ABO Locus Research Articles

Regions on Chromosomes 1 and 14 Are Associated with VWF:Ag Levels in African Americans Using Mapping By Admixture Linkage Disequilibrium

Background: VWF:Ag is highly heritable, however, despite genome-wide linkage and association analysis, mostly in European derived populations, the genetic basis for VWF levels is only partially understood. African Americans (AfAm) have significantly higher VWF:Ag than European Americans: although variants in VWF and ABO can account for some of this, it is not clear whether they explain all of this ethnic difference. A powerful method to identify chromosomal regions that account for ethnic differences is mapping by admixture linkage disequilibrium (MALD). MALD uses markers that differ markedly in allele frequency between ancestral populations, estimates the global ancestry for each individual, and compares local ancestry between subjects with different trait values to global estimates to identify regions of the genome that account for the ethnic differences of a trait.Hypothesis: Loci that are associated with VWF:Ag levels in AfAm can be mapped using MALD.Methods: From 188 AfAm healthy volunteers from the Zimmerman Program for the Molecular and Clinical Biology of VWD, 96 were selected to have 98≤VWF:Ag≥ 164 IU which represent the <25% and >75% of VWF:Ag distribution. They were genotyped using Illumina HumanCoreExome genome-wide SNP chip. SNPs were selected for MALD if they had allele frequency difference between ancestral population (YRI and CEU from HapMap) of >0.4. Related and non-admixed individuals were excluded. Extreme trait analysis was performed using ADMIXMAP.Results: 16 males and 68 females (mean age 41 years, SD=13) of whom 41 had with Ag≤98and 43 with Ag ≥164 IU were subjected to analysis with 2254 ancestry informative markers across the genome with a mean spacing of 1.8 cM (1.3 Mb). Estimated African ancestry was 79% (SD=13%, range 24-96%), while European ancestry was 20% (SD=12%, range 4-72%). Comparing the subjects at extremes of VWF, regions on chrs 1 (110-147 Mb) and 14 (22-40 Mb) had |Z| scores >3 (p<0.0025) which is the conventional cut-off in MALD studies. At chrs 1 and 14, greater African admixture was associated with higher VWF:Ag, consistent with the expected direction. No significant admixture signal was observed at the VWF (p=0.39) or ABO (p=0.48) loci, which may represent low power due to small sample size.Discussion: These pilot results require replication in a larger number of independent subjects, as well as fine-mapping to identify the underlying variants responsible for differences in VWF between individuals. DisclosuresNo relevant conflicts of interest to declare.

Abstract 16411: Abo Blood Group and Risk of Myocardial Infarction in Hispanics

Hypothesis: ABO blood group has been associated with myocardial infarction (MI) in Caucasians. This study evaluated whether genotype-derived ABO blood group associated with MI in Hispanics, and whether lifestyle risk factors modified the associations. Methods: Cases (n=2273) with a first acute nonfatal MI and population-based controls (n=2274) living in Costa Rica were studied. Five ABO single-nucleotide polymorphisms (SNPs) were genotyped. RESULTS: Three SNPs (rs687289, rs507666, and rs579459) at ABO locus showed significant associations with MI risk, with odds ratios (ORs, 95% confidence interval) of 1.17(1.05-1.30), 1.18(1.05-1.32), and 1.14(1.02-1.28), respectively. Compared to subjects with blood group O, the ORs for blood group A, AB and B were 1.24 (95% CI, 1.08-1.43), 1.15 (95% CI, 0.95-1.39), and 1.10 (95% CI, 0.77-1.57), respectively. Subjects with non-O blood group had an adjusted OR for MI of 1.20 (95% CI, 1.05-1.37) when compared to subjects with O blood group after adjustment for age, sex, area of residence, smoking, alcohol consumption, physical activity, total calories, and family history of MI. CONCLUSIONS: Our results indicate both the consistency and disparity of ABO genetic effects on MI risk between Hispanics and Caucasians.

Reappraisal of known malaria resistance loci in a large multicenter study.

Many human genetic associations with resistance to malaria have been reported but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. There was strong evidence of association with the HBB, ABO, ATP2B4, G6PD and CD40LG loci but previously reported associations at 22 other loci did not replicate in the multi-centre analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anaemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

ABO and Rh (D) Blood Groups Polymorphism in Four Tehsils of Bajaur Agency (Federally Administered Tribal Areas), Pakistan

The tribal populations at the Pakistan-Afghanistan border are of great scientific interest because of their transitionary status which is due to the volatile law-and-order situation in this region from the last few decades. The present study aimed at elucidating the ABO and Rh blood groups polymorphisms in the Bajaur population, which is a war affected territory in the in north-western Pakistan. Blood groups data were obtained from 1,200 unrelated male subjects belonging to four tehsils of Bajaur Agency. Phenotyping was performed through forward typing. At the ABO locus, allele (O) was observed to be highly frequent (0.544), followed by alleles (B) and (A) with the frequencies of 0.231 and 0.225, respectively. At the Rh locus, allele frequencies for (D) and (d) were found to be 0.707 and 0.293, respectively. The total sample was in confirmity with the Hardy-Weinberg expectations. A comparison of allelic frequencies at both loci with neigboring populations through Nei's genetic distance D revealed that Bajaur sample had close affinities with Dir-Lower and Swat populations but least with Swabi and Peshawar populations. This study would be useful in the appreciating the genetic diversity of north-western populations of Pakistan.

Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population.

ABO blood serotype A is known to be associated with risk of gastric cancer (GC), but little is known how ABO alleles and the fucosyltransferase (FUT) enzymes and genes which are involved in Lewis antigen formation [and in Helicobacter pylori (H. pylori) binding and pathogenicity] may be related to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group A (AO+AA, odds ratio=1.84, 95%CI=1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes) in FUT2 (Se), FUT3 (Le) and FUT6 with intestinal-type GC. Further, one variant in ABO, two in FUT3 and two in FUT6 were associated with H. pylori infection status in controls, and two of these (in FUT3 and FUT6) were weakly associated with intestinal-type GC risk. None of the individual variants surpassed a Bonferroni corrected p-value cutoff of 0.0016; however, after a gene-based permutation test, two loci [FUT3(Le)/FUT5/FUT6 and FUT2(Se)] were significantly associated with diffuse- and intestinal-type GC, respectively. Replication and functional studies are therefore recommended to clarify the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis.

Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism

IntroductionWe investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case–control study (n=2753) from Sweden. Materials and Methods39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression. ResultsOnly rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n=7181). ConclusionsIt appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.

Pleiotropic Effect of Common Variants at ABO Glycosyltranferase Locus in 9q32 on Plasma Levels of Pancreatic Lipase and Angiotensin Converting Enzyme

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.

Erratum: Ischemic stroke is associated with the ABO locus: The EuroCLOT study

Erratum: Ischemic stroke is associated with the ABO locus: The EuroCLOT study

A Case of Dispermic Chimerism with Normal Phenotype Identified During ABO Blood Grouping

Human chimerism with normal phenotype derived from the fusion of two different zygotes is a rare phenomenon. We describe a case of a phenotypically normal 17-year-old diagnosed with dispermic chimerism during routine ABO blood grouping. ABO grouping, ABO genotyping, karyotyping, human leukocyte antigen (HLA) typing, and short tandem repeat (STR) analysis were performed. Forward typing with anti-A and anti-B sera resulted in mixed-field agglutination of red blood cells. The mother and father were blood group O and AB, respectively. The proposita had O1, A201 and B alleles in the ABO locus; O1 was a maternal allele, while A201 and B were the paternal alleles. The proposita karyotype was 46,XX/46,XY. HLA typing revealed that the proposita had three alleles (46, 51, 54) at the HLA-B locus, with the additional allele of paternal origin. STR analysis identified three alleles for five of the 15 markers (D2S1338, TPOX, D8S1179, D19S433, and D21S11) analyzed in the proposita's blood- and skin fibroblast-derived DNA. The additional alleles of TPOX, D8S1179, and D21S11 were of paternal origin. The genetic findings suggest that this proposita was produced by dispermic fertilization of two identical haploid ova formed by parthenogenetic activation.

Molecular characterization of weaker variants of A and B in Indian population – The first report

The ABO blood group system is extremely important blood group system in transfusion medicine and weaker variants of A and B are subgroups of the system. From a Country like India with 1.2 billion population sporadic reports detecting weaker variants of A and B serologically are published. Therefore the main objective of the present study is to identify weaker variants of A and B serologically and characterize them at molecular level. Eight samples which were referred to us for resolving discrepancies in forward and reverse grouping were first phenotype in our laboratory by standard serologic techniques for ABO blood groups. Molecular genotyping for the ABO locus was done by PCR-SSCP. Altered SSCP patterns were analysed by DNA sequencing. Sequencing of intron 6 and exons 1-5 was done in one sample each. Nine rare alleles affecting the normal expression of A and B antigens have been identified among Indians. They were two Aw06, one A209, one Ax20, two O05, one O49, one O56 and one O19 alleles. This is the first report demonstrating molecular studies on weaker variants of A and B from India.

