Genetic variants in loci 1p13 and 9p21 and fatal coronary heart disease in a Norwegian case-cohort study

Single nucleotide polymorphisms (SNPs) in loci 1p13 and 9p21 have previously been found to be associated with incident coronary heart disease (CHD). This study aimed to investigate whether these SNPs show associations with fatal CHD in a population-based cohort study after adjustment for socioeconomic- and lifestyle-related CHD risk factors not commonly included in genetic association studies. Using the population-based Cohort of Norway (CONOR), a nested case-cohort study was set up and DNA from 2,953 subjects (829 cases and 2,124 non-cases) were genotyped. The association with fatal CHD was estimated for four SNPs, three from locus 1p13 and one from locus 9p21. Multivariable Cox regression was used to estimate unstratified and gender-stratified hazard ratios while adjusting for major CHD risk factors. The associations between three SNPs from locus 1p13 and non-HDL cholesterol levels were also estimated. Men homozygous for the risk alleles on rs1333049 (9p21) and rs14000 (1p13) were found to have significantly increased hazard ratios in crude and adjusted models, and the hazard ratios remained statistically significant when both genders were analyzed together. Adjustment for additional socioeconomic- and lifestyle-related CHD risk factors influenced the association estimates only slightly. No significant associations were observed between the other two SNPs in loci 1p13 (rs599839 and rs646776) and CHD mortality in either gender. Both rs599839 and rs646776 showed significant, gradual increases in non-HDL cholesterol levels with increasing number of risk alleles. This study confirms the association between 9p21 (rs1333049) and fatal CHD in a Norwegian population-based cohort. The effect was not influenced by several socioeconomic- and lifestyle-related risk factors. Our results show that 1p13 (rs14000) may also be associated with fatal CHD. SNPs at 1p13 (rs599839 and rs646776) were associated with non-HDL cholesterol levels.     

Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium

Background

Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

Methods

We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10⁻⁶ in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

Results

In Stage I 15 loci passed the threshold of 5×10⁻⁶; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10⁻³) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10⁻⁹). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10⁻³).

Conclusions

QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.     

Identifying the Genetic Variation of Gene Expression Using Gene Sets: Application of Novel Gene Set eQTL Approach to PharmGKB and KEGG

Genetic variation underlying the regulation of mRNA gene expression in humans may provide key insights into the molecular mechanisms of human traits and complex diseases. Current statistical methods to map genetic variation associated with mRNA gene expression have typically applied standard linkage and/or association methods; however, when genome-wide SNP and mRNA expression data are available performing all pair wise comparisons is computationally burdensome and may not provide optimal power to detect associations. Consideration of different approaches to account for the high dimensionality and multiple testing issues may provide increased efficiency and statistical power. Here we present a novel approach to model and test the association between genetic variation and mRNA gene expression levels in the context of gene sets (GSs) and pathways, referred to as gene set - expression quantitative trait loci analysis (GS-eQTL). The method uses GSs to initially group SNPs and mRNA expression, followed by the application of principal components analysis (PCA) to collapse the variation and reduce the dimensionality within the GSs. We applied GS-eQTL to assess the association between SNP and mRNA expression level data collected from a cell-based model system using PharmGKB and KEGG defined GSs. We observed a large number of significant GS-eQTL associations, in which the most significant associations arose between genetic variation and mRNA expression from the same GS. However, a number of associations involving genetic variation and mRNA expression from different GSs were also identified. Our proposed GS-eQTL method effectively addresses the multiple testing limitations in eQTL studies and provides biological context for SNP-expression associations.     

Association of TERC and OBFC1 Haplotypes with Mean Leukocyte Telomere Length and Risk for Coronary Heart Disease

Objective

To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology.

Methods

Four SNPs at three loci BICD1 (rs2630578 GγC), 18q12.2 (rs2162440 GγT), and OBFC1 (rs10786775 CγG, rs11591710 AγC) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 CγG, rs10936601G>T and rs16847897 GγC) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method.

Results

Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (β=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61–0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61–0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing.

Conclusion

Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects.     

