Background and Objectives-Identification of STRK1 locus by the deCODE group followed by the discovery of phosphodiesterase 4D (PDE4D) gene in strong association with ischemic stroke patients has provided useful insights toward understanding the genetic etiology of the disease. In this study, we aimed at investigating the association between 3 polymorphisms of the PDE4D gene and ischemic stroke in the Pakistani population. Methods-Three polymorphisms in PDE4D gene were analyzed in 200 patients of ischemic stroke and 250 controls of Pakistani origin using polymerase chain reaction-restriction fragment length polymorphism method. Data were coded and entered in SPSS Windows (version 12.0). Odds ratios and 95% CIs were calculated using multivariate logistic regression analysis. Although the past 3 decades have seen a decline in the incidence of the disease in the Western population, 1 the burden of the disease in South Asian countries (India, Pakistan, Bangladesh, and Sirilanka) has inclined and is expected to rise. 3 Several epidemiologic studies in families and in twins have indicated a distinctive genetic component predisposing to stroke. 4 However, identification of these factors remained elusive until the discovery of STRK1 locus by deCODE group, 5 followed by association of the phosphodiesterase 4D (PDE4D) with ischemic stroke in the Icelandic population. 6 In this study, we investigated the association between 3 polymorphisms of the PDE4D gene and ischemic stroke in the Pakistani population. Results-Marker MethodsThe study was conducted at the Liaqat National Hospital and Aga Khan University Hospital Karachi in 2001 to 2002. The study population consisted of 200 patients of ischemic stroke and 250 controls. Ischemic stroke was defined as a sudden loss of global or focal cerebral function persisting for Ͼ24 hours with corresponding infarction on brain imaging with a probable vascular cause. All patients underwent a complete neurological examination. Data were collected with the help of a pretested and coded data extraction sheet. Controls were free of stroke and were from local population sharing the same environment. The study was approved by the ethics committee of both hospitals.An individual was classified as having arterial hypertension with a previous diagnosis of hypertension or if systolic or diastolic blood pressure was Ͼ140 mm Hg or Ͼ90 mm Hg, respectively, on Ն2 different occasions. Subjects were classified as having diabetes mellitus if he or she already had the diagnosis of diabetes mellitus or if his or her fasting plasma glucose was Ͼ126 mg/dL. Ischemic heart disease was established on past medical history, review of ECGs, and other relevant clinical information. Sample size of 200 cases and 250 controls based on allele frequencies was calculated for a power of 80% using the software Quanto. 7 Laboratory Measurement and TechniquesA total of 10 mL of venous blood was collected in an EDTA tube and plain tubes separately for DNA extraction from white blood cells and serum analysis. DNA was extracted...

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 (PϽ10 Ϫ2) 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; Pϭ2ϫ10 Ϫ3) 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 (Pϭ1ϫ10 Key Words: myocardial infarction Ⅲ 9p21 Ⅲ Pakistanis Ⅲ risk factor Ⅲ South Asia Ⅲ meta-analysis V ariants at the 9p21.3 locus have been established as among the strongest common genetic factors associated with the risk of coronary artery disease (CAD) in people of European continental ancestry. [1][2][3][4][5] These variants are in highlinkage disequilibrium (LD) and span a 58-kb region that has multiple neighboring genes (CDKN2A, CDNK2B, and MTAP), without annotating to any single protein sequence. 5 An RNA coding gene, ANRIL, that overlaps with the risk To our knowledge, we report the first large-scale study of variants at the 9p21 locus in relation to risk of acute myocardial infarction (MI) in Pakistanis. This study involved 1851 patients with confirmed diagnoses of first-ever MI and 1903 control subjects from the Pakistan Risk of Myocardial Infarction Study 8 (PROMIS). Genotyping was conducted on 89 tagging single-nucleotide polymorphisms (SNPs) at the 9p21.3 locus, including the lead variant (rs1333049) identified by the Wellcome Trust Case Control Consortium in association with CAD. 1,2 To place our findings in context, we also report a literaturebased meta-analysis of relevant studies, encompassing information on 23 variants at the 9p21 locus in up to 38 250 CAD cases and 84 820 controls. The current meta-analysis substantially updates a previous relevant review, 5 involving data from an additional 82 117 participants and 20 additional variants. Methods Study DesignThis article follows the reporting recommendations of STrengthening the REporting of Genetic Association studies. 9 PROMIS is a casecontrol study of acute first-ever MI in urban Pakistan. 8 Patients with MI experienced the following: (1) symptoms within 24 hours of hospital presentation, (2) typical ECG characteristics (eg, Ն1-mm ST elevation in any Ն2 contiguous limb leads or new-onset left bundle branch block), and (3) a positive troponin test result (Ͼ1 ng/mL). Controls were indi...

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Background-Evidence is sparse about the genetic determinants of major lipids in Pakistanis. Methods and Results-Variants (nϭ45 000) across 2000 genes were assessed in 3200 Pakistanis and compared with 2450Germans 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,