Limits...
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.

Show MeSH

Related in: MedlinePlus

Gene-Burden Test ResultsWe evaluated whether cases were more likely to carry rare functional variants in a gene compared to controls using sequencing data from 67 cases and 376 controls. Variants were annotated using the Variant Effect Predictor tool and divided into three sets of severity. The most severe category consists of loss-of-function (LOF) variants annotated as being nonsense and splice site (green). The intermediate category included all LOF variants as well as missense variants annotated as probably damaging by PolyPhen-2 (magenta). The least severe category consisted of all LOF, missense, and untranslated region (UTR) variants (blue). We had varying minor allele frequency (MAF) cutoffs with the most restrictive being 0–1% MAF and the most inclusive being 0–5%. For each MAF and variant set, we assessed whether any genes deviated from expectation as demonstrated by the diagonal line. The only gene that showed enrichment was BTNL2 (P=7.0×10−8, Fisher’s Exact Test).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC4155508&req=5

Figure 3: Gene-Burden Test ResultsWe evaluated whether cases were more likely to carry rare functional variants in a gene compared to controls using sequencing data from 67 cases and 376 controls. Variants were annotated using the Variant Effect Predictor tool and divided into three sets of severity. The most severe category consists of loss-of-function (LOF) variants annotated as being nonsense and splice site (green). The intermediate category included all LOF variants as well as missense variants annotated as probably damaging by PolyPhen-2 (magenta). The least severe category consisted of all LOF, missense, and untranslated region (UTR) variants (blue). We had varying minor allele frequency (MAF) cutoffs with the most restrictive being 0–1% MAF and the most inclusive being 0–5%. For each MAF and variant set, we assessed whether any genes deviated from expectation as demonstrated by the diagonal line. The only gene that showed enrichment was BTNL2 (P=7.0×10−8, Fisher’s Exact Test).

Mentions: Next, we used a burden test to evaluate whether cases were more likely to be carriers of a functional variant in a gene compared to controls in the exome sequencing data. We divided rare variants into different functional categories and MAF ranges and found that BTNL2 (P=7.0×10−8) was the only gene to exceed a conservative significance threshold of P=2.5×10−6, corresponding to a Bonferroni correction of 20,000 genes tested12 (Figure 3). None of the protein products of these genes is known to bind clozapine10. The BTNL2 signal is driven by two independent variants: the top SNP noted above (rs28362679) and a conditionally independent missense variant annotated as benign by PolyPhen-2 (rs143211074; P=6.0×10−6, OR=4.4, 95% CI 1.10–17.8). These associations replicated using the exome array and NHLBI Exome Sequencing Project data (Supplementary Fig. 4). BTNL2 is in the MHC region and is in strong LD with HLA-DQB1 and HLA-DRB1, which have been associated with autoimmune diseases and adverse drug reactions including CIAG7, 13. BTNL2 codes for the butyrophilin-like protein 2, a member of the immunoglobulin gene superfamily with a role in regulating T-cell activation14. Given its location in a region of very high LD, the BTNL2 association could implicate it directly or reflect indirect associations with classical HLA alleles.


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)

Gene-Burden Test ResultsWe evaluated whether cases were more likely to carry rare functional variants in a gene compared to controls using sequencing data from 67 cases and 376 controls. Variants were annotated using the Variant Effect Predictor tool and divided into three sets of severity. The most severe category consists of loss-of-function (LOF) variants annotated as being nonsense and splice site (green). The intermediate category included all LOF variants as well as missense variants annotated as probably damaging by PolyPhen-2 (magenta). The least severe category consisted of all LOF, missense, and untranslated region (UTR) variants (blue). We had varying minor allele frequency (MAF) cutoffs with the most restrictive being 0–1% MAF and the most inclusive being 0–5%. For each MAF and variant set, we assessed whether any genes deviated from expectation as demonstrated by the diagonal line. The only gene that showed enrichment was BTNL2 (P=7.0×10−8, Fisher’s Exact Test).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 3: Gene-Burden Test ResultsWe evaluated whether cases were more likely to carry rare functional variants in a gene compared to controls using sequencing data from 67 cases and 376 controls. Variants were annotated using the Variant Effect Predictor tool and divided into three sets of severity. The most severe category consists of loss-of-function (LOF) variants annotated as being nonsense and splice site (green). The intermediate category included all LOF variants as well as missense variants annotated as probably damaging by PolyPhen-2 (magenta). The least severe category consisted of all LOF, missense, and untranslated region (UTR) variants (blue). We had varying minor allele frequency (MAF) cutoffs with the most restrictive being 0–1% MAF and the most inclusive being 0–5%. For each MAF and variant set, we assessed whether any genes deviated from expectation as demonstrated by the diagonal line. The only gene that showed enrichment was BTNL2 (P=7.0×10−8, Fisher’s Exact Test).
Mentions: Next, we used a burden test to evaluate whether cases were more likely to be carriers of a functional variant in a gene compared to controls in the exome sequencing data. We divided rare variants into different functional categories and MAF ranges and found that BTNL2 (P=7.0×10−8) was the only gene to exceed a conservative significance threshold of P=2.5×10−6, corresponding to a Bonferroni correction of 20,000 genes tested12 (Figure 3). None of the protein products of these genes is known to bind clozapine10. The BTNL2 signal is driven by two independent variants: the top SNP noted above (rs28362679) and a conditionally independent missense variant annotated as benign by PolyPhen-2 (rs143211074; P=6.0×10−6, OR=4.4, 95% CI 1.10–17.8). These associations replicated using the exome array and NHLBI Exome Sequencing Project data (Supplementary Fig. 4). BTNL2 is in the MHC region and is in strong LD with HLA-DQB1 and HLA-DRB1, which have been associated with autoimmune diseases and adverse drug reactions including CIAG7, 13. BTNL2 codes for the butyrophilin-like protein 2, a member of the immunoglobulin gene superfamily with a role in regulating T-cell activation14. Given its location in a region of very high LD, the BTNL2 association could implicate it directly or reflect indirect associations with classical HLA alleles.

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