Variants at the endocannabinoid receptor CB1 gene (CNR1) and insulin sensitivity, type 2 diabetes, and coronary heart disease

Inhibition of the endocannabinoid receptor CB1 improves insulin sensitivity, lowers glycemia, and slows atherosclerosis. We analyzed whether common variants in the gene encoding CB1, CNR1, are associated with insulin resistance, risk of type 2 diabetes (T2D) or coronary heart disease (CHD). We studied 2,411 participants of the Framingham Offspring Study (mean age 60 years, 52% women) for quantitative traits and CHD, and the Framingham SHARe database for T2D risk. We genotyped 19 single-nucleotide polymorphisms (SNPs) that tagged 85% (at r(2) = 0.8) of common (>5%) CNR1 SNPs. Fasting blood glucose and insulin at the 7th (1999-2001) exam were collected. We used age-, sex-, BMI-adjusted models to test additive associations of genotype with homeostasis model assessment of insulin resistance (HOMA(IR)) (linear mixed-effect models), T2D, or CHD. To account for multiple tests of SNPs, we generated empirical P values. The C allele at SNP rs806365 (frequency, 57.4%), ~4.1 kb 3' from CNR1, was associated with increased HOMA(IR) (n = 2,261, β = 0.05 per C, empirical P = 0.01), risk of T2D (674 cases, odds ratio = 1.19 per C, nominal P = 0.01) and CHD (237 cases, hazard ratio = 1.23 per C, nominal P = 0.04). The association of rs806365 with HOMA(IR) was replicated in a meta-analysis of two independent cohorts (National Health and Nutrition Examination Survey III genetic cohort (NHANES-III) plus Partners Case-Control Diabetes Study; 2,540 white individuals, β = 0.037, nominal P = 0.007), but not in the large Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Consortium (n = 29,248, nominal P = 0.74). The association of rs806365 was not replicated either with T2D in Diabetes Genetics Replication and Meta-analysis (DIAGRAM) (n = 10,128, nominal P = 0.31), or with CHD in PROCARDIS (n = 13,614, nominal P = 0.37). Although supported by initial results, we found no reproducible statistical association of common variation at CNR1 with insulin resistance, T2D, or CHD.     

Validated context-dependent associations of coronary heart disease risk with genotype variation in the chromosome 9p21 region: the Atherosclerosis Risk in Communities study

Markers of the chromosome 9p21 region are regarded as the strongest and most reliably significant genome-wide association study (GWAS) signals for Coronary heart disease (CHD) risk; this was recently confirmed by the CARDIoGRAMplusC4D Consortium meta-analysis. However, while these associations are significant at the population level, they may not be clinically relevant predictors of risk for all individuals. We describe here the results of a study designed to address the question: What is the contribution of context defined by traditional risk factors in determining the utility of DNA sequence variations marking the 9p21 region for explaining variation in CHD risk? We analyzed a sample of 7,589 (3,869 females and 3,720 males) European American participants of the Atherosclerosis Risk in Communities study. We confirmed CHD-SNP genotype associations for two 9p21 region marker SNPs previously identified by the CARDIoGRAMplusC4D Consortium study, of which ARIC was a part. We then tested each marker SNP genotype effect on prediction of CHD within sub-groups of the ARIC sample defined by traditional CHD risk factors by applying a novel multi-model strategy, PRIM. We observed that the effects of SNP genotypes in the 9p21 region were strongest in a sub-group of hypertensives. We subsequently validated the effect of the region in an independent sample from the Copenhagen City Heart Study. Our study suggests that marker SNPs identified as predictors of CHD risk in large population based GWAS may have their greatest utility in explaining risk of disease in particular sub-groups characterized by biological and environmental effects measured by the traditional CHD risk factors.     

Replication of the 4p16 Susceptibility Locus in Congenital Heart Disease in Han Chinese Populations

