A Genome-Wide Association Study Identifies Protein Quantitative Trait Loci (pQTLs)

Abstract

There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts – cis effects, and elsewhere in the genome – trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8×10−57), CCL4L1 (p = 3.9×10−21), IL18 (p = 6.8×10−13), LPA (p = 4.4×10−10), GGT1 (p = 1.5×10−7), SHBG (p = 3.1×10−7), CRP (p = 6.4×10−6) and IL1RN (p = 7.3×10−6) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8×10−40), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

ABO Blood Groups and Risk of Cancer: a Systematic Review and Meta-analysis

“…Modified expression of blood group antigens on the surface of cancer cells may alter cell motility, sensitivity to apoptosis and immune escape, and thus influence the initiation and spread of cancer (Le Pendu et al, 2001). In addition, recent studies have reported associations between ABO blood groups and circulating levels of tumor necrosis factor-alpha and soluble ICAM-1, E-selectin and P-selectin (Melzer et al, 2008;Paterson et al, 2009;Barbalic et al, 2010;Qi et al, 2010), suggesting that blood group antigens may influence the systemic inflammatory response. Chronic inflammation has been extensively linked with cancer development (Grivennikov et al, 2010), and provides a further potential mechanism by which ABO antigens may influence cancer risk.…”

ABO and Rh Blood Groups in Relation to Ovarian, Endometrial and Cervical Cancer Risk Among The Population of South-East Siberia

“…It has been shown that the presence of A and B antigens may increase cellular motility and facilitate the interactions between tumor cells (Le Pendu et al, 2001). Moreover, it has been observed that ABO antigens may contribute to the resistance to apoptosis and immune escape (Melzer et al, 2008). Alternatively, some research has shown that structure of certain tumor antigens is similar to the structure of antigens of ABO system.…”

De novo rates and selection of large copy number variation

“…Illumina Hap550 genotyping data used for this purpose consisted of lymphoblastoid cell line DNA from 671 neurologically normal Caucasian controls from a study of Parkinson's disease (dbGaP accession no. phs000089; Simon-Sanchez et al 2007) and peripheral blood DNA from 699 individuals of European ancestry from the InCHIANTI study of aging (http://www.inchiantistudy.net; Melzer et al 2008).…”