Diabetes-specific genetic effects on obesity traits in American Indian populations: the Strong Heart Family Study

Background

The prevalence of genotypes of the 677C>T polymorphism for the MTHFR gene varies among humans. In previous studies, we found changes in the genotypic frequencies of this polymorphism in populations of different ages, suggesting that this could be caused by an increase in the intake of folate and multivitamins by women during the periconceptional period. The aim was to analyze changes in the allelic frequencies of this polymorphism in a Spanish population, including samples from spontaneous abortions (SA).

Methods

A total of 1305 subjects born in the 20th century were genotyped for the 677C>T polymorphism using allele specific real-time PCR with Taqman^® probes. A section of our population (n = 276) born in 1980–1989 was compared with fetal samples (n = 344) from SA of unknown etiology from the same period.

Results

An increase in the frequency of the T allele (0.38 vs 0.47; p < 0.001) and of the TT genotype (0.14 vs 0.24; p < 0.001) in subjects born in the last quarter of the century was observed. In the 1980–1989 period, the results show that the frequency of the wild type genotype (CC) is about tenfold lower in the SA samples than in the controls (0.03 vs 0.33; p < 0.001) and that the frequency of the TT genotype increases in the controls (0.19 to 0.27) and in the SA samples (0.20 to 0.33 (p < 0.01)); r = 0.98.

Conclusion

Selection in favor of the T allele has been detected. This selection could be due to the increased fetal viability in early stages of embryonic development, as is deduced by the increase of mutants in both living and SA populations.     

Familial resemblance for hostility: the National Heart, Lung, and Blood Institute Family Heart Study

OBJECTIVE: The purpose of this study was to examine whether several aspects of hostility as measured by the Cook-Medley Hostility Scale (ie, aggressive responding, hostile affect, cynicism, and overall hostility score) were determined in part by family factors (ie, genes and/or familial environments). METHODS: Analyses were based on 680 European-American families (2525 individuals) from the NHLBI Family Heart Study (FHS), a population-based study of genetic and nongenetic determinants of CHD, atherosclerosis, and cardiovascular risk factors. The influence of family relationships, age, and education on the variation in each of the four hostility scores were estimated. RESULTS: Significant familial resemblance in all hostility scores was found, accounting for 42% of the variance in total hostility, 30% in cynicism, 38% in aggressive responding, and 18% in hostile affect. Very little of this resemblance could be explained by similarities in education. Familial resemblance for cynicism was solely due to significant parent-offspring and sibling correlations (ie, no spouse resemblance), suggesting the possibility of genetic influences. Gender and generation differences were also evident in the familial correlations. CONCLUSIONS: Hostility aggregates in families. Both family environmental and genetic sources of resemblance are suggested for hostility.     

Family History is a Coronary Heart Disease Risk Factor in the Second Northwick Park Heart Study

We have estimated the risk of coronary heart disease (CHD) from family history of CHD (FHCHD) in 2827 healthy European middle‐aged men, and explored the extent to which this can be explained by classical and genetic risk factors. Men with FHCHD (obtained by questionnaire) had a hazard ratio of CHD of 1.73 (95% confidence interval: 1.30, 2.31) compared to those without FHCHD; after adjusting for classical risk factors this did not change substantially. Those with FHCHD had 2.3% lower Factor VIIc (p = 0.03) and 1.14% higher systolic and 1.21% higher diastolic blood pressure (p = 0.04 and p = 0.02 ), with evidence of interaction between blood pressure and FHCHD status on risk (p = 0.01) . The risk for those with a positive family history who were also current smokers was 3.01 compared to non‐smokers without FHCHD, which is greater than the risk posed by smoking or FHCHD alone (1.96 and 2.05 respectively compared to non‐smokers without FHCHD), but not significantly different from a multiplicative model (p‐value for interaction 0.33). Allele frequencies for 13 candidate gene variants were not significantly different between those with and without FHCHD. In those with FHCHD, current smokers who carried the APOE4 allele (e4+) had a hazard ratio of 5.66 compared to non‐smokers who had no FHCHD and were not APOE4+, with a significant interaction between smoking and APOE4 in those with FHCHD p = 0.001 . These data demonstrate the complex interaction between genetic and environmental factors in determining CHD risk, and suggest that the causes of the familial clustering of CHD remain largely unexplained.     

