Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

Funder: PfizerFunder: NovartisFunder: National Institute for Health ResearchFunder: MerckBackgroundGenetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies.MethodsWe characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci.ResultsWe identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci.ConclusionsOur findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci

Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci.

The authors would like to thank Michael Inouye for his helpful comments on an earlier version of the manuscript.Peer reviewe

Observational Assessment of Blood Pressure Goal Achievement in Patients on Antihypertensive Therapy in Urban Pakistan: Results of ACTION Registry

Background: To assess the proportion of Pakistanipatients achieving blood pressure goal while on existingantihypertensive therapy and reasons for not achieving BPgoal.Methods: This descriptive study was conducted in 60centers across 10 cities of Pakistan by simple randomsampling. It was a national, multi-centre, noninterventional,cross-sectional, epidemiological diseaseregistry. Patients, who were ≥15 years of age, onantihypertensive medications for ≥4 weeks and had takena dose on the day of visit, were included. Investigatorswere randomly selected from a list of physicians within agiven geographical territory (Urban) in major cities ofPakistan. Approximately 58% of the physicians weregeneral practitioners and 42% were specialist such asmedical internist and cardiologist. Reasons for notachieving BP goal was determined by assessing differentvariables. Changes made in BP management in patientsnot at BP goal and therapeutic regimens prescribed topatients at BP goal were also documented. Differences inthe profile of patients according to the attainment of BPgoal were analyzed using bi-variate analysis. A p <0.05was considered significant.Results: Mean age of patients (n=1130) was 52.6 ± 11.9years. Of them 49% were females. Mean duration of HTNwas 6.1 (±6.2) years. Of 1130 patients, 23.80% achieved BPgoal. In patients not achieving BP goal, history ofsedentary lifestyle (60.27%), diabetes (42.97%), anddyslipidemia (40.30%) were identified as risk factors.Coronary artery disease (21.25%) was the most common comorbidcondition. Lack of patient understanding ontreatment importance (47.03%) was major reason for notachieving BP goal. Lifestyle modification (37.74%) andaddition of another drug (37.74%) were recommended.Majority of patients at BP goal received angiotensinconvertingenzyme inhibitors (36.05%).Conclusion: In Pakistan, only one in four patientstaking antihypertensive medications and presenting tophysicians achieves BP goal as per JNC VII guidelines.This has significantly improved as compared withprevious survey. Lack of understanding of importance ofBP treatment remains the major impediment in achievingbetter BP contro

Genetic determinants of major blood lipids in Pakistanis compared with Europeans.

BACKGROUND: Evidence is sparse about the genetic determinants of major lipids in Pakistanis. METHODS AND RESULTS: Variants (n=45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450 Germans using the same gene array and similar lipid assays. We also did a meta-analysis of selected lipid-related variants in Europeans. Pakistani genetic architecture was distinct from that of several ethnic groups represented in international reference samples. Forty-one variants at 14 loci were significantly associated with levels of HDL-C, triglyceride, or LDL-C. The most significant lipid-related variants identified among Pakistanis corresponded to genes previously shown to be relevant to Europeans, such as CETP associated with HDL-C levels (rs711752; P<10(-13)), APOA5/ZNF259 (rs651821; P<10(-13)) and GCKR (rs1260326; P<10(-13)) with triglyceride levels; and CELSR2 variants with LDL-C levels (rs646776; P<10(-9)). For Pakistanis, these 41 variants explained 6.2%, 7.1%, and 0.9% of the variation in HDL-C, triglyceride, and LDL-C, respectively. Compared with Europeans, the allele frequency of rs662799 in APOA5 among Pakistanis was higher and its impact on triglyceride concentration was greater (P-value for difference <10(-4)). CONCLUSIONS: Several lipid-related genetic variants are common to Pakistanis and Europeans, though they explain only a modest proportion of population variation in lipid concentration. Allelic frequencies and effect sizes of lipid-related variants can differ between Pakistanis and Europeans

Association of the 9p21.3 locus with risk of first-ever myocardial infarction in Pakistanis: Case-control study in South Asia and updated meta-analysis of Europeans

Objective: To examine variants at the 9p21 locus in a case-control study of acute myocardial infarction (MI) in Pakistanis and to perform an updated meta-analysis of published studies in people of European ancestry.Methods and results: A total of 1851 patients with first-ever confirmed MI and 1903 controls were genotyped for 89 tagging single-nucleotide polymorphisms at locus 9p21, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium. Minor allele frequencies and extent of linkage disequilibrium observed in Pakistanis were broadly similar to those seen in Europeans. In the Pakistani study, 6 variants were associated with MI (P\u3c10(-2)) in the initial sample set, and in an additional 741 cases and 674 controls in whom further genotyping was performed for these variants. For Pakistanis, the odds ratio for MI was 1.13 (95% CI, 1.05 to 1.22; P=2 x 10(-3)) for each copy of the C allele at rs1333049. In comparison, a meta-analysis of studies in Europeans yielded an odds ratio of 1.31 (95% CI, 1.26 to 1.37) for the same variant (P=1 x 10(-3) for heterogeneity). Meta-analyses of 23 variants, in up to 38,250 cases and 84,820 controls generally yielded higher values in Europeans than in Pakistanis.Conclusions: To our knowledge, this study provides the first demonstration that variants at the 9p21 locus are significantly associated with MI risk in Pakistanis. However, association signals at this locus were weaker in Pakistanis than those in European studies

Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study

AbstractBackgroundAlthough epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain.ObjectivesThrough a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF).MethodsThis study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls.ResultsSerum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations.ConclusionsEvidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions