BackgroundNumerous risk prediction algorithms based on conventional risk factors for Coronary Heart Disease (CHD) are available but provide only modest discrimination. The inclusion of genetic information may improve clinical utility.MethodsWe tested the use of two gene scores (GS) in the prospective second Northwick Park Heart Study (NPHSII) of 2775 healthy UK men (284 cases), and Pakistani case-control studies from Islamabad/Rawalpindi (321 cases/228 controls) and Lahore (414 cases/219 controls). The 19-SNP GS included SNPs in loci identified by GWAS and candidate gene studies, while the 13-SNP GS only included SNPs in loci identified by the CARDIoGRAMplusC4D consortium.ResultsIn NPHSII, the mean of both gene scores was higher in those who went on to develop CHD over 13.5 years of follow-up (19-SNP p=0.01, 13-SNP p=7x10-3). In combination with the Framingham algorithm the GSs appeared to show improvement in discrimination (increase in area under the ROC curve, 19-SNP p=0.48, 13-SNP p=0.82) and risk classification (net reclassification improvement (NRI), 19-SNP p=0.28, 13-SNP p=0.42) compared to the Framingham algorithm alone, but these were not statistically significant. When considering only individuals who moved up a risk category with inclusion of the GS, the improvement in risk classification was statistically significant (19-SNP p=0.01, 13-SNP p=0.04). In the Pakistani samples, risk allele frequencies were significantly lower compared to NPHSII for 13/19 SNPs. In the Islamabad study, the mean gene score was higher in cases than controls only for the 13-SNP GS (2.24 v 2.34, p=0.04). There was no association with CHD and either score in the Lahore study.ConclusionThe performance of both GSs showed potential clinical utility in European men but much less utility in subjects from Pakistan, suggesting that a different set of risk loci or SNPs may be required for risk prediction in the South Asian population.

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Background: Obesity has become global epidemic in the last three decades, whereas Coronary Heart Disease (CHD) still remains the most important cause of mortality in the world. The study was aimed at determining the pattern of lipid profile for the obese and CHD population in Pakistan. As obesity is a strong predisposing risk factor for CHD, we aimed to analyze the lipid parameters in both conditions and compare them with the healthy controls of the same ethnicity. Methods: Blood samples were collected from one thousand individuals (500 with CHD, 250 with obesity, 250 healthy controls). The lipid profile (total Cholesterol, triglycerides, HDL-C, LDL-C and VLDL) was measured using commercially available kits. The pattern of dyslipidemia was then studied by comparing the results in both groups with controls as well as population cutoffs. The quantitative variables were checked for normality and log transformation was done for variables where appropriate. Analysis of variance and logistic regression were done to check the association of lipid parameters with obesity and CHD. Results: The obese and CHD groups showed a dyslipidemic profile than the healthy controls. CHD group had a higher proportion of CHD in any of the first degree blood relatives (36.0% vs. 1.8%), a similar trend was observed in the obese group, where 63.9% cases had positive family history. Among cases, 50.7% had combined lipid abnormalities, i.e., the values of TC, LDL-C, TG and HDL-C, all were deranged. Whereas 49.52% had TC more than normal cut off (> 200 mg/dl), 51.6% had LDL-C > 100 mg/dl. Similarly, 80.4% of patients had TG levels more than upper normal range (> 150 mg/dl) and 64% had HDL values in moderate CHD risk group (< 50 mg/dl). The results show that Pakistani cases are hyperlipidemic for lipid traits except for HDL which is lowered. Patients with comorbidities also had lipid profiles deviated from the normal range. Conclusion: The study provides information regarding the aberration of lipid profile in the metabolic disorders that can increase the predisposition to complications.

Back ground and Aims: Conventional risk factors like age, gender, blood lipids, hypertension and smoking have been the basis of coronary artery disease (CAD) risk prediction algorithms, but provide only modest discrimination. A genetic risk score (GRS) may provide improved discrimination over and above conventional risk factors alone. The current study analysed the genetic risk of CAD in Pakistani subjects using a GRS of 21 loci in 18 genes and examined whether its association with blood lipids in this cohort.Methods: 625 subjects were genotyped for the variants, NOS3 rs1799983, SMAD3 rs17228212, APOBrs1042031, LPArs3798220, LPA rs10455872, SORT1rs646776, APOE rs429358, GLUL rs10911021 and FTO rs9939609 (by TaqMan) and MIA3 rs17465637,CDKN2A rs10757274, DAB2IP rs7025486, CXCL12 rs1746048, ACE rs4341, APOA5 rs662799, CETP rs708272, MRAS rs9818870, LPL rs328,LPL rs1801177, PCSK9 rs11591147and APOE rs7412 (by KASPar technique).Results: Individually, risk allele frequencies were not significantly higher in cases than controls (p>0.05) except for APOB rs1042031 and FTO rs9939609 (p=0.007 and 0.003 respectively), and did not associate with CAD except rs1042031 and rs993969 (p=0.01 and 0.009 respectively). However, the GRS of 21 SNPs was significantly higher in cases than controls (17.53±2.52 vs16.64±2.44, p<0.001) and was associated with CAD risk. CAD risk in the top quintile of GRS was 2.96 (95% CI 1.71-5.13). Atherogenic blood lipid levels showed significant positive association with GRS. Conclusion:The GRS was quantitatively associated with d CAD risk and showed association with blood lipid levels, suggesting that the mechanism of these variants is likely to be in part at least through creating an atherogenic lipid profile in subjects carrying high numbers of risk alleles.