Genome-wide scans for microalbuminuria in Mexican Americans: the San Antonio Family Heart Study.

PURPOSE: Microalbuminuria, defined as urine albumin-to-creatinine ratio of 0.03 to 0.299 mg/mg, is a major risk factor for cardiovascular disease. Several genetic epidemiological studies have established that microalbuminuria clusters in families, suggesting a genetic predisposition. METHOD: We estimated heritability of microalbuminuria and performed a genome-wide linkage analysis to identify chromosomal regions influencing urine albumin-to-creatinine ratio in 486 Mexican Americans from 26 multiplex families. RESULTS: Significant heritability was demonstrated for urine albumin-to-creatinine ratio (h = 24%, P < 0.003) after accounting for age, sex, body mass index, triglycerides, and hypertension. Genome scan revealed significant evidence of linkage of urine albumin-to-creatinine ratio to a region on chromosome 20q12 (LOD score of 3.5, P < 0.001) near marker D20S481. This region also exhibited a LOD score of 2.8 with diabetes status as a covariate and 3.0 with hypertension status as a covariate suggesting that the effect of this locus on urine albumin-to-creatinine ratio is largely independent of diabetes and hypertension. CONCLUSION: Findings indicate that there is a gene or genes located on human chromosome 20q12 that may have functional relevance to albumin excretion in Mexican Americans. Identifying and understanding the role of the genes that determine albumin excretion would lead to the development of novel therapeutic strategies targeted at high-risk individuals in whom intensive preventive measures may be most beneficial.     

Familial aggregation of QT-interval variability in a general population: results from the NHLBI Family Heart Study

QT-interval prolongation is associated with increased risk of cardiac death. Although information on genetics and molecular mechanisms of the congenital long QT syndrome is mounting, limited data are available on the genetics of QT interval in the general population. Heart rate adjusted QT intervals (Bazett's QTc, and QT index (QTI)) were assessed by electrocardiography in 2399 members aged 25-91 years of 468 randomly selected families participating in the NHLBI Family Heart Study. Familial correlation and segregation analyses were performed to evaluate the genetics of the variability of QT interval in this population. The parent-offspring (0.14+/-0.03) and sibling (0.18+/-0.03) correlations for age and sex-adjusted QTc were moderate, while the spouse correlation was close to zero (0.09+/-0.06). This suggests that there are familial/genetic influences on QT-interval variability. Segregation analysis results suggest that there is a major effect in addition to heritable multifactorial effects (h2=0.34), but the major effect did not follow Mendelian inheritance. Further adjustments of QTc for other major cardiovascular risk factors did not significantly change the results. Similar results were found for QTI. The QT-interval variation in the general population is influenced by moderate heritable multifactorial effects in addition to a major effect. A major gene effect is not directly supported.     

Readiness for lifestyle advice: self-assessments of coronary risk prior to screening in the British family heart study. Family Heart Study Group.

BACKGROUND. Where health professionals and patients hold similar views of a problem, health outcomes may be better. AIM. The aims of this paper were to document how attenders at primary care cardiovascular screening clinics perceived their risks of coronary heart disease prior to screening; the degree of similarity between perceived level of risk and an epidemiologically derived risk score; and the relative importance assigned to individual risk factors by subjects compared with those assigned by the risk score. METHOD: These issues were investigated in 3725 middle aged men and women who accepted an invitation to attend health screening as part of the British family heart study. RESULTS. Overall, there was a tendency for subjects to be optimistic (37%) rather than pessimistic (21%) when judging their risk of coronary heart disease. Nevertheless, there were strong significant associations between perceived risk and the levels of individual risk factors, particularly personal and family medical history and body mass index. There was also a strong association with the overall risk score though a large minority (31%) held views of their risk of coronary heart disease that were quite different from those based upon the epidemiologically derived index of risk. Respondents accorded greater importance to smoking and parental death from coronary heart disease and less importance to cholesterol level and blood pressure than did the risk score. CONCLUSION. Possible explanations for the observed disagreement are over-optimism or the relative importance given to individual risk factors. The relationships between patients' perceptions of risk and the epidemiological indices likely to be espoused by health professionals are important in understanding the difficulties in communication that might arise in offering lifestyle advice after screening for cardiovascular risk.     

Linkage and association with pulmonary function measures on chromosome 6q27 in the Framingham Heart Study

Spirometric measures of pulmonary function have been shown to be highly heritable and evidence for major genes influencing forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) have been reported. A genome scan of pulmonary traits in the Framingham Heart Study identified a region on chromosome 6qter with evidence for linkage to FEV1 and the FEV1/FVC ratio. For this study, additional markers were genotyped in the region to refine the location of linkage and test for association. Variance component linkage analysis was performed using GENEHUNTER, and family-based association tests were performed using FBAT. The chromosome 6 telomeric region provided significant evidence of linkage with the additional markers, resulting in a maximum multipoint LOD score of 5.0 for FEV1 at 184.5 cM. LOD scores for FVC and the FEV1/FVC ratio were also above 1.0 in this region. Evidence for association with FEV1 and FVC was observed with D6S281 at 190 cM. The strongest effect was seen with the 224 allele, which was associated with higher levels of FEV1 and FVC in allele carriers compared with those carrying other alleles. This study supports the presence of a gene influencing pulmonary function on the q-terminus of chromosome 6 in the region of 184 cM (D6S503) to 190 cM (D6S281).     

Segregation analysis of HDL cholesterol in the NHLBI Family Heart Study and in Utah pedigrees

We investigated the genetic determination of high-density-lipoprotein cholesterol (HDL-C) levels in the NHLBI Family Heart Study by segregation analysis. Included was a total of 3755 subjects from 560 randomly selected nuclear families and 522 families selected due to a high family risk of coronary heart disease (CHD). In the whole dataset, there was no evidence for an allele at a major gene locus responsible for HDL-C levels lower than the population mean or even for significant bimodality for low levels of HDL-C. However, we observed evidence for a recessive allele that was associated with higher HDL-C levels than average. This evidence for a recessive major gene was independent of triglyceride concentrations and was most strongly observed in families recruited for CHD. The environmental model was rejected (P=0.0027) while the codominant and recessive models were not rejected (P=0.085 and P=0.133, respectively). The dominant model was also rejected (P<0.0001). In the recessive segregation model, the means of those inferred to be homozygous for the high HDL-C allele and those without the high HDL-C allele were separated by about 25 mg/dl HDL-C (73.9+/-1.99 vs 48.2+/-0.36 mg/dl). Because these results were unexpected, segregation was tested in a separate sample of 2013 individuals in 85 large pedigrees ascertained for early heart disease deaths, early stroke deaths, and early hypertension in Utah. Similar evidence for an allele at a major gene locus for high HDL-C was found. In summary, we did not find evidence for an allele at a major gene locus associated with low HDL-C levels segregating in pedigrees recruited for the NHLBI Family Heart Study, or in pedigrees ascertained in Utah for early CHD or related phenotypes. Instead we found some evidence for the segregation of an allele associated with high HDL-C. d     

Familial Dyslexia in a Large Swedish Family: A Whole Genome Linkage Scan

There is a compelling body of evidence that developmental dyslexia runs in families and seems to be highly inheritable. Several investigations during the last two decades have shown possible locations of genes that might be involved in dyslexia, including regions of chromosomes 1, 2, 3, 6, 11, 13, 15 and 18. In addition, six candidate genes (KIAA0319, DYX1C1, DCDC2, ROBO1, MRPL19 and C2ORF3) seem to be related to dyslexia. The present study carried out a whole genome scan in a six-generation pedigree. In addition to literacy skills the assessment included cognitive skills and records concerning the history of reading and writing ability. Thirty-five percent were regarded as dyslexic in the family. A linkage analysis using both a quantitative and a qualitative approach has been performed. No evidence was obtained to support the hypothesis that the transmission of dyslexia in this pedigree is due to a highly penetrant major gene, and previous linkage findings were not replicated; however, power in this small study was not adequate to confirm linkage of genes with small to moderate effects. The results were discussed in relation to diagnostic procedures and sample characteristics.     

