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Biomedical subjects

C A Alper

Publications and source records attributed to C A Alper.

At least 37 records · Page 2Linked to original sources
PubMed1997

Tumor necrosis factor constellation polymorphism and clozapine-induced agranulocytosis in two different ethnic groups.

Genes of the major histocompatibility complex (MHC) are associated with susceptibility to different immune and nonimmune mediated diseases. We had reported that the drug adverse reaction, clozapine-induced agranulocytosis (CA), is associated with different HLA types and HSP70 variants in Ashkenazi Jewish and non-Jewish patients, suggesting that a gene within the MHC region is associated with CA. This study was designed to find common genetic markers for this disorder in both ethnic groups. The tumor necrosis factor (TNF) microsatellites d3 and b4 were found in higher frequencies in both Jewish and non-Jewish patients: 51 of 66 (77%) and 48 of 66 (57%), respectively. Comparisons of these frequencies with those of controls, 28 of 66 (42%) and 18 of 66 (27%), were statistically significant (corrected P value = .001 for the d3 allele and .0005 for the b4 allele). On the other hand, the TNF microsatellite b5 was underrepresented in the group of patients, 9 of 66 (14%), when compared with the control subjects, 43 of 66 (65%) (corrected P value = .0005), probably related to protection from CA. Our results show a strong association of some genetic variants of the TNF loci with susceptibility to CA in two different ethnic groups suggesting involvement of TNF and/or associated gene(s) products in the pathogenesis of this hematologic-drug adverse reaction.

Agranulocytosis↗
PubMed1997

Pemphigus vulgaris autoantibody response is linked to HLA-DQB1*0503 in Pakistani patients.

Pemphigus vulgaris (PV) is an autoimmune disease of the skin and mucous membranes characterized by an autoantibody response against an epidermal cadherin. We performed high resolution HLA class II typing in 19 patients with PV from Rawalpindi, Pakistan and 19 non-Jewish European PV patients from Boston by sequence-specific oligonucleotide probe hybridization. The results were compared with two separate ethnically matched control populations. WE found that PV patients from Pakistan had significantly increased frequencies of DRB1*1404 (p = 0.01), DQA1*0101 (p = 0.02), and DQB1*0503 (p = 0.01). Among the patients of non-Jewish European ancestry, DRB1*1401 (p < 10(-6)), DQA1*0101 (p < 10(-5)) and DQB1*0503 (p < 10(-6)), were increased in PV patients. Formal linkage analysis between the major histocompatibility complex and the PV antibody was performed in 67 relatives of the 19 Pakistani patients. The results showed strong evidence for linkage of HLA-DRB1*1404, DQA1*0101, DQB1*0503, with the presence of PV antibody in relatives' families with a significant logarithm of the odds score of 6.06. Based on the three dimensional structure of class II molecules, we propose that HLA-DQA1*0101 and DQB1*0503, encode a negatively charged P9 peptide binding pocket of the DQ molecule and are significantly associated with susceptibility to PV in non-Jewish populations.

Alleles↗
PubMed1997

Defect in Th1-like cells of nonresponders to hepatitis B vaccine.

Peripheral blood lymphocytes from nonresponders to hepatitis B vaccine (HBsAg) failed to undergo a proliferative response to recombinant HBsAg in vitro, whereas cells from responders proliferated vigorously. The lack of proliferative response was not due to defective antigen presentation in that MHC-identical responder and nonresponder antigen presenting cells were equally effective in stimulating responder T cells. Nonresponder T cells did not proliferate in response to antigen-pulsed MHC identical responder antigen presenting cells. The present study demonstrated that: 1) there were no detectable (1 in < 20 x 10(4) HBsAg-precursor T cells in any of the nonresponders, while in responders the frequency of HBsAg-precursor T cells ranged from 1 in 3.2 x 10(3) to 1 in 40 x 10(3); 2) nonresponder cell cultures did not secrete IL-2 in response to HBsAg stimulation; 3) exogenous recombinant IL-2 did not restore the proliferative response of the T cells in HBsAg-pulsed cultures of nonresponders. These results suggest that the cellular basis for the lack of response to HBsAg is a defect in HBsAg-specific Th1-like cells; either there is an absence of the Th1 cells or cells with TCR specificity for HBsAg are present but are unresponsive to the HBsAg peptide-MHC complex (i.e., anergy or tolerance).

