A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses

Ripatti, Samuli; Tikkanen, Emmi; Orho‐Melander, Marju; Havulinna, Aki S.; Silander, Kaisa; Sharma, Amitabh; Guiducci, Candace; Perola, Markus; Jula, Antti; Sinisalo, Juha; Lokki, Marja-Liisa; Nieminen, Markku S.; Melander, Olle; Salomaa, Veikko; Peltonen, Leena; Kathiresan, Sekar

doi:10.1016/s0140-6736(10)61267-6

Cited by 503 publications

(390 citation statements)

References 28 publications

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“…Recently, variations in this gene have been associated with early-onset myocardial infarction 35 and with coronary heart disease. 36 Considering our limited sample size, further replication studies in Chinese and other ethnic populations are needed to reconfirm our identified associations and to explore the genetic correlation between PP and the risk of cardiac disorders. Finally, we note that the quantile-quantile plot in Figure 3 departs relatively early from the line of identity, which could mean a systematic effect due to the population substructure in our sib-pair data that is not completely accounted for in our analysis.…”

Section: Discussionmentioning

confidence: 91%

Genome-wide linkage and association scans for pulse pressure in Chinese twins

Zhang

Pang

et al. 2012

Hypertens Res

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Elevated pulse pressure (PP) is associated with cardiovascular disorders and mortality in various populations. The genetic influence on PP has been confirmed by heritability estimates using related individuals. Recently, efforts have been made by mapping genes that are linked to the phenotype. We report the results of our gene mapping studies conducted in the Chinese population in mainland China. The genome-wide linkage and association scans were carried out on 63 middle-aged dizygotic twin pairs using high-density markers. The linkage analysis identified three significant linkage peaks (all with a single point Po1e À05 ) on chromosome 11 (LOD core 4.06 at 30.5 cM), chromosome 12 (LOD score 3.97 at 100.7 cM) and chromosome 18 (LOD score 4.01 at 70.7 cM), with the last two peaks closely overlapping with linkage peaks reported by two American studies. Multiple regions with suggestive linkages were identified, with many of the peaks overlapping with published linkage regions. The genome-wide association analysis detected a suggestive association on chromosome 4 (rs17031508, Po8.34e À08 ) located within a wide region of suggestive linkage. Our results provide some evidence for genetic linkages and associations with PP in the Chinese population. Further investigation is warranted to replicate the findings and to explore the susceptibility loci or genes for PP.

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Section: Discussionmentioning

confidence: 91%

Genome-wide linkage and association scans for pulse pressure in Chinese twins

Zhang

Pang

et al. 2012

Hypertens Res

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“…35,36 Also, although we attempted to explore CAD susceptibility loci with rather prominent effect sizes, the power cannot be necessarily sufficient; for example, the power to detect OR¼1.2 is very low (Supplementary Table X). We should keep these limitations in mind when we interpret the genetic association results.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of coronary artery disease in the Japanese

et al. 2011

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A new understanding of the genetic basis of coronary artery disease (CAD) has recently emerged from genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs), thus far performed mostly in European-descent populations. To identify novel susceptibility gene variants for CAD and confirm those previously identified mostly in populations of European descent, a multistage GWA study was performed in the Japanese. In the discovery phase, we first genotyped 806 cases and 1337 controls with 451 382 SNP markers and subsequently assessed 34 selected SNPs with direct genotyping (541 additional cases) and in silico comparison (964 healthy controls). In the replication phase, involving 3052 cases and 6335 controls, 12 SNPs were tested; CAD association was replicated and/or verified for 4 (of 12) SNPs from 3 loci: near BRAP and ALDH2 on 12q24 (P¼1.6Â10 À34 ), HLA-DQB1 on 6p21 (P¼4.7Â10 À7 ), and CDKN2A/B on 9p21 (P¼6.1Â10 À16 ). On 12q24, we identified the strongest association signal with the strength of association substantially pronounced for a subgroup of myocardial infarction cases (P¼1.4Â10 À40 ). On 6p21, an HLA allele, DQB1*0604, could show one of the most prominent association signals in an B8-Mb interval that encompasses the LTA gene, where an association with myocardial infarction had been reported in another Japanese study. CAD association was also identified at CDKN2A/B, as previously reported in different populations of European descent and Asians. Thus, three loci confirmed in the Japanese GWA study highlight the likely presence of risk alleles with two types of genetic effects -population specific and common -on susceptibility to CAD.

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“…In line, SNP-based risk score designed in a Finnish cohort of 30 725 participants free of CVD was associated with the risk of a first CAD event, with a relative risk of 1.7 between the highest and lowest quintiles of the score adjusted for traditional risk factors; sex, LDL-C, HDL-C, current smoking, BMI, systolic and diastolic blood pressure, blood pressure treatment an prevalent type 2 diabetes. 28 In contrast, Paynter et al 29 did not observe an independent association between genetic risk factors and CAD risk in a cohort of 19 313 initially healthy women during 12.3 years follow-up. A risk score based on 12 SNPs was clearly associated with CAD risk after adjustment for age.…”

Section: Discussionmentioning

confidence: 89%

Common genetic variants do not associate with CAD in familial hypercholesterolemia

et al. 2013

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In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G4T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49-0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.

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A multilocus genetic risk score for coronary heart disease: case-control and prospective cohort analyses

Cited by 503 publications

References 28 publications

Genome-wide linkage and association scans for pulse pressure in Chinese twins

Genome-wide linkage and association scans for pulse pressure in Chinese twins

Genome-wide association study of coronary artery disease in the Japanese

Common genetic variants do not associate with CAD in familial hypercholesterolemia

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