海南汉族人群九个纤维蛋白原基因多态性及其与血浆纤维蛋白原水平的关系

目的 调查海南汉族健康人群αTaqⅠ和βBclⅠ、HinfⅠA／C、448G／A、βBsmA ⅠG／C、＋1689T／G、-148C／T、-249C／T、-455G／A多态性的等位基因频率及其与血浆纤维蛋白原（fibrinogen，Fg）水平的关系。方法 用比浊法测定238名健康个体的血浆Fg浓度，用PCR-限制性片段长度多态性方法及测序法分析多态性基因型，并用协方差分析比较9个位点的基因型与血浆Fg水平的关系。结果 海南汉族人群αTaqⅠ、βBclⅠ、HinfⅠA／C、C448、βBsmAⅠG／C、＋1689T／G、-148C／T、-249C／T、-455G／A稀有位点的等位基因频率分别为0．445、0．239、0．134、0．235、0．273、0．241、0．265、0．441、0．254，9个位点之间存在连锁不平衡；在总人群中，-455GA和AA基因型、-148CT和TT基因型、αTaqⅠT1T1基因型组的血浆Fg水平比野生型组高（P值均〈0．01）；在男性人群中，-455GA和AA基因型、-148CT和TT基因型、αTaqⅠT1T1、αTaqⅠT1T2基因型组的血浆Fg水平比野生型组高（P值均〈0．01）。在女性人群中，携带稀有位点A^-455、T^-148、αTaⅠT1的基因型组与野生型组之间的血浆赡水平差异无统计学意义。结论 在9个多态性位点之间存在连锁不平衡；A^-455、T^-148、αTaqⅠT1位点与血浆Fg水平增高关联，β-Fg-455G／A、-148C／T及α-TaqⅠ多态性与男性血浆Fg水平关联。     

The Troms? Heart Study: coronary risk factor levels in treated and untreated hypertensives

Coronary risk factors are described in 288 medically treated hypertensives, 1293 untreated hypertensives and 15,029 normotensives. Cholesterol in untreated men and women was 0.37 mmol/l and 0.35 mmol/l higher than in normotensives (p less than 0.001). Non-significant differences were observed between those untreated and treated. Treated men and women had 0.16 mmol/l and 0.14 mmol/l lower HDL cholesterol than untreated (p less than 0.01). Between untreated and normotensives non-significant differences were found. Triglycerides were 0.27 mmol/l and 0.22 mmol/l higher in treated than in untreated men and women (p less than 0.01). Normotensive men and women had 0.33 mmol/l and 0.10 mmol/l lower triglycerides than untreated (p less than 0.01). The results suggest that the increased cholesterol in hypertensives was present originally, while the decreased HDL cholesterol and elevated triglycerides probably were evoked by drugs. The importance of consideration of the whole constellation of risk factors in order to reduce the mortality from coronary heart disease by antihypertensive drug treatment is emphasized.     

Genome-wide association study of electrocardiographic and heart rate variability traits: the Framingham Heart Study

Background

Heritable electrocardiographic (ECG) and heart rate variability (HRV) measures, reflecting pacemaking, conduction, repolarization and autonomic function in the heart have been associated with risks for cardiac arrhythmias. Whereas several rare monogenic conditions with extreme phenotypes have been noted, few common genetic factors contributing to interindividual variability in ECG and HRV measures have been identified. We report the results of a community-based genomewide association study of six ECG and HRV intermediate traits.

Methods

Genotyping using Affymetrix 100K GeneChip was conducted on 1345 related Framingham Heart Study Original and Offspring cohort participants. We analyzed 1175 Original and Offspring participants with ECG data (mean age 52 years, 52% women) and 548 Offspring participants with HRV data (mean age 48 years, 51% women), in relation to 70,987 SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, Hardy-Weinberg p-value ≥ 0.001. We used generalized estimating equations to test association of SNP alleles with multivariable-adjusted residuals for QT, RR, and PR intervals, the ratio of low frequency to high frequency power (LF/HFP), total power (TP) and the standard deviation of normal RR intervals (SDNN).

Results

Associations at p < 10^-3 were found for 117 (QT), 105 (RR), 111 (PR), 102 (LF/HF), 121 (TP), and 102 (SDNN) SNPs. Several common variants in NOS1AP (4 SNPs with p-values < 10^-3; lowest p-value, rs6683968, p = 1 × 10^-4) were associated with adjusted QT residuals, consistent with our previously reported finding for NOS1AP in an unrelated sample of FHS Offspring and other cohorts. All results are publicly available at NCBI's dbGaP at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

In the community-based Framingham Heart Study none of the ECG and HRV results individually attained genomewide significance. However, the presence of bona fide QT-associated SNPs among the top 117 results for QT duration supports the importance of efforts to validate top results from the reported scans. Finding genetic variants associated with ECG and HRV quantitative traits may identify novel genes and pathways implicated in arrhythmogenesis and allow for improved recognition of individuals at high risk for arrhythmias in the general population.