Congenital heart disease (CHD) is the most common form of congenital human birth anomalies and a leading cause of perinatal and infant mortality. Some studies including our published genome-wide association study (GWAS) of CHD have indicated that genetic variants may contribute to the risk of CHD. Recently, Cordell et al. published a GWAS of multiple CHD phenotypes in European Caucasians and identified 3 susceptibility loci (rs870142, rs16835979 and rs6824295) for ostium secundum atrial septal defect (ASD) at chromosome 4p16. However, whether these loci at 4p16 confer the predisposition to CHD in Chinese population is unclear. In the current study, we first analyzed the associations between these 3 single nucleotide polymorphisms (SNPs) at 4p16 and CHD risk by using our existing genome-wide scan data and found all of the 3 SNPs showed significant associations with ASD in the same direction as that observed in Cordell’s study, but not with other subtypes- ventricular septal defect (VSD) and ASD combined VSD. As these 3 SNPs were in high linkage disequilibrium (LD) in Chinese population, we selected one SNP with the lowest P value in our GWAS scan (rs16835979) to perform a replication study with additional 1,709 CHD cases with multiple phenotypes and 1,962 controls. The significant association was also observed only within the ASD subgroup, which was heterogeneous from other disease groups. In combined GWAS and replication samples, the minor allele of rs16835979 remained significant association with the risk of ASD (OR = 1.22, 95% CI = 1.08–1.38, P = 0.001). Our findings suggest that susceptibility loci of ASD identified from Cordell’s European GWAS are generalizable to Chinese population, and such investigation may provide new insights into the roles of genetic variants in the etiology of different CHD phenotypes.     

BARCSoySNP23: a panel of 23 selected SNPs for soybean cultivar identification

This report describes a set of 23 informative SNPs (BARCSoySNP23) distributed on 19 of the 20 soybean linkage groups that can be used for soybean cultivar identification. Selection of the SNPs to include in this set was made based upon the information provided by each SNP for distinguishing a diverse set of soybean genotypes as well as the linkage map position of each SNP. The genotypes included the ancestors of North American cultivars, modern North American cultivars and a group of Korean cultivars. The procedure used to identify this subset of highly informative SNP markers resulted in a significant increase in the power of identification versus any other randomly selected set of equal number. This conclusion was supported by a simulation which indicated that the 23-SNP panel can uniquely distinguish 2,200 soybean cultivars, whereas sets of randomly selected 23-SNP panels allowed the unique identification of only about 50 cultivars. The 23-SNP panel can efficiently distinguish each of the genotypes within four maturity group sets of additional cultivars/lines that have identical classical pigmentation and morphological traits. Comparatively, the 13 trinucleotide SSR set published earlier (BARCSoySSR13) has more power on a per locus basis because of the multi-allelic nature of SSRs. However, the assay of bi-allelic SNP loci can be multi-plexed using non-gel based techniques allowing for rapid determination of the SNP alleles present in soybean genotypes, thereby compensating for their relatively low information content. Both BARCSoySNP23 and BARCSoySSR13 were highly congruent relative to identifying genotypes and for estimating population genetic differences.     

Effects of Polymorphisms in APOA4-APOA5-ZNF259-BUD13 Gene Cluster on Plasma Levels of Triglycerides and Risk of Coronary Heart Disease in a Chinese Han Population

Background/Aim

Recent genome-wide association studies have identified several loci influencing lipid levels. The present study focused on the triglycerides (TG)-associated locus, the APOA4-APOA5-ZNF259-BUD13 gene cluster on chromosome 11, to explore the role of genetic variants in this gene cluster in the development of increasing TG levels and coronary heart disease (CHD).

Methodology/Principal Findings

Six single nucleotide polymorphisms (SNPs), rs4417316, rs651821, rs6589566, rs7396835, rs964184 and rs17119975, in the APOA4-APOA5-ZNF259-BUD13 gene cluster were selected and genotyped in 5374 healthy Chinese subjects. There were strong significant associations between the six SNPs and TG levels (P<1.0×10⁻⁸). Moreover, a weighted genotype score was found to be associated with TG levels (P = 3.28×10⁻¹³). The frequencies of three common haplotypes were observed to be significantly different between the high TG group and the low TG group (P<0.05). However, no significant effects were found for the SNPs regarding susceptibility to CHD in the Chinese case-control populations.

Conclusions/Significance

This study highlights the genotypes, genotype scores and haplotypes of the APOA4-APOA5-ZNF259-BUD13 gene cluster that were associated with TG levels in a Chinese population; however, the genetic variants in this gene cluster did not increase the risk of CHD in the Chinese population.     

Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study

Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-alpha (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.     