Genome-wide association study on serum alkaline phosphatase levels in a Chinese population

BackgroundSerum alkaline phosphatase (ALP) is a complex phenotype influenced by both genetic and environmental factors. Recent Genome-Wide Association Studies (GWAS) have identified several loci affecting ALP levels; however, such studies in Chinese populations are limited. We performed a GWAS analyzing the association between 658,288 autosomal SNPs and serum ALP in 1,461 subjects, and replicated the top SNPs in an additional 8,830 healthy Chinese Han individuals. The interactions between significant locus and environmental factors on serum ALP levels were further investigated.ResultsThe association between ABO locus and serum ALP levels was replicated (P = 2.50 × 10-21, 1.12 × 10-56 and 2.82 × 10-27 for SNP rs8176720, rs651007 and rs7025162 on ABO locus, respectively). SNP rs651007 accounted for 2.15% of the total variance of serum ALP levels independently of the other 2 SNPs. When comparing our findings with previously published studies, ethnic differences were observed across populations. A significant interaction between ABO rs651007 and overweight and obesity was observed (FDR for interaction was 0.036); for individuals with GG genotype, those with normal weight and those who were overweight or obese have similar serum ALP concentrations; minor allele A of rs651007 remarkably reduced serum ALP levels, but this effect was attenuated in overweight and obese individuals.ConclusionsOur findings indicate that ABO locus is a major determinant for serum ALP levels in Chinese Han population. Overweight and obesity modifies the effect of ABO locus on serum ALP concentrations.

Quantitative Variation in Plasma Angiotensin‐I Converting Enzyme Activity Shows Allelic Heterogeneity in the ABO Blood Group Locus

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.

INTERRELATION BETWEEN BLOOD GROUPS / RHESUS FACTOR AND DIABETIC INCIDENCE OF FEMALE IN ALJABAL ALAKHDAR IN LIBYA

Diabetic disease has considered a major worldwide public health problem , has bad complications and also has different etiological agents such as environmentally – physiologically – immunologically – genetically reasons . It is found that the genetic variants at ABO Locus affect diabetes risk and thus ABO blood group phenotypes may be associated with diabetic incidence . So ,the present study aims to determine frequency of blood groups ABO and rhesus factor Rh phenotypes in female diabetic patients .This research includes number of diabetic populations samples which are collected from some clinical laboratories , hospitals in some regions of Aljabal Alakhdar in Libya . By current criteria for diagnosis and taking patient history , the diabetes could be classified into three types (the first type (1) , the second type( 2) and the third type (3)). Then, ABO group techniques were worked by agglutination test and statistical analysis was carried out by split plot design .The findings in this research have supported the hypothesis that diabetes and blood group types are associated. Also, it could be suggested that the factor Rh which is on red blood cells may have a role to some extent in determine the type of diabetes in related to ABO groups .

Mediation analysis reveals a sex-dependent association between ABO gene variants and TG/HDL-C ratio that is suppressed by sE-selectin level

ObjectivePrevious investigations have revealed an association between the ABO locus/blood group and total cholesterol and inflammatory biomarker levels. We aimed to test the statistical association of ABO locus variants with lipid profiles and levels of thirteen inflammatory markers in a Taiwanese population. Methods and resultsA sample population of 617 Taiwanese subjects was enrolled. Five ABO gene region polymorphisms were selected and genotyped. After adjusting for clinical covariates and inflammatory marker levels, the genetic-inferred ABO blood group genotypes were associated with sE-selectin level (P = 3.5 × 10−36). Significantly higher total and low-density lipoprotein cholesterol (LDL-C) levels were noted in individuals with blood group A (P = 7.2 × 10−4 and P = 7.3 × 10−4, respectively). Interestingly, after adjusting for sE-selectin level, significantly lower high-density lipoprotein cholesterol (HDL-C) level as well as higher triglyceride (TG) level and ratio of triglyceride to HDL-C (TG/HDL-C ratio) were noted in individuals with blood group A comparing to non-A individuals (P = 0.009, P = 0.004 and P = 0.001, respectively); these associations were also observed in the group A male subjects (P = 0.027, P = 0.001, and P = 0.002, respectively). Mediation analysis further revealed a suppression effect of sE-selectin level on the association between genetic-inferred ABO blood group genotypes and TG/HDL-C ratio in total participants (P = 1.18 × 10−6) and in males (P = 5.99 × 10−5). ConclusionGenetic variants at the ABO locus independently affect sE-selectin level in Taiwanese subjects, while the association of ABO locus variants with TG/HDL-C ratio is suppressed by sE-selectin level in Taiwanese males. These results provided further evidence for the mechanism in the association of ABO blood groups with atherosclerotic cardiovascular diseases.

Genetic Diversity among Coastal Populations of Maharashtra, Goa and Odisha, India

India has served as a gateway between continents, with waves of human migration leaving rich cultural and linguistic diversity in their wake. Studies of genetic variation provide inferences about the nature and intensity of forces that have modulated our evolutionary course. The researchers analyzed genetic diversity using 5 genetic markers (ABO, MN, Rh, Se and tasters/non-tasters) in seven populations sampled from Maharashtra, Goa (western coastal zone) and Odisha (eastern coastal zone) of India. The genetic distance estimated by the DISPAN program revealed that geographic segregation has led to genetic divergence among the population of similar ethnicity while population inhabiting same geographical region had higher genetic affinity despite their ethnic origin. ABO locus among all showed maximum genetic divergence between the populations. However, more studies referring to the coastal populations of India could provide new insights into the processes of admixture, selection and drift which lead to population dispersal and differentiation.