     

The association of combined alpha and beta fibrinogen genotype on plasma fibrinogen levels in smokers and non-smokers.

OBJECTIVE--To determine in healthy men: (1) whether an extended genotype of the fibrinogen gene cluster using the G/A-455 and the BclI polymorphism of the beta fibrinogen gene and TaqI of the alpha fibrinogen gene explains a significantly larger proportion of variance in plasma fibrinogen levels in either smokers or non-smokers than a single polymorphism (G/A-455); (2) whether there is any evidence for genotype-smoking interaction in the determination of fibrinogen levels. DESIGN--A cross sectional study of healthy, white men recruited at the screening for entry into the Thrombosis Prevention Trial. SETTING--The subjects were drawn from four general practices in the United Kingdom. RESULTS--The frequency of the rare alleles in the sample was 0.19 for the G/A-455 polymorphism (A-455), 0.15 for BclI (B+), and 0.27 for TaqI (T+) alleles. BMI and age made significant contributions to the variance in plasma fibrinogen levels only in non-smokers of 5.4% and 2.3% respectively and, in the group as a whole, smoking accounted for 6.6% of the variance. In the non-smokers, of the individual polymorphisms only the G/A-455 showed a significant association with plasma fibrinogen levels (p = 0.03). The mean fibrinogen in non-smokers homozygous for the G-455 allele was 2.54 g/l v 2.85 g/l in those homozygous for the A-455 allele, with the polymorphism explaining 3.6% of the variance in plasma fibrinogen levels in this group. On investigation of the association of fibrinogen levels with combined genotypes, the most significant effect was seen with the combination of the G/A-455 and TaqI polymorphisms, with those with no "fibrinogen raising alleles" having a mean fibrinogen of 2.57 g/l v 3.10 g/l for those with four "fibrinogen raising alleles" (p = 0.0036), and this combination explained 8.9% of the variance in plasma fibrinogen levels (p < 0.005). Although the contribution to variance was greater with the G/A-455/TaqI combination than the G/A-455 polymorphism alone (8.9% v 3.6%), this did not reach significance (p = 0.09). By contrast, in the smoking group, the only significant contribution to the difference in plasma fibrinogen levels was the G/A-455 genotype alone which, after adjustment for BMI and age, contributed 3.8% to the variance (p < 0.05). No interaction was shown between smoking and genotype. CONCLUSION--These data suggest that in non-smokers an extended genotype using the G/A-455 beta fibrinogen gene polymorphism and the TaqI alpha fibrinogen gene polymorphism explains a larger proportion of the variance in plasma fibrinogen levels than any one polymorphism alone, but that smoking has an overriding effect so that other variables such as age and BMI make little additional contribution.     

Evidence for a major gene accounting for mild elevation in LDL cholesterol: The NHLBI Family Heart Study

Studies of rare Mendelian disorders of low density lipoprotein cholesterol (LDL-C) metabolism have identified specific genetic mutations in the LDL receptor and apolipoprotein B. Although these rare mutations account for a small proportion of LDL-C variation, twin and adoption studies indicate that at least 50% of the overall LDL-C observed variation is genetically determined. In a heterogeneous sample of 3227 subjects from the NHLBI Family Heart Study collected from four US centres, we find evidence for a common major gene accounting for mild elevations (1.25 standard deviations) in LDL-C. The analysis favored a recessive model with a frequency of 0.52 for the gene influencing elevated LDL-C, phenotypic means of 113 mg/dl for the normal genotypes and 146 mg/dl for the abnormal genotype, and a significant polygenic heritability. This statistically-inferred major gene accounted for 24% of the variation in LDL-C, with polygenes accounting for another 28% of the variation. Using parameters for major gene transmission estimated in the segregation analysis, LDL-C showed no linkage to the LDL receptor gene ( LDLR ), nor to the apolipoprotein E gene ( APOE ), nor to the cholesterol 7α-hydroxylase gene ( CYP7A1 ), indicating the major gene effect influencing mild elevation in LDL-C is not explained by any of these candidate loci.     