Association of common DNA sequence variants at 33 genetic loci with blood lipids in individuals of African ancestry from Jamaica

The relevance of loci associated with blood lipids recently identified in European populations in individuals of African ancestry is unknown. We tested association between lipid traits and 36 previously described single-nucleotide polymorphisms (SNPs) in 1,466 individuals of African ancestry from Spanish Town, Jamaica. For the same allele and effect direction as observed in individuals of European ancestry, SNPs at three loci (1p13, 2p21, and 19p13) showed statistically significant association (p < 0.05) with LDL, two loci (11q12 and 20q13) showed association with HDL cholesterol, and two loci (11q12 and 2p24) showed association with triglycerides. The most significant association was between a SNP at 1p13 and LDL cholesterol (p = 4.6 × 10^?8). This SNP is in a linkage disequilibrium region containing four genes (CELSR2, PSRC1, MYBPHL, and SORT1) and was recently shown to relate to risk for myocardial infarction. Overall, the results of this study suggest that much of the genetic variation which influences blood lipids is shared across ethnic groups.     

Rank and Order: Evaluating the Performance of SNPs for Individual Assignment in a Non-Model Organism

Single nucleotide polymorphisms (SNPs) are valuable tools for ecological and evolutionary studies. In non-model species, the use of SNPs has been limited by the number of markers available. However, new technologies and decreasing technology costs have facilitated the discovery of a constantly increasing number of SNPs. With hundreds or thousands of SNPs potentially available, there is interest in comparing and developing methods for evaluating SNPs to create panels of high-throughput assays that are customized for performance, research questions, and resources. Here we use five different methods to rank 43 new SNPs and 71 previously published SNPs for sockeye salmon: F_ST, informativeness (I_n), average contribution to principal components (LC), and the locus-ranking programs BELS and WHICHLOCI. We then tested the performance of these different ranking methods by creating 48- and 96-SNP panels of the top-ranked loci for each method and used empirical and simulated data to obtain the probability of assigning individuals to the correct population using each panel. All 96-SNP panels performed similarly and better than the 48-SNP panels except for the 96-SNP BELS panel. Among the 48-SNP panels, panels created from F_ST, I_n, and LC ranks performed better than panels formed using the top-ranked loci from the programs BELS and WHICHLOCI. The application of ranking methods to optimize panel performance will become more important as more high-throughput assays become available.     

Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women

BackgroundGeneralized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.MethodsUsing the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses’ Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.ResultsIn both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.ConclusionsIn these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity.     

Human paraoxonase gene cluster polymorphisms as predictors of coronary heart disease risk in the prospective Northwick Park Heart Study II

The anti-atherogenic effect of HDL has been suggested to be partly due to the action of HDL-associated paraoxonase (PON). Three distinct enzymes have been identified, encoded by PON1, PON2 and PON3, clustered on chromosome 7q21-q22. Two cSNPs in PON1 (L55M and Q192R) and one in PON2 (S311C) have been implicated as independent risk factors for coronary heart disease (CHD) in some, but not all, studies. A PON3 SNP (A99A) was identified and the effect of these four PON SNPs on HDL levels and CHD risk was examined in the prospective Northwick Park Heart Study II (NPHSII). Genotype frequencies did not differ between cases and controls but the CHD risk associated with smoking was significantly modified by PON1 L55M genotype. Compared to LL non-smokers, LL smokers had a hazard ratio (HR) of 1.30 (95% CI 0.81-2.06) while M-allele carriers had a HR of 1.76 (1.17-2.67). When genotypes were analysed in combination, men with the genotype PON1 55 LM/MM+PON2 311 CC, had HR of 3.54 (1.81-6.93) compared to PON1 LL+PON2 SS/SC men (interaction P=0.004). These effects were independent of classical risk factors. These data demonstrate the importance of stratifying by environmental factors and the use of multiple SNPs for genetic analysis.     

Genetic variation in heat shock protein 60 gene and coronary heart disease in China: tagging-SNP haplotype analysis in a case-control study

Background High levels of circulating heat shock protein 60 (Hsp60) and antibody to human Hsp60 have been associated with greater risk of coronary heart disease (CHD) in several studies, but associations between polymorphisms of the hsp60 gene and CHD risk have not been investigated. Methods By resequencing DNA from 30 unrelated Han Chinese and using HapMap Phase I Chinese data of hsp60 gene, we selected four tagging single nucleotide polymorphisms (tagSNPs) named rs2340690, rs788016, rs2305560, and rs2565163, and determined their frequencies in 1,003 Chinese CHD patients and 1,003 age- and sex-frequency-matched controls. Furthermore, we used PHASE 2.0 software to reconstruct haplotypes and logistic regression to control for potential confounders in multivariate analyses. Results We found 13 SNPs in hsp60 gene (including four novel SNPs) in Han Chinese subjects. Our results showed no significant differences in four selected SNPs in patients with CHD and controls after adjusting for other conventional risk factors and stratifying by age, sex, smoking status, past history of hypertension and DM; however, our results showed that subjects with the GCTC haplotype had about twofold higher risk of CHD than those with the GTTC haplotype (OR = 1.91, 95%CI: 1.26–2.89, P = 0.002). Conclusions Our results suggest that the GCTC haplotype in the hsp60 gene is significantly associated with higher CHD risk in a Chinese population. The first two authors contributed equally to this paper.     