ABO blood groups and pancreatic cancer risk and survival: results from the PANcreatic Disease ReseArch (PANDoRA) consortium.

There is strong epidemiologic evidence indicating that common genetic variability could be implicated in pancreatic cancer risk and, to date, various loci have been proposed. In particular, there is increasing evidence of the involvement of ABO gene variability and pancreatic cancer risk. In a large multicentric study of 1,028 pancreatic ductal adenocarcinoma cases and 2,257 controls in the context of the PANcreatic Disease ReseArch (PANDoRA) consortium, we investigated the suggested association with increased risk for carriers of single nucleotide polymorphisms (SNPs) determining the A or Ballele in comparison with the Oallele, which encodes for a non-functional enzyme. Since glycosyltransferase activity, encoded by ABO, is higher for the A1 variant compared with the A2 variant, we investigated the hypothesis that A1 carriers were at an increased risk of pancreatic cancer. In our analysis, carriers of the A1 were indeed at greater risk of developing the disease. In addition, we investigated the possible influence that genetic variability at the ABO locus may have in pancreatic cancer survival, but we observed no effect in our population.

Plant sterols and atherosclerosis

Plant sterols as ingredients to functional foods are recommended for lowering LDL cholesterol. However, there is an ongoing discussion whether the use of plant sterols is safe. Genetic analyses showed that common variants of the ATP binding cassette transporter G8 (ABCG8) and ABO genes are associated with elevated circulating plant sterols and higher risk for cardiovascular disease. However, these data do not prove a causal role for plant sterols in atherosclerosis because the risk alleles in ABCG8 and ABO are also related to elevated total and LDL cholesterol levels. The ABO locus exhibits still further pleiotropy. Moreover, analyses in the general population indicated that moderately elevated circulating plant sterols are not correlated with present or future vascular disease. In agreement, novel studies using food frequency questionnaires, studies in experimental animals, and dietary intervention studies support that ingestion of plant sterols may be beneficial to cardiovascular health. Taken together, current evidence supports the recommendations for the use of plant sterols as LDL cholesterol-lowering agents. Nevertheless, a prospective, randomized, controlled, double-blinded, intervention trial conclusively showing that plant sterol supplementation will prevent hard cardiovascular endpoints is not available to date.

Ischemic stroke is associated with the ABO locus: the EuroCLOT study.

ObjectiveEnd-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy REFVIDunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.MethodsCommon genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).ResultsStage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10–8) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10–186), rs10665 with FVII (p = 2.4 × 10–47), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10–57) and factor VIII (p = 1.2 × 10–36). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88–0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).InterpretationABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Ann Neurol 2013

A Variant In the Abo Gene Explains the Variation in Soluble E-Selectin Levels—Results from Dense Genotyping in Two Independent Populations

BackgroundElevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.Methodology/ Principal FindingsData of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of −0.37 ng/ml (p = 1.87×10−103) in KORA and −0.35 ng/ml (p = 5.11×10−84) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.Conclusions/ SignificanceOur findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.

A gene-centric analysis of activated partial thromboplastin time and activated protein C resistance using the HumanCVD focused genotyping array

Activated partial thromboplastin time (aPTT) is an important routine measure of intrinsic blood coagulation. Addition of activated protein C (APC) to the aPTT test to produce a ratio, provides one measure of APC resistance. The associations of some genetic mutations (eg, factor V Leiden) with these measures are established, but associations of other genetic variations remain to be established. The objective of this work was to test for association between genetic variants and blood coagulation using a high-density genotyping array. Genetic association with aPTT and APC resistance was analysed using a focused genotyping array that tests approximately 50 000 single-nucleotide polymorphisms (SNPs) in nearly 2000 cardiovascular candidate genes, including coagulation pathway genes. Analyses were conducted on 2544 European origin women from the British Women's Heart and Health Study. We confirm associations with aPTT at the coagulation factor XII (F12)/G protein-coupled receptor kinase 6 (GRK6) and kininogen 1 (KNG1)/histidine-rich glycoprotein (HRG) loci, and identify novel SNPs at the ABO locus and novel locus kallikrein B (KLKB1)/F11. In addition, we confirm association between APC resistance and factor V Leiden mutation, and identify novel SNP associations with APC resistance in the HRG and F5/solute carrier family 19 member 2 (SLC19A2) regions. In conclusion, variation at several genetic loci influences intrinsic blood coagulation as measured by both aPTT and APC resistance.