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The cellular adhesion pathway is critical in the pathophysiology of atherosclerosis, and genetic factors contributing to regulation of circulating levels of related proteins may be relevant to risk prediction of cardiovascular disease. In contrast to conducting separate genome-wide protein quantitative trait loci (pQTL) mapping analyses of each individual protein, joint genetic association analyses of multiple quantitative traits can leverage cross-trait co-variation and identify simultaneous regulatory effects on protein levels across the pathway. We conducted a multi-pQTL (mpQTL) analysis of 15 proteins related to cellular adhesion assayed on 2313 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). We applied the MQFAM multivariate association analysis method in PLINK on normalized protein level residuals derived from univariate linear regression, adjusting for age, sex, and principal components of ancestry. Race/ethnicity-stratified analyses identified nine genome-wide significant (P < 5e-08) loci associated with co-variation of protein levels. Although the majority of these SNPs were in proximity to structural genes of the assayed proteins, we discovered multiple loci demonstrating co-association with the circulation of at least two proteins. Of these, two significant loci specific to non-Hispanic white participants, rs17074898 at ALOX5AP (P = 1.78E-08) and rs7521237 at KIAA1614 (P = 2.2E-08), would not have met statistical significance using univariate analyses. Moreover, common patterns of multi-protein associations were discovered at the ABO locus across race/ethnicity. These results indicate the biological relevance of blood group antigens on regulation of circulating cellular adhesion pathway proteins while also demonstrating race/ethnicity-specific co-regulatory effects.

L-Selectin is constitutively expressed on leukocytes and mediates their interaction with endothelial cells during inflammation. Previous studies on the association of soluble L-selectin (sL-selectin) with cardiovascular disease (CVD) are inconsistent. Genetic variants associated with sL-selectin levels may be a better surrogate of levels over a lifetime. We explored the association of genetic variants and sL-selectin levels in a race/ethnicity stratified random sample of 2,403 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Through a genome-wide analysis with additive linear regression models, we found that rs12938 on the SELL gene accounted for a significant portion of the protein level variance across all four races/ethnicities. To evaluate potential additional associations, elastic net models were used for variants located in the SELL/SELP/SELE genetic region and an additional two SNPs, rs3917768 and rs4987361, were associated with sL-selectin levels in African Americans. These variants accounted for a portion of protein variance that ranged from 4 % in Hispanic to 14 % in African Americans. To investigate the relationship of these variants with CVD, 6,317 subjects were used. No significant association was found between any of the identified SNPs and carotid intima-media thickness or presence of carotid plaque using linear and logistic regression, respectively. Similarly no significant results were found for coronary artery calcium or coronary heart disease events. In conclusion, we found that variants within the SELL gene are associated with sL-selectin levels. Despite accounting for a significant portion of the protein level variance, none of the variants was associated with clinical or subclinical CVD.

Aims/hypothesis: Hyperglycaemia disproportionately affects African-Americans (AfAs). We tested the transferability of 18 single-nucleotide polymorphisms (SNPs) associated with glycaemic traits identified in European ancestry (EuA) populations in 5,984 non-diabetic AfAs., Methods: We meta-analysed SNP associations with fasting glucose (FG) or insulin (FI) in AfAs from five cohorts in the Candidate Gene Association Resource. We: (1) calculated allele frequency differences, variations in linkage disequilibrium (LD), fixation indices (F(st)s) and integrated haplotype scores (iHSs); (2) tested EuA SNPs in AfAs; and (3) interrogated within ± 250 kb around each EuA SNP in AfAs., Results: Allele frequency differences ranged from 0.6% to 54%. F(st) exceeded 0.15 at 6/16 loci, indicating modest population differentiation. All iHSs were <2, suggesting no recent positive selection. For 18 SNPs, all directions of effect were the same and 95% CIs of association overlapped when comparing EuA with AfA. For 17 of 18 loci, at least one SNP was nominally associated with FG in AfAs. Four loci were significantly associated with FG (GCK, p = 5.8 × 10(-8); MTNR1B, p = 8.5 × 10(-9); and FADS1, p = 2.2 × 10(-4)) or FI (GCKR, p = 5.9 × 10(-4)). At GCK and MTNR1B the EuA and AfA SNPs represented the same signal, while at FADS1, and GCKR, the EuA and best AfA SNPs were weakly correlated (r(2) <0.2), suggesting allelic heterogeneity for association with FG at these loci., Conclusions/interpretation: Few glycaemic SNPs showed strict evidence of transferability from EuA to AfAs. Four loci were significantly associated in both AfAs and those with EuA after accounting for varying LD across ancestral groups, with new signals emerging to aid fine-mapping.