Genetic Markers Enhance Coronary Risk Prediction in Men: The MORGAM Prospective Cohorts

Background

More accurate coronary heart disease (CHD) prediction, specifically in middle-aged men, is needed to reduce the burden of disease more effectively. We hypothesised that a multilocus genetic risk score could refine CHD prediction beyond classic risk scores and obtain more precise risk estimates using a prospective cohort design.

Methods

Using data from nine prospective European cohorts, including 26,221 men, we selected in a case-cohort setting 4,818 healthy men at baseline, and used Cox proportional hazards models to examine associations between CHD and risk scores based on genetic variants representing 13 genomic regions. Over follow-up (range: 5–18 years), 1,736 incident CHD events occurred. Genetic risk scores were validated in men with at least 10 years of follow-up (632 cases, 1361 non-cases). Genetic risk score 1 (GRS1) combined 11 SNPs and two haplotypes, with effect estimates from previous genome-wide association studies. GRS2 combined 11 SNPs plus 4 SNPs from the haplotypes with coefficients estimated from these prospective cohorts using 10-fold cross-validation. Scores were added to a model adjusted for classic risk factors comprising the Framingham risk score and 10-year risks were derived.

Results

Both scores improved net reclassification (NRI) over the Framingham score (7.5%, p = 0.017 for GRS1, 6.5%, p = 0.044 for GRS2) but GRS2 also improved discrimination (c-index improvement 1.11%, p = 0.048). Subgroup analysis on men aged 50–59 (436 cases, 603 non-cases) improved net reclassification for GRS1 (13.8%) and GRS2 (12.5%). Net reclassification improvement remained significant for both scores when family history of CHD was added to the baseline model for this male subgroup improving prediction of early onset CHD events.

Conclusions

Genetic risk scores add precision to risk estimates for CHD and improve prediction beyond classic risk factors, particularly for middle aged men.     

Association of heat stress protein 90 and 70 gene polymorphism with adaptability traits in Indian sheep (<Emphasis Type="Italic">Ovis aries</Emphasis>)

Heat stress proteins assist cellular proteins in the acquisition of native structure. The present research was conducted to study how thermo-tolerance is modulated by HSP90 and HSP70 gene polymorphism and its association with hemato-physio-biochemical parameters, supported by their expression profiles in Chokla, Magra, Marwari, and Madras Red sheep breeds. Least square analysis revealed significant effect (P < 0.05) of season and breed on all the physiological parameters, i.e., temperature, respiratory rate, and pulse rate (a.m. and p.m.), as well as hematological parameters like Hb, packed cell volume, total erythrocyte count (TEC), neutrophil/lymphocyte (N/L) ratio, and total leukocyte count (TLC). There was a significant influence (P < 0.05) of breed on biochemical parameters such as glucose, SGOT, phosphorous, triglyceride, and cholesterol. Eight fragments were amplified and sequenced in HSP90, and 70 genes and 13 single-nucleotide polymorphisms (SNPs) were identified. Tetra-primer amplification refractory mutation system PCR, PCR-RFLP, and allele-specific PCR genotyping protocols were developed for large-scale genotyping of five SNPs. A significant difference (P < 0.05) of rectal temperature (a.m.), respiratory rate (p.m.), triglyceride, and total protein was observed at SNP01; albumin at SNP2; pulse rate (p.m.) at SNP3; and rectal temperature (p.m.), pulse rate (p.m.), Hb (g/dL), and N/L ratio at SNP4 and TLC at SNP5. Gene expression analysis revealed lower expression in less adapted animals with Madras Red < Magra < Chokla < Marwari expression pattern. Predominant allele was found to be superior in most of the SNPs (SNP1–4) indicating the selection acting in directional manner (positive selection). Finally, it is concluded that TACCA haplotype combination of SNP1-SNP2-SNP3-SNP4-SNP5 might be of some selection advantage for the identification of animals more adaptable to heat stress.     

