Comment on de Vries et al , page 3949 GWA study for ADAMTS 13 activity

ADAMTS13 is a plasma metalloprotease that specifically cleaves the plasma adhesive protein von Willebrand factor (VWF). VWF is a large plasma glycoprotein and mediates platelet adhesion at sites of vascular injury. VWF is synthesized in an ultralarge multimeric form that has a very strong platelet aggregation activity. VWF-induced platelet aggregation depends on its multimeric size, which is controlled by ADAMTS13. ADAMTS13 has a discrete domain structure, and the gene consists of 29 exons located on chromosome 9. Severe deficiency of ADAMTS13 activity due to ADAMTS13 variants or acquired autoantibodies that inhibit ADAMTS13 activity leads to thrombotic thrombocytopenic purpura (TTP), a disease caused by platelet aggregation by ultralarge VWF multimers. Rare causative loss-of-function genetic variants have been identified in patients with congenital TTP. In addition to TTP, ADAMTS13 may contribute to other thrombotic disorders. Low plasma levels of ADAMTS13 are associated with an increased risk for myocardial infarction and stroke. In addition, low plasma level is observed in severe sepsis, disseminated intravascular coagulation, and complicated malarial infection. These findings suggest a contribution of VWF-dependent platelet aggregation in some thrombotic disease states. If so, the identification of genetic and acquired factors that affect plasma ADAMTS13 activity is very important. So far, rare variants of the ADAMTS13 gene causing TTP have been identified. In addition, a few common genetic variants with modest effects on ADAMTS13 are reported. However, it is not clear whether the genetic variants exhibit strong associations at the locus. Furthermore, genetic variations outside the ADAMTS13 locus remain unknown. In this issue, de Vries et al adopted a systematic hypothesis-free GWA study approach to identify genetic variants that affect plasma ADAMTS13 activity by using a large, prospective, population-based cohort study, the Rotterdam Study. ADAMTS13 activity was measured using a fluorogenic peptidyl substrate (fluorescence resonance energy transfer substrate [FRETS]-VWF73) in.6000 individuals. Genome-wide single nucleotide polymorphisms (SNPs) for common genetic variants and exome-wide SNPs for rare genetic variants were genotyped. After careful examination of these genotyped data, de Vries et al identified p.Ala732Val (rs41314453) in ADAMTS13 as the strongest genetic determinant of ADAMTS13 activity; the minor allele was associated with a decrease of.20% (see figure). Furthermore, they identified independent associations with a common variant in SUPT3H outside the ADAMTS13 locus and 5 genetic variants at the ADAMTS13 locus. The variant p.Ala732Val in ADAMTS13 explained 3.6% to 6.5% of the variance in ADAMTS13 activity, which was comparable to the variance explained by age (3.9%-6.5%) or by sex (4.5%-6.7%). The 4 independently significant common SNPs (boxed with red in the figure) explained 5.8% to 8.2% of the variance. The genetic variants influencing plasma ADAMTS13 activity have been mostly restricted to the ADAMTS13 locus (see figure). The only exception was SUPT3H outside the ADAMTS13 locus, and its effect was relatively small. This restriction is in sharp contrast to genetic factors influencing VWF. Genome-wide analysis for plasma VWF levels showed that multiple loci are involved. Various steps, including VWF synthesis, packaging into Weibel-Palade bodies, secretion, and removal from the circulation, are involved in determining VWF levels, and genetic variants of proteins involved in these steps could affect plasma VWF levels. ADAMTS13 activity may be ADAMTS13 domain structure and functional genetic variants. Variants boxed with green are located within the ADAMTS13 locus. Variants boxed with red are significantly associated common variants among genome-wide SNPs. Variants boxed with blue are significantly associated rare variants among exome-wide SNPs. Act., percentage of increased or decreased plasma ADAMTS13 activity; C, Cys-rich domain; CUB, complement C1r/C1s; D, disintegrin-like domain; Freq., allele frequency; M, metalloprotease domain; P, propeptide; S, signal peptide sequence; Sp, spacer domain; T, thrombospondin type 1 repeat.