Ribonucleotide reductase (RNR) is an essential enzyme that catalyzes the synthesis of DNA building blocks in virtually all living cells. NrdR, an RNR-specific repressor, controls the transcription of RNR genes and, often, its own, in most bacteria and some archaea. NrdR senses the concentration of nucleotides through its ATP-cone, an evolutionarily mobile domain that also regulates the enzymatic activity of many RNRs, while a Zn-ribbon domain mediates binding to NrdR boxes upstream of and overlapping the transcription start site of RNR genes. Here, we combine biochemical and cryo-EM studies of NrdR from Streptomyces coelicolor to show, at atomic resolution, how NrdR binds to DNA. The suggested mechanism involves an initial dodecamer loaded with two ATP molecules that cannot bind to DNA. When dATP concentrations increase, an octamer forms that is loaded with one molecule each of dATP and ATP per monomer. A tetramer derived from this octamer then binds to DNA and represses transcription of RNR. In many bacteria — including well-known pathogens such as Mycobacterium tuberculosis — NrdR simultaneously controls multiple RNRs and hence DNA synthesis, making it an excellent target for novel antibiotics development.

BackgroundSerum Triglyceride (TG) and High Density Lipoprotein (HDL-C) levels are modifiable coronary artery disease (CAD) risk factors. Polymorphisms in the genes regulating TG and HDL-C levels contribute to the development of CAD. The objective of the current study was to investigate the effect of four such single nucleotide polymorphism (SNPs) in the genes for Lipoprotein Lipase (LPL) (rs328, rs1801177), Apolipoprotein A5 (APOA5) (rs66279) and Cholesteryl ester transfer protein (CETP) (rs708272) on HDL-C and TG levels and to examine the association of these SNPs with CAD risk.MethodsA total of 640 subjects (415 cases, 225 controls) were enrolled in the study. The SNPs were genotyped by KASPar allelic discrimination technique. Serum HDL-C and TG were determined by spectrophotometric methods.ResultsThe population under study was in Hardy Weinberg equilibrium and minor allele of SNP rs1801177 was completely absent in the studied subjects. The SNPs were association with TG and HDL-C levels was checked through regression analysis. For rs328, the effect size of each risk allele on TG and HDL-C (mmol/l) was 0.16(0.08) and −0.11(0.05) respectively. Similarly, the effect size of rs662799 for TG and HDL-C was 0.12(0.06) and −0.13(0.0.3) and that of rs708272 was 0.08(0.04) and 0.1(0.03) respectively. The risk allele frequencies of the SNPs were higher in cases than controls, but the difference was not significant (p > 0.05) and SNPs were not associated with CAD risk (p > 0.05). The combined gene score of four SNPs significantly raised TG and lowered HDL-C but did not increase CAD risk.ConclusionThe studied SNPs were associated with TG and HDL-C levels, but not with CAD in Pakistani population under study.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-017-0419-4) contains supplementary material, which is available to authorized users.

BackgroundMany SNPs have been identified in genes regulating LDL-C metabolism, but whether their influence is similar in subjects from different ethnicities is unclear. Effect of 4 such SNPs on LDL-C and coronary heart disease (CHD) was examined in Pakistani subjects and was compared with middle aged UK men from Northwick Park Heart Study II (NPHSII).MethodsOne thousand nine hundred sixty-five (1770 non CHD, 195 CHD) UK and 623 (219 non CHD, 404 CHD) Pakistani subjects were enrolled in the study. The SNPs SORT1 rs646776, APOB rs1042031 and APOE rs429358, rs7412 were genotyped by TaqMan/KASPar technique and their gene score was calculated. LDL-C was calculated by Friedewald equation, results were analyzed using SPSS.ResultsAllele frequencies were significantly different (p = <0.05) between UK and Pakistani subjects. However, the SNPs were associated with LDL-C in both groups. In UK non CHD, UK CHD, Pakistani non CHD and Pakistani CHD respectively, for rs646776, per risk allele increase in LDL-C(mmol/l) was 0.18(0.04), 0.06(0.11), 0.15(0.04) and 0.27(0.06) respectively. For rs1042031, per risk allele increase in LDL-C in four groups was 0.11(0.04), 0.04(0.14), 0.15(0.06) and 0.25(0.09) respectively. For APOE genotypes, compared to Ɛ3, each Ɛ2 decreased LDL-C by 0.11(0.06), 0.07(0.15), 0.20(0.08) and 0.38(0.09), while each Ɛ4 increased LDL-C by 0.43(0.06), 0.39(0.21), 0.19(0.11) and 0.39(0.14) respectively. Overall gene score explained a considerable proportion of sample variance in four groups (3.8 %, 1.26 % 13.7 % and 12.3 %). Gene score in both non-CHD groups was significantly lower than CHD subjects.ConclusionsThe SNPs show a dose response association with LDL-C levels and risk of CHD in both populations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0253-0) contains supplementary material, which is available to authorized users.