Analysis of Whole Exome Sequencing with Cardiometabolic Traits Using Family‐Based Linkage and Association in the IRAS Family Study

Family‐based methods are a potentially powerful tool to identify trait‐defining genetic variants in extended families, particularly when used to complement conventional association analysis. We utilized two‐point linkage analysis and single variant association analysis to evaluate whole exome sequencing (WES) data from 1205 Hispanic Americans (78 families) from the Insulin Resistance Atherosclerosis Family Study. WES identified 211,612 variants above the minor allele frequency threshold of ≥0.005. These variants were tested for linkage and/or association with 50 cardiometabolic traits after quality control checks. Two‐point linkage analysis yielded 10,580,600 logarithm of the odds (LOD) scores with 1148 LOD scores ≥3, 183 LOD scores ≥4, and 29 LOD scores ≥5. The maximal novel LOD score was 5.50 for rs2289043:T>C, in UNC5C with subcutaneous adipose tissue volume. Association analysis identified 13 variants attaining genome‐wide significance (P < 5 × 10^?08), with the strongest association between rs651821:C>T in APOA5 and triglyceride levels (P = 3.67 × 10^?10). Overall, there was a 5.2‐fold increase in the number of informative variants detected by WES compared to exome chip analysis in this population, nearly 30% of which were novel variants relative to the Database of Single Nucleotide Polymorphisms (dbSNP) build 138. Thus, integration of results from two‐point linkage and single‐variant association analysis from WES data enabled identification of novel signals potentially contributing to cardiometabolic traits.     

Effects of oral contraceptive on fibrinogen levels in African women.

Fibrinogen levels were determined in 100 women on oral contraceptive pills (OCP), aged 17-46 years, and 100 apparently healthy women with regular menstruation and no previous history of hormonal therapy, aged 20-40 years, who served as controls. The women on OCP had significantly higher plasma fibrinogen concentration than the control (P less than 0.001). There was a cumulative increase in plasma fibrinogen level from three months of usage. We conclude that prolonged use of OCP may result in the development of circulatory and vascular disorders related to hyper-fibrinogenaemia and other clotting factors.     

The Life Events Stress-Performance Linkage: An Exploratory Study

Abstract

For a long time, the relationship between life events, psychological adjustment, and illness has been a subject of much concern in the medical literature. Very recently, several management theorists have proposed a life events stress-performance linkage. In the present study, such a linkage was tested in a classroom setting. One hundred fifty-nine university students were asked to estimate the degree of readjustment required for each of 43 life events and, subsequently, to identify events that they had experienced during the past year. Weighted and unweighted life event stress scores were later correlated with six indices of classroom performance. As hypothesized, measures of stress collected early in the semester were inversely related to future performance. The predictive ability of the stress scores was not enhanced by using readjustment values to weight life events experienced.     

Tel Aviv-Heidelberg three-generation offspring study: Genetic determinants of plasma fibrinogen level

Elevated plasma fibrinogen concentrations (fibrinogen) are an important independent risk factor of atherosclerotic disease. Using the kinetic method, we measured fibrinogen in 808 individuals, of which 757 were members of 204 pedigrees. Correlation analysis and two-way analysis of variance (ANOVA) showed a significant association of fibrinogen with age, body mass index (BMI), sex, smoking habits, sport activity, and other lifestyle factors. However, multivariate regression analysis of fibrinogen established an independent significant contribution of only the first three factors. Fibrinogen levels adjusted respectively were subjected to complex segregation analysis. Our aim was to identify the contribution of major gene effects and residual (within the genotype) family correlations on fibrinogen variation. Results of this study suggest codominant alleles at a major locus accounting for 39% of variation. There was also evidence of a significant residual parent/offspring correlation. © 1996 Wiley-Liss, Inc.     

Genome-wide association analysis of total cholesterol and high-density lipoprotein cholesterol levels using the Framingham Heart Study data

Background  

Cholesterol concentrations in blood are related to cardiovascular diseases. Recent genome-wide association studies (GWAS) of cholesterol levels identified a number of single-locus effects on total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels. Here, we report single-locus and epistasis SNP effects on TC and HDL-C using the Framingham Heart Study (FHS) data.