Figure 1.
Figure 1a: Strategy for exploring the association of LDLR polymorphism rs2228671 with LDL-C levels and CAD across multiple populations. Studies based on imputed genotypes for rs2228671 are marked with a *. Figure 1b: Schematic overview of study populations
Figure 2.
Figure 2a: Association of the chromosomal locus 19p13.2 with LDL-C levels in population-based sample. Presented are p-values from linear regression of LDL-C on SNPs adjusted for age and gender. p-values of the SNPs genotyped on the Affymetrix GeneChip® 500K Mapping Array Set are displayed as closed squares, p-values predicted by HapMap-based imputation are displayed as blank circles. SNP rs2228671 is highlighted as a red circle. Figure 2b: Linkage disequilibrium structure of the genomic region surrounding SNP rs2228671. Displayed are the HapMap data (r2;[19]) of all SNPs surrounding rs2228671 (11030947–11079189) and the genes within this region.
Figure 3.
Figure 3a: Association of SNP rs2228671 with LDL-C levels across populations. Displayed are means of LDL-C and standard error of means stratified by rs2228671 genotype. Unadjusted levels of significance are displayed for each individual study. Effects for the pooled study are from a random effect linear regression model. Figure 3b: Pooled analysis of the association of rs2228671 with LDL-C across populations stratified by age groups and gender. Displayed are means of LDL-C and standard error of means stratified by rs2228671 genotype, separately for age groups (<20, 21–35, 36–50, >50), men and women.
Figure 4.
Association of rs2228671 with risk of CAD in six case-control studies.
Displayed are heterozygous and homozygous ORs for CAD and 95% CI per study from two-sided asymptotic Cochrane-Armitage trend test. Pooled ORs, 95% CIs and p-values are from random effect logistic regression models. The number of individuals in each study is represented by size of the closed square. SNP rs2228671 was imputed from the Affymetrix GeneChip® 500K Mapping Array Set in the WTCCC and German MI Family Study I and genotyped directly in the remaining studies.
Figure 5.
Results of Mendelian Randomisation study.
Exploration of the causal relationship between LDL-C associated with rs2228671 and CAD (Mendelian Randomisation). In the structural equation model, carriage of the T allele at rs2228671 leads to lower LDL-C levels, and higher LDL-C levels lead to an increased risk of CAD. Given this, there is no additional direct path from rs2228671 to CAD risk, indicating that the functional pathway between the genetic variant at the LDLR gene locus and risk of CAD is through changes in LDL-C.