New variants of <i>VKORC1</i> identified in this study and their impact on acenocoumarol dose in whole sample (3949 patients) and in 57 outlier patients.

*<p>mean ±SD of acenocoumarol expressed as mg/week. P value is calculated by t test to compare acenocoumarol dose depending on genotypes in the whole sample. One sample is missed for genotyping rs17878544 and three for R12R.</p

Summary of the additive regression model (stepwise method): predictor contribution to steady therapeutic dose of acenocumarol in 3949 anticoagulated patients.

<p>Summary of the additive regression model (stepwise method): predictor contribution to steady therapeutic dose of acenocumarol in 3949 anticoagulated patients.</p

Clinical characteristics and genetic profiles of 6 patients who lost the LD between <i>VKORC1</i> polymorphisms rs2323991 and rs9934438.

<p>#Dose as mg of acenocoumarol per week PE: pulmonary embolism; AF: atrial fibrillation; DVT: deep venous thrombosis</p

Study design: selection of patients from a retrospective cohort of subjects anticogulated with acenocoumarol (N = 3949).

<p>Study design: selection of patients from a retrospective cohort of subjects anticogulated with acenocoumarol (N = 3949).</p

Ranking of acenocoumarol dose distribution in VKORC1 and CYP2C9 combined genetic profiles in 3949 anticoagulated patients.

<p>Ranking of acenocoumarol dose distribution in VKORC1 and CYP2C9 combined genetic profiles in 3949 anticoagulated patients.</p

Novel Susceptibility Variants at 10p12.31-12.2 for Childhood Acute Lymphoblastic Leukemia in Ethnically Diverse Populations

BackgroundAcute lymphoblastic leukemia (ALL) is the most common cancer in children and the incidence of ALL varies by ethnicity. Although accumulating evidence indicates inherited predisposition to ALL, the genetic basis of ALL susceptibility in diverse ancestry has not been comprehensively examined.MethodsWe performed a multiethnic genome-wide association study in 1605 children with ALL and 6661 control subjects after adjusting for population structure, with validation in three replication series of 845 case subjects and 4316 control subjects. Association was tested by two-sided logistic regression.ResultsA novel ALL susceptibility locus at 10p12.31-12.2 (BMI1-PIP4K2A, rs7088318, P = 1.1 × 10(-11)) was identified in the genome-wide association study, with independent replication in European Americans, African Americans, and Hispanic Americans (P = .001, .009, and .04, respectively). Association was also validated at four known ALL susceptibility loci: ARID5B, IKZF1, CEBPE, and CDKN2A/2B. Associations at ARID5B, IKZF1, and BMI1-PIP4K2A variants were consistent across ethnicity, with multiple independent signals at IKZF1 and BMI1-PIP4K2A loci. The frequency of ARID5B and BMI1-PIP4K2A variants differed by ethnicity, in parallel with ethnic differences in ALL incidence. Suggestive evidence for modifying effects of age on genetic predisposition to ALL was also observed. ARID5B, IKZF1, CEBPE, and BMI1-PIP4K2A variants cumulatively conferred strong predisposition to ALL, with children carrying six to eight copies of risk alleles at a ninefold (95% confidence interval = 6.9 to 11.8) higher ALL risk relative to those carrying zero to one risk allele at these four single nucleotide polymorphisms.ConclusionsThese findings indicate strong associations between inherited genetic variation and ALL susceptibility in children and shed new light on ALL molecular etiology in diverse ancestry