Lymphotoxin-α Gene and Risk of Myocardial Infarction in 6,928 Cases and 2,712 Controls in the ISIS Case-Control Study

Lymphotoxin-α (LTA) is a pro-inflammatory cytokine that plays an important role in the immune system and local inflammatory response. LTA is expressed in atherosclerotic plaques and has been implicated in the pathogenesis of atherosclerosis and coronary heart disease (CHD). Polymorphisms in the gene encoding lymphotoxin-α (LTA) on Chromosome 6p21 have been associated with susceptibility to CHD, but results in different studies appear to be conflicting. We examined the association of seven single nucleotide polymorphisms (SNPs) across the LTA gene, and their related haplotypes, with risk of myocardial infarction (MI) in the International Study of Infarct Survival (ISIS) case-control study involving 6,928 non-fatal MI cases and 2,712 unrelated controls. The seven SNPs (including the rs909253 and rs1041981 SNPs previously implicated in the risk of CHD) were in strong linkage disequilibrium with each other and contributed to six common haplotypes. Some of the haplotypes for LTA were associated with higher plasma concentrations of C-reactive protein (p = 0.004) and lower concentrations of albumin (p = 0.023). However, none of the SNPs or related haplotypes were significantly associated with risk of MI. The results of the ISIS study were considered in the context of six previously published studies that had assessed this association, and this meta-analysis found no significant association with CHD risk using a recessive model and only a modest association using a dominant model (with narrow confidence intervals around these risk estimates). Overall, these studies provide reliable evidence that these common polymorphisms for the LTA gene are not strongly associated with susceptibility to coronary disease.     

A Retrospective Observational Study of the Relationship between Single Nucleotide Polymorphisms Associated with the Risk of Developing Colorectal Cancer and Survival

BackgroundThere is variability in clinical outcome for patients with apparently the same stage colorectal cancer (CRC). Single nucleotide polymorphisms (SNPs) mapping to chromosomes 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and Xp22 have robustly been shown to be associated with the risk of developing CRC. Since germline variation can also influence patient outcome the relationship between these SNPs and patient survivorship from CRC was examined.MethodsAll enrolled into the National Study of Colorectal Cancer Genetics (NSCCG) were genotyped for 1q41, 3q26.2, 6p21, 8q23.3, 8q24.21, 10p14, 11q13, 11q23.1, 12q13.13, 14q22, 14q22.2, 15q13.3, 16q22.1, 18q21.1, 19q13.11, 20p12, 20p12.3, 20q13.33 and xp22 SNPs. Linking this information to the National Cancer Data Repository allowed patient genotype to be related to survival.ResultsThe linked dataset consisted of 4,327 individuals. 14q22.22 genotype defined by the SNP rs4444235 showed a significant association with overall survival. Specifically, the C allele was associated with poorer observed survival (per allele hazard ratio 1.13, 95% confidence interval 1.05–1.22, P = 0.0015).ConclusionThe CRC susceptibility SNP rs4444235 also appears to exert an influence in modulating patient survival and warrants further evaluation as a potential prognostic marker.     

Genome-wide association analysis of incident coronary heart disease (CHD) in African Americans: a short report

African Americans have the highest rate of mortality due to coronary heart disease (CHD). Although multiple loci have been identified influencing CHD risk in European-Americans using a genome-wide association (GWAS) approach, no GWAS of incident CHD has been reported for African Americans. We performed a GWAS for incident CHD events collected during 19 years of follow-up in 2,905 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. We identified a genome-wide significant SNP (rs1859023, MAF = 31%) located at 7q21 near the PFTK1 gene (HR = 0.57, 95% CI 0.46 to 0.69, p = 1.86×10(-08)), which replicated in an independent sample of over 8,000 African American women from the Women's Health Initiative (WHI) (HR = 0.81, 95% CI 0.70 to 0.93, p = 0.005). PFTK1 encodes a serine/threonine-protein kinase, PFTAIRE-1, that acts as a cyclin-dependent kinase regulating cell cycle progression and cell proliferation. This is the first finding of incident CHD locus identified by GWAS in African Americans.