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Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Goldstein JI, Jarskog LF, Hilliard C, Alfirevic A, Duncan L, Fourches D, Huang H, Lek M, Neale BM, Ripke S, Shianna K, Szatkiewicz JP, Tropsha A, van den Oord EJ, Cascorbi I, Dettling M, Gazit E, Goff DC, Holden AL, Kelly DL, Malhotra AK, Nielsen J, Pirmohamed M, Rujescu D, Werge T, Levy DL, Josiassen RC, Kennedy JL, Lieberman JA, Daly MJ, Sullivan PF - Nat Commun (2014)

Bottom Line: Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine.Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing.These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

View Article: PubMed Central - PubMed

Affiliation: 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

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Absolute Neutrophil Count Stratified by HLA Risk Allele Carrier Status(A) For cases in which the lowest recorded absolute neutrophil count (ANC) data were available, we ordered samples by the ANC and colored the points by their imputed carrier status of HLA-DQB1 126Q and HLA-B 158T (black=no risk alleles, red=only a carrier of HLA-DQB1 risk alleles as tagged by 126Q, green=only a carrier of HLA-B 158T, blue=carrier of both HLA-DQB1 and HLA-B risk alleles). The background colors demonstrate the clinical definitions for agranulocytosis (red: ANC<500) and severe granulocytopenia (yellow: 500≤ANC≤1000). (B) The same data are shown as a box plot to demonstrate that HLA-B 158T carriers demonstrate a trend towards lower ANC than non-carriers of HLA-B 158T.
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Figure 5: Absolute Neutrophil Count Stratified by HLA Risk Allele Carrier Status(A) For cases in which the lowest recorded absolute neutrophil count (ANC) data were available, we ordered samples by the ANC and colored the points by their imputed carrier status of HLA-DQB1 126Q and HLA-B 158T (black=no risk alleles, red=only a carrier of HLA-DQB1 risk alleles as tagged by 126Q, green=only a carrier of HLA-B 158T, blue=carrier of both HLA-DQB1 and HLA-B risk alleles). The background colors demonstrate the clinical definitions for agranulocytosis (red: ANC<500) and severe granulocytopenia (yellow: 500≤ANC≤1000). (B) The same data are shown as a box plot to demonstrate that HLA-B 158T carriers demonstrate a trend towards lower ANC than non-carriers of HLA-B 158T.

Mentions: Finally, we tested for differences in CIAG severity (as indexed by minimum absolute neutrophil count, ANC) according to risk allele status of HLA-DQB1 and HLA-B among 149 cases with these data. Cases who were carriers of HLA-B 158T demonstrated significantly lower ANC than non-carriers (P<0.01, Figure 5). However, as nearly all cases with substantial Ashkenazi Jewish ancestry carried the HLA-B 158T allele (Supplementary Fig. 7), it is not possible to determine conclusively whether some of this signal could be driven by an unexplored feature of ascertainment or population difference. Hence we repeated the analysis after excluding cases with Ashkenazi Jewish ancestry (PC1>0.02) and subsequently correcting the phenotype for ancestry and sample cohort and observed a consistent effect but of reduced significance (P=0.049) owing to reduced power because of the number of 158T alleles excluded (Supplementary Fig. 8). Similar analyses of time to onset of CIAG were not significant (data not shown).


Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Goldstein JI, Jarskog LF, Hilliard C, Alfirevic A, Duncan L, Fourches D, Huang H, Lek M, Neale BM, Ripke S, Shianna K, Szatkiewicz JP, Tropsha A, van den Oord EJ, Cascorbi I, Dettling M, Gazit E, Goff DC, Holden AL, Kelly DL, Malhotra AK, Nielsen J, Pirmohamed M, Rujescu D, Werge T, Levy DL, Josiassen RC, Kennedy JL, Lieberman JA, Daly MJ, Sullivan PF - Nat Commun (2014)

Absolute Neutrophil Count Stratified by HLA Risk Allele Carrier Status(A) For cases in which the lowest recorded absolute neutrophil count (ANC) data were available, we ordered samples by the ANC and colored the points by their imputed carrier status of HLA-DQB1 126Q and HLA-B 158T (black=no risk alleles, red=only a carrier of HLA-DQB1 risk alleles as tagged by 126Q, green=only a carrier of HLA-B 158T, blue=carrier of both HLA-DQB1 and HLA-B risk alleles). The background colors demonstrate the clinical definitions for agranulocytosis (red: ANC<500) and severe granulocytopenia (yellow: 500≤ANC≤1000). (B) The same data are shown as a box plot to demonstrate that HLA-B 158T carriers demonstrate a trend towards lower ANC than non-carriers of HLA-B 158T.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4155508&req=5

Figure 5: Absolute Neutrophil Count Stratified by HLA Risk Allele Carrier Status(A) For cases in which the lowest recorded absolute neutrophil count (ANC) data were available, we ordered samples by the ANC and colored the points by their imputed carrier status of HLA-DQB1 126Q and HLA-B 158T (black=no risk alleles, red=only a carrier of HLA-DQB1 risk alleles as tagged by 126Q, green=only a carrier of HLA-B 158T, blue=carrier of both HLA-DQB1 and HLA-B risk alleles). The background colors demonstrate the clinical definitions for agranulocytosis (red: ANC<500) and severe granulocytopenia (yellow: 500≤ANC≤1000). (B) The same data are shown as a box plot to demonstrate that HLA-B 158T carriers demonstrate a trend towards lower ANC than non-carriers of HLA-B 158T.
Mentions: Finally, we tested for differences in CIAG severity (as indexed by minimum absolute neutrophil count, ANC) according to risk allele status of HLA-DQB1 and HLA-B among 149 cases with these data. Cases who were carriers of HLA-B 158T demonstrated significantly lower ANC than non-carriers (P<0.01, Figure 5). However, as nearly all cases with substantial Ashkenazi Jewish ancestry carried the HLA-B 158T allele (Supplementary Fig. 7), it is not possible to determine conclusively whether some of this signal could be driven by an unexplored feature of ascertainment or population difference. Hence we repeated the analysis after excluding cases with Ashkenazi Jewish ancestry (PC1>0.02) and subsequently correcting the phenotype for ancestry and sample cohort and observed a consistent effect but of reduced significance (P=0.049) owing to reduced power because of the number of 158T alleles excluded (Supplementary Fig. 8). Similar analyses of time to onset of CIAG were not significant (data not shown).

Bottom Line: Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine.Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing.These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

View Article: PubMed Central - PubMed

Affiliation: 1] Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [2] Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

Show MeSH
Related in: MedlinePlus