Markers of monocyte activation play a critical role in atherosclerosis, but little is known about the genetic influences on cellular levels. Therefore, we investigated the influence of genetic variants in monocyte differentiation antigen (CD14), toll-like receptor-4 (TLR4), toll-like receptor-2 (TLR2), and myeloperoxidase (MPO) on monocyte surface receptor levels. The study sample consisted of 1,817 members of a biracial cohort of adults from the Atherosclerosis Risk in Communities Carotid MRI Study. Monocyte receptors were measured using flow cytometry on fasting whole blood samples. TLR2 rs1816702 genotype was significantly associated with CD14+/TLR2+ percent of positive cells (%) and median fluorescence intensity (MFI) in whites but not in blacks (p < 0.001). Specifically, the presence of the minor T-allele was associated with increased receptor levels. In blacks, TLR4 rs5030719 was significantly associated with CD14+/TLR4+ monocytes (MFI) with mean ± SE intensities of 16.7 ± 0.05 and 16.0 ± 0.14 for GG and GT/TT genotypes, respectively (p < 0.001). Variants in TLR2 and TLR4 were associated with monocyte receptor levels of TLR2 and TLR4, respectively, in a biracial cohort of adults. To our knowledge, this is the first study to look at associations between variants in the toll-like receptor family and toll-like receptor levels on monocytes.

Type 2 diabetes mellitus (T2DM) is characterized by impaired insulin secretion, peripheral insulin resistance, and increased hepatic glucose production. Genes that contribute to genetic susceptibility to T2DM function in numerous biochemical pathways. Uncoupling protein-2 (UCP2) functions as a negative regulator of insulin secretion. Animal studies show induction of UCP2 plays a pathogenic role in the progression of obesity-induced T2DM and some human studies have shown an association between a common UCP2 polymorphism, Ala55Val (rs660339), and T2DM, obesity, and resting metabolic rate with the Val/Val genotype conferring increased risk. We investigated the relationship between the Ala55Val variant and incidence of T2DM among 12,056 participants in the Atherosclerosis Risk in Communities (ARIC) Study aged 45-64 years at baseline. Incident T2DM (n = 1,406) cases were identified over 9 years of follow-up. The Val55 allele frequency was 44% in blacks and 41% in whites. The rate of T2DM per 1,000 person was 15.0, 15.6, and 15.6 yearsfor Ala/Ala, Ala/Val, and Val/Val genotypes, respectively. We found no significant association between UCP2 genotypes and incident T2DM in the whole cohort, in race-gender subgroups, or in categories of body mass index (normal, overweight and obese). The Ala55Val polymorphism of UCP2 was not associated with incident T2DM in the ARIC cohort.

Aims/hypothesis: We hypothesised that TCF7L2 single nucleotide polymorphisms (SNPs) are associated with cardiovascular disease (CVD) and that the associations differ in diabetic and non-diabetic persons., Methods: Our analysis included black and white participants from the Atherosclerosis Risk in Communities study who were free of prevalent CVD at baseline and had been genotyped for rs7903146, rs12255372, rs7901695, rs11196205 and rs7895340 (n=13,369). Cox proportional hazard regression was used to estimate the associations between polymorphisms and incident events; logistic and linear regression were used for associations with baseline risk factor levels., Results: TCF7L2 SNPs were not significantly associated with incident coronary heart disease, ischaemic stroke, CVD, prevalent peripheral artery disease (PAD) or all-cause mortality in the full cohort or when stratified by race., Conclusions/interpretation: In the whole cohort, TCF7L2 SNPs were not associated with incident CVD, all-cause mortality or prevalent PAD. This result suggests that the increased health risk associated with rs7903146 genotype is specific to diabetes.

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD=3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD=3.0 at 182 cM) and 12 (LOD=3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD >or= 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.