Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

Trégouët, David‐Alexandre; König, Inke R.; Erdmann, Jeanette; Munteanu, Alexandru; Braund, Peter S.; Hall, Alistair S.; Großhennig, Anika; Linsel-Nitschke, Patrick; Perret, Claire; DeSuremain, Maylis; Meitinger, Thomas; Wright, Barlow C.; Preuss, Michael; Balmforth, Anthony J.; Ball, Stephen G.; Meisinger, Christa; Germain, Cécile; Evans, Alun; Arveiler, Dominique; Luc, Gérald; Ruidavets, Jean‐Bernard; Morrison, Caroline; Harst, Pim van der; Schreiber, Stefan; Neureuther, Katharina; Schäfer, Arne; Bugert, Peter; Mokhtari, Nour Eddine El; Schrezenmeir, Jürgen; Stark, Klaus; Rubin, Diana; Wichmann, H‐Erich; Hengstenberg, Christian; Ouwehand, Willem H.; Ziegler, Andreas; Tiret, Laurence; Thompson, John R.; Cambien, François; Schunkert, Heribert; Samani, Nilesh J.

doi:10.1038/ng.314

Cited by 416 publications

(274 citation statements)

References 11 publications

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“…4) also indicates decreased hepatic OCT3 protein levels. The rs3088442 variant is in complete linkage to the intronic OCT3 variant rs2048327 and, of note, in a genome-wide association study investigating susceptibility for coronary artery disease, 54 this variant was recently identified. Thus, in addition to a potential clinical relevance of OCT3 for drug response (such as efficacy of oxaliplatin chemotherapy, 55 lamivudine as drug substrate 19,20 ) OCT3 (SLC22A3) may contribute also as a susceptibility factor for development of certain diseases such as coronary artery disease 54 but also other diseases (such as obsessive-compulsive disorder 37 ).…”

Section: Discussionmentioning

confidence: 99%

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

et al. 2009

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An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

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Section: Discussionmentioning

confidence: 99%

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

et al. 2009

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“…In the first years of GWAS discoveries, identification of further loci came from individual genome‐wide association studies (Erdmann et al , 2009; Myocardial Infarction Genetics Consortium et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Wang et al , 2011), whereas more recently the formation of large, international consortia has accumulated a sufficient statistical power for new discoveries. The joint forces of the CARDIoGRAM (Schunkert et al , 2011), C4D (Coronary Artery Disease C4D Genetics Consortium, 2011) and finally the CARDIoGRAMplusC4D (CARDIoGRAMplusC4D Consortium et al , 2013; Nikpay et al , 2015) consortium allowed the analysis of up to 180,000 individuals, about half of which had CAD.…”

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

“…(B) The number of SNP s detected with genome‐wide significance after replication correlates with the number of individuals included in the discovery studies. Symbols denote the numbers of genotyped SNP s [dots: ≤ 500,000 SNP s (Samani et al , 2007; McPherson et al , 2007; Helgadottir et al , 2007; Myocardial Infarction Genetics Consortium, 2009; Erdmann et al , 2009; Tregouet et al , 2009; IBC 50K CAD Consortium, 2011; Lu et al , 2012); asterisks: 2,500,000 SNP s (Coronary Artery Disease C4D Genetics Consortium, 2011; Schunkert et al , 2011; CARDIoGRAMplusC4D Consortium et al , 2013); arrow: 940,000 SNP s (Nikpay et al , 2015)].…”

Section: Genome‐wide Association Studies In Coronary Artery Disease Amentioning

confidence: 99%

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

2016

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Cardiovascular diseases are leading causes for death worldwide. Genetic disposition jointly with traditional risk factors precipitates their manifestation. Whereas the implications of a positive family history for individual risk have been known for a long time, only in the past few years have genome‐wide association studies (GWAS) shed light on the underlying genetic variations. Here, we review these studies designed to increase our understanding of the pathophysiology of cardiovascular diseases, particularly coronary artery disease and myocardial infarction. We focus on the newly established pathways to exemplify the translation from the identification of risk‐related genetic variants to new preventive and therapeutic strategies for cardiovascular disease.

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“…[3][4][5][6][7][8] We performed screening of these SNPs in the discovery phase sample (Figure 1). In addition, as we found prominent CAD associations of variants other than those previously identified on 6p21 and 12q24 in the Japanese, 20,21 we investigated in the whole sample (4399 CAD cases and 7672 controls) the genetic impacts of 3 SNPs from 3 known genes in the LTA (lymphotoxin-a) cascade -rs1041981 in LTA, rs7291467 in LGALS2, and rs11066001 in BRAP.…”

Section: Replication Study Of Candidate Locimentioning

confidence: 99%

“…1 Genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) have recently been reported to identify susceptibility loci for CAD and/or MI mostly in populations of European descent. [2][3][4][5][6][7][8][9] Although reproducible evidence of disease association has been obtained at a few candidate loci that were originally detected through GWA scan, for example, near the CDKN2A/B gene on chromosome 9p21, in different populations of European descent and Asians, 1,10,11 the extent to which disease association differs or overlaps between populations remains unknown. Besides comparing the genetic associations between European-descent and Japanese populations, we aim to identify new genetic variants through a GWA study.…”

Section: Introductionmentioning

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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Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease

Cited by 416 publications

References 11 publications

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

The impact of genome‐wide association studies on the pathophysiology and therapy of cardiovascular disease

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

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