Adult↗
PubMed1996

Tumor necrosis factor (TNF) microsatellite haplotypes in relation to extended haplotypes, susceptibility to diseases associated with the major histocompatibility complex and TNF secretion.

TNFabc microsatellite haplotypes were determined on normal, type I diabetes and multiple sclerosis Caucasian MHC haplotypes in family studies. Although independent examples of conserved extended haplotypes usually had the same TNFabc haplotypes, there were a number of exceptions, suggesting that these loci are more mutable than most loci in the human MHC. Some TNFabc haplotypes were characteristic of only one extended haplotype, whereas others were shared by several different extended haplotypes. From the analysis of TNFabc on extended haplotype fragments, and assuming that the fragments arose by ancient homologous crossing over, it was possible to "map" TNF and how that it was somewhat closer to HLA-B than the complement region, corresponding to the physical map of this region. TNF haplotype associations with type I diabetes and multiple sclerosis were attributable to the known extended haplotype associations of these diseases. There was also a trend for higher TNF-alpha secretion by peripheral blood mononuclear cells from individuals homozygous for [HLA-B8, SC01, DR3] than from individuals homozygous for [HLA-B7, SC31, DR2].

Alleles↗
PubMed1996

A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease seen primarily in elderly persons. It is characterized clinically by the development of tense bullae and by the presence of an antibasement membrane antibody. In BP, the antigens involved in the autoimmunity are epidermal basement membrane peptides BPAg1 and BPAg2. We have compared high resolution typing of major histocompatibility complex class II loci (HLA-DRB1, DQB1) in 21 patients with BP, 17 with ocular cicatricial pemphigoid (OCP), and 22 with oral pemphigoid (OP) to a panel of 218 haplotypes of normal individuals. We found that the three diseases (BP, OCP, and OP) have significant association with DQB1*0301 (P = 0.005, P < 0.0001, and P = 0.001, respectively). The frequencies of alleles DQB1*0302, 0303, and 06, which share a specific amino acid sequence from position 71 to 77 (Thr-Arg-Ala-Glu-Leu-Val-Thr) were also increased (P = 0.01). We suggest that an identical major histocompatibility complex class II allele (DQB1*0301) is a common marker for enhanced susceptibility and that the same amino acid residues in positions 71-77 (DQB1*0301, -0302, -0305, -0602, -0603 alleles) are found in patients with BP, OCP and OP. Our findings propose that the autoimmune response in the three different clinical variants of pemphigoid, involves the recognition by T cells of a class II region of DQB1, bound to a peptide from the basement membrane of conjunctiva, oral mucosa, and skin.

Alleles↗
PubMed1996

Excess admixture proportion of extended major histocompatability complex haplotypes of Caucasian origin among rheumatoid arthritis associated haplotypes in African Americans and Afro-Caribbeans.

Several extended major histocompatability complex (MHC) haplotypes are associated with susceptibility to autoimmune disease in Caucasian populations. It is known that African Americans and Afro-Caribbeans are ethnic groups descended from west, central and southern black African populations which are admixed with Caucasians. To examine the possible association of some marker of Caucasian MHC genes and susceptibility to rheumatoid arthritis (RA) in African Americans, we studied extended MHC haplotypes (HLA-B, complement and DR) in a sample of 18 African American and Afro-Caribbean probands with RA, their first degree relatives and in 15 non-RA families. We defined 36 disease-associated RA haplotypes among the probands and 96 normal haplotypes in normal individuals. To obtain the most conservative estimate, we excluded recognized Caucasian, DR4-bearing, extended MHC haplotypes from the analysis. Admixture proportions for non-HLA-DR4 extended MHC haplotypes of known Caucasian origin among RA-associated and normal haplotypes were computed (0.40 versus 0.163 respectively). When we compared the difference in proportions between RA and normal haplotypes, the proportion of extended MHC haplotypes of known Caucasian origin was significantly increased among RA-associated haplotypes (Z = 3.16, p (one sided) < 0.001, p (adjusted) < 0.008). Our results suggest that racial admixture with Caucasian MHC genes may augment RA susceptibility and thus may be one mechanism to explain the higher prevalence of RA in African Americans and Afro-Caribbeans than in black African populations.

