Consortium claims evaluation indicates that many previously suggested CAD risk loci are spurious.

Scientists have identified new genes linked with coronary artery disease (CAD) and heart attack risk. They claim that results from their studies indicate that many previously suggested candidate genes may not, in fact, have any impact on CAD risk.

Researchers from the IBC 50K CAD Consortium examined 49,094 genetic variants in 2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls of European descent and South Asian origin. Any novel genetic links identified were then re-examined  in another 17,121 cases and 40,473 controls. The potential mechanisms via which the novel variants might impact on CAD risk were evaluated through association tests with vascular risk factors and gene expression.

Reporting in PLoS Genetics, the authors say that novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8 were identified and verified. In addition, the work confirmed associations of several previoisly known CAD susceptibility loci, including confirmed associations of several previously known CAD susceptibility loci like 9p21.3, LPA, and 1p13.3. The researchers add, however, “We found essentially null results for most previously suggested CAD candidate genes.”

The results are reported in a paper titled “Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease.” The study’s co-principal investigators are Nilesh Samani, M.D., British Heart Foundation professor of cardiology at the University of Leicester, Hugh Watkins, M.D., British Heart Foundation professor of cardiovascular medicine at the University of Cambridge, and John Danesh, Ph.D. at the University of Cambridge.

The researchers’ study utilized a customized gene array enriched with common and low frequency variants in about 2,100 candidate genes that reflected a wide variety of biological pathways. In the discovery phase they genotyped participants from 12 association studies of CAD/myocardial infarction (MI), including a total of 11,202 cases and 30,733 controls of European descent (10 studies) plus 4,394 South Asian cases and 4,259 South Asian controls.

This identified 27 loci in total: 15 in the European-only analysis, 3 in the South Asian-only analysis, and 9 in the combined analysis. The data confirmed associations with CAD for a number of loci identified through previous genome-wide association studies (GWAS), including variants at 9p21.3 and 1p13.3. The findings in addition supported a link between CAD and other genes with strong prior evidence, including a variant at the apolipoprotein E locus, the apolipoprotein (a) gene (LPA), and the low densitiy lipoprotein receptor (LDOR).

Association loci at COL4A1/COL4A2, ZC3HC1, and CYP17A1  had previously been flagged by the CARDIoGRAM consortium’s GWA meta-analysis. However, the authors stress, “we found no persuasive evidence of association of several prominently studied genes and variants for which the previous epidemiological evidence has been inconclusive, even though the majority of these loci were well-tagged.”

Variants that were particularly notable in terms of an absence of association, included the angiotensin converting enzyme (ACE) insertion/deletion polymorphism, the cholesteryl-ester transferase protein (CETP) Taq1B polymorphism, and the paraoxonase 1 (PONT) Q192R polymorphism.

In fact, they continue, “apart from the LPA variant rs3798220, we did not observe any other strong association among the 4,500 low frequency (1–5%) variants and/or variants with suspected or known functional impact on protein structure/function or gene expression specifically selected for the inclusion on the array.”

SNPs at 24 loci identified in the first phase of the study (not including the three already verified via the CARDIoGRAM study) were then evaluated in a second replication study of 17,121 CAD European cases and 40,473 European controls derived from the CARDIoGRAM and EPIC-NL studies. This confirmed an association with CAD for four of the candidate variants sited in or adjacent to LIPA, IL5, TRIB1, and ABCG5/ABCG8.

To try and get some insight into the biological impact of these variants, the researchers evaluated data from previous GWA meta-analyses of diabetes, systolic blood pressure, LDL-cholesterol and HDL-cholesterol, as well as triglycerides. This indicated that the risk allele at the TRIB1 locus was associated with higher triglyceride, higher LDL-C, and lower HDL-C. The ABCG5/ABCG8 risk allele, on the other hand, was associated with higher LDL-C.

Interestingly, for most of the loci the frequency of risk alleles and pattern of risk associations were no different qualitatively between the European and South Asian populations, although the evidence of association was often weaker in South Asians, possibly due to lower power, the authors note.

However, the discovery phase of the study did identify three variants at TUB, LCT, and MICB that showed association with CAD specifically in the South Asian cohort. These loci were taken forward into the replication phase but didn’t show any association in this European cohort. The three loci will therefore require replication in additional South Asian samples, they state.

The investigators further point out that the odds ratios observed for the novel loci were generally lower than those of previously identified loci, suggesting that most of the common variants with moderate effects have already been identified, and that increasingly larger sample sizes will be needed to detect other common variants that affect risk of CAD.

Nevertheless, they stress, “the modest odds ratios associated with such variants do not necessarily imply that they are not of potential clinical or therapeutic relevance.” For example, common variants in the LDLR gene have only a modest impact on CAD risk, but the pathway involved has nevertheless become a major target for the development of statins.

“Our study brings to 33 the number of confirmed loci with common variants affecting risk of CAD,” the researchers conclude. “We estimate that in aggregate these variants explain about 9% of the heritability of CAD.” 

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