to have first degree relatives with CHD before age 60 (p=.017). After covariance adjusting for age, race, and Quetelet index, men with CHD (vs. those CHD free) had higher systolic and diastolic blood pressures (p=.0001,.0001), higher LDL cholesterol (p=.04), higher total cholesterol (p=.014), and higher triglycerides (p=.03). By Poisson regression, significant independent predictors of CHD events were age (p=.0007), cigarette smoking (p=.001), diastolic blood pressure (p=.056), and family history of CHD at ave ≤60 (p=.048). Men who later developmed CHD and those without CHD did not differ by histroy of smoke inhalation (p > 0.3). The calculated ratio of savings to cost attributable to the program per year was 5.9/1 ($258.500/$43,600). In the current study, firefighting as an occupation was not associated with increased CHD event rates. CHD events that did develop were, for the most part, associated with modifiable CHD risk factors.     

Segregation analysis of two-locus models regulating apolipoprotein-A1 levels

For quantitative traits associated with risk to complex diseases, such as heart disease, single major locus models are likely to be too simplistic. Currently, researchers have begun to use oligogenic models of inheritance, but the resolving power of these models remains to be determined. As the major apoprotein of high density lipoprotein (HDL), apolipoprotein A1 (apo-A1) is generally accepted as a protective factor for coronary artery disease. Although familial aggregation of apo-A1 levels has been reported, the mode of inheritance of apo-A1 remains ill defined. In the present study, we conducted a segregation analysis comparing a series of one-locus and two-locus univariate models for apo-A1 levels in a sample of 137 families ascertained through probands undergoing elective, diagnostic coronary angiography. A two-locus Mendelian model fit these data significantly better than any one-locus model. The incorporation of the second major locus into the model of inheritance leads to a significant improvement in the fit, and a significant decrease of the residual heritability. The best-fitting model included two loci with a reciprocal pattern of epistasis generating 4 distinct genotypic distributions. Taken together, these two major loci account for 58% of the variance of adjusted apo-A1 levels. This demonstration of a second major locus controlling apo-A1 levels may explain the equivocal results obtained from previous studies. This two-locus model may be more powerful for linkage analysis to map one or both of these quantitative trait loci. Genet. Epidemiol. 15:73–86,1998. © 1998 Wiley-Liss, Inc.