Arthritis, Rheumatoid↗
PubMed1996

MHC class II alleles and haplotypes in patients with pemphigus vulgaris from India.

Pemphigus vulgaris (PV) is a blistering disease of the skin and mucous membranes characterized by an autoantibody response against a keratinocyte adhesion molecule, desmoglein 3, causing acantholysis and blister formation. We compared high resolution MHC class II alleles and haplotype frequencies (HLA-DRB, DQA1 and DQB1) in 37 patients with PV to 89 haplotypes of normal relatives from New Delhi and Ahmedabad. We found that PV patients had significantly increased frequencies of DRB1*1404 (P < 0.0001), DQA1*0101 (P = 0.001), and DQB1*0503 (P < 0.0001). These associations were due to the increased frequencies of the haplotype HLA-DRB1*1404, DRB3*0202, DQA1*0101, DQB1*0503 in patients compared to control haplotypes (p < 0.0001). Also, patients from Ahmedabad had a significant increase in HLA-DQB1*0302 (p = 0.03). An identical amino acid sequence (Leu-Leu-Glu-Arg-Arg-Arg-Ala-Glu), in positions 67-74 of the beta domain of DRB alleles is restricted to some DR14 alleles. Therefore, there are three possible explanations for class II allele involvement in autoantibody in PV patients with class II haplotypes marked by HLA-DR14. First, the class II alleles could be markers for an unidentified susceptibility gene in linkage disequilibrium with them. Second, the primary association could be with DQB1*0503 and the association with HLA-DR14 alleles would be the result of linkage disequilibrium. Third, the HLA-DRB1 locus susceptibility could involve a specific amino acid sequence in the third hypervariable region shared by several HLA-DR14 alleles.

Alleles↗
PubMed1995

The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups.

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.

Agranulocytosis↗
PubMed1995

Normal HBsAg presentation and T-cell defect in the immune response of nonresponders.

Lymphocytes from nonresponders to HBsAg fail to proliferate in vitro in the presence of HBsAg-pulsed antigen presenting cells. We studied four pairs of major histocompatibility complex (MHC)-matched, mixed lymphocyte reaction-negative individuals discordant for HBsAg response. For each pair, responder lymphocytes proliferated in the presence of nonresponder antigen-pulsed antigen presenting cells. Responder and nonresponder antigen presenting cells were equally effective. There was no evidence for inhibition of responder T-cell proliferation by nonresponder lymphocytes or antigen presenting cells. The defect is thus in the helper T cells of nonresponders and not in the antigen processing or binding of processed peptides to MHC molecules on antigen presenting cells.

Adult↗
PubMed1995

Predictability of alloreactivity among unrelated individuals: role for HLA-DPB1.

We compared the mixed lymphocyte culture reaction (MLR-1) among unrelated individuals who are carriers of the extended haplotype [HLA-B8,SC01,DR3,DRB1*0301,DQB1*0201] on one chromosome and the generic specificity HLA-DR4 on the second chromosome. Genomic DNA samples from the same individuals were also analyzed for HLA-DRB1, DQB1 and DPB1 alleles by PCR and SSOPH typing and for DOB polymorphism by RFLP. HLA-DRB1 alleles, in paired MLR responses between unrelated individuals indicated that matching of HLA-DRB1 was a better predictor of non-reactivity than identity in HLA-DR generic types, (43% vs 22%). Moreover, 90% of the DRB1 matched pairs had nonreactive and weakly reactive MLR, whereas only 37% of DRB1 mismatched unrelated individuals gave weak or no reactions. Matching for HLA-DRB1 and HLA-DPB1 alleles eliminates a significant number of cell mixtures with MLR-I reactivity. Furthermore, some DPB1 mismatches, but not all, do not seem to elicit MLR-I reactivity.

