Pleiotropic effect of common variants at ABO Glycosyltranferase locus in 9q32 on plasma levels of pancreatic lipase and angiotensin converting enzyme

Abstract

For forty-three clinical test values presumably associated to common complex human diseases, we carried out a genome-wide association study using 600K SNPs in a general Japanese population of 1,639 individuals (1,252 after quality control procedures) drawn from a regional cohort, followed by a replication study for statistically significant SNPs (p = 1.95 × 10(-9)-8.34 × 10(-39)) using an independent population of 1,671 from another cohort. In this single two-stage study, we newly found strong and robust associations of common variants at the ABO histo-blood glycosyltransferase locus in 9q32 with the plasma levels of pancreatic lipase (P-LIP), in addition to successful confirmation of the known ABO association of angiotensin converting enzyme (ACE) independent of the ACE1 gene in 17q23.2 with the ACE level. Our results are compatible with the previously reported association between the ABO gene and pancreatic cancer, and show that the effect of these common variants at the ABO locus on the P-LIP and ACE levels is largely opposing and pleiotropic.

Figure 1. Manhattan plot for genome-wide association signals with the P-LIP (upper panel) and ACE (lower) levels in the Takahata population by linear regression with adjustment for age and gender as covariates.

The red line represents a genome-wide significance level (5×10⁻⁸), whereas the blue line represents a genome-wide suggestive level (1×10⁻⁷). The red broken boxes indicate loci having the SNPs that attained a genome-wide significance level or the Bonferroni's corrected level by the number of phenotypes.

Figure 2. Gene map from RefSeq (upper panel), association pattern (middle), and LD structure (lower) by D′ measure in the Takahata population, in the 186 kb region from 136,040,829 to 136,227,260 of 9q32, using the coordinate system of the human genomic DNA sequence (GRCh37/hg19).

The association pattern is expressed by plots of −log(p-value) with lines connecting five-point moving averages for SNPs around the ABO and ACE1 loci in the Takahata (1st) and Yamagata (2nd) populations. The numbered black bars indicate LD blocks defined by a confidence-interval of D′ measure that reflects those in the LD structure panel.

Figure 3. Gene map from RefSeq (upper panel), association pattern (middle), and LD structure (lower) by D′ measure in the Takahata population, in the 183 kb region from 61,481,619 to 61,664,990 of 17q23.2, using the coordinate system of the human genomic DNA sequence (GRCh37/hg19).

The association pattern is expressed by plots of −log(p-value) with lines connecting five-point moving averages for SNPs around the ABO and ACE1 loci in the Takahata (1st) and Yamagata (2nd) populations. The numbered black bars indicate LD blocks defined by a confidence-interval of D′ measure that reflects those in the LD structure panel.

Figure 4. ABO locus and PLIP/ACE levels.

(a) Box plots for the P-LIP and ACE level per each genotype of the significant SNPs at the ABO locus in the combined population of Takahata and Yamagata with adjustment for age and gender as covariates. These plots show the difference and direction of effects of each SNP on P-LIP and ACE. (b) One-way ANCOVA for the means of the P-LIP and ACE levels per genomically-deduced ABO group in the combined population with adjustment for age and gender as well as rs4356 (the effect of ACE1), in which AA is set as the baseline group in the corner-point parameterization denoted as “base”. Asterisks denote that the significance level reached in the one-way ANCOVA (*** <0.001).

Figure 5. Scatter plots of the P-LIP levels with each of the other clinical test values in the Takahata population, where the plotted values are residuals from linear regression of each test value on age and gender.

These plots show no strong correlation of each of other phenotypes to P-LIP. Each r denotes Pearson's (product-moment) correlation coefficient. The names and abbreviations of the total of 43 quantitative values are listed below (asterisks denote that it is plasma level); ACE (angiotensin converting enzyme*), ADP (adiponectin*), albumin*, amylase*, ANA (antinuclear antibody*), HBs (hepatitis Bs antigen*), HCV3 (hepatitis C virus 3 antibody, index*), HPE (Helicobacter pylori antibody E*), BMI (body mass index), BNP (B-type natriuretic peptide*), BUN (blood urea nitrogen*), ChE (cholinesterase*), cholesterol (total cholesterol*), creatinine*, D dimer*, diastolic BP (diastolic blood pressure), Fe (iron*), FEV1/FVC (forced expiratory volume in 1s/forced vital capacity), fibrinogen*, FM (fibrin monomer complex*), gGTP (gamma glutamyl transpeptidase*), GOT (asparate aminotransferase*), GPT (alanine aminotransferase*), HbA1c (hemoglobin A1c*), HDL-C (high density lipoprotein cholesterol*), hematocrit, hemoglobin, H-cys (homocysteine*), H-FABP (Heart type fatty acid-binding protein*), insulin (before a meal*), LDL-C (low density lipoprotein cholesterol*), P-LIP (pancreatic lipase*), neutral fat*, PG1/PG2 (pepsinogen 1/2 ratio), P-AMY (pancreatic amylase*), RBC (red blood cell counts), renin*, RLP-C (remnant-like particle cholesterol*), FBG (fasting blood glucose*), systolic BP (systolic blood pressure), TP (total protein*), UA (uric acid*), and U albumin (urinary albumin).

Figure 6. Scatter plots of the ACE levels with each of the other clinical test values in the Takahata population.

These plots show no strong correlation of each of other phenotypes to ACE. Each r denotes Pearson's (product-moment) correlation coefficient. The names and abbreviations of the total of 43 quantitative values are same as Figure 5.