Alleles↗
PubMed1995

The human immune response to hepatitis B surface antigen.

The anti-HBs response is bimodal with 4.2% of healthy persons producing no antibody and an additional 10% being hyporesponders. In the study of nonresponders, 2 extended haplotypes, [HLA-B8, SC01, DR3] and [HLA-B44, FC31, DR7], were found to be enriched in a pattern suggesting recessive inheritance. In the prospective immunization of homozygotes and heterozygotes for [HLA-B8, SC01, DR3], the homozygotes had less antibody than the heterozygotes. Family studies confirmed that the anti-HBs response was dominant and MHC linked, whereas nonresponse was recessive. In studies in vitro, it was shown that nonresponders failed to show lymphoproliferation in response to hepatitis B surface antigen (HBsAg) or an immunodominant nonapeptide. The lymphoproliferative response of responders to these stimuli was comparable and inhibited by anti-DR but not antibody to DQ or DP. The removal of CD8+ T cells did not produce lymphoproliferation to HBsAg in nonresponders. From mixtures of antigen-presenting cells and T cells from MHC-identical response discordant pairs, it was shown that the defect in the nonresponders was in their T cells and not their antigen-presenting cells, ruling out defective MHC binding or antigen processing as the basis of nonresponse.

Animals↗
PubMed1995

Linkage of familial dysalbuminemic hyperthyroxinemia to the albumin gene in a large Amish kindred.

Familial dysalbuminemic hyperthyroxinemia (FDH) is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasians. Transmitted as an autosomal dominant trait, it is always associated with high serum total T4 (TT4) and more rarely with elevated total T3 (TT3) and/or rT3 (TrT3) concentrations. Free T4, by dialysis, and TSH levels are normal, suggesting the presence of a T4-binding protein abnormality. The abnormal serum T4 carrier shares some physical and immunological properties with albumin, suggesting that it may be albumin itself. Here we show linkage between FDH and the albumin gene in a large Amish family of Swiss descent, using as markers a SacI polymorphism in the coding sequence of the albumin gene and the group-specific component (Gc) gene, located less than 1 centimorgan from the albumin gene. Blood samples were obtained from 160 members of this kindred, and 22 had FDH identified by the pattern of T4 binding to serum proteins separated by isoelectric focusing. Serum TT4 values were above the normal range in all subjects expressing the FDH phenotype, and TrT3 levels were above the normal range in only one half. TT4 concentrations correlated positively with TrT3 and TT3. All TT3 values were, however, within the normal range. Free T4 and TSH levels were normal, confirming the euthyroid state in these subjects. FDH was associated with the albumin SacI(+)/Gc 1S haplotype, yielding a LOD (logarithm of the odds ratio) score of 5.53, with a recombination frequency of 0. These data provide strong support that a variant albumin is the cause of FDH in this kindred.

Base Sequence↗
PubMed1995

HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM.

HLA-DQB1 alleles confer susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). We investigated whether the susceptibility alleles DQB1*0302 and DQB1*0201 affect progression to diabetes among islet cell antibody-positive (ICA+) first-degree relatives of IDDM patients and whether the protective allele DQB1*0602 can be found and is still protective among such relatives. We human leukocyte antigen-typed and periodically tested beta-cell function (first-phase insulin release [FPIR] during the intravenous glucose tolerance test) in 72 ICA+ relatives, of whom 30 became diabetic on follow-up (longest follow-up 12 years); 54 (75%) relatives carried DQB1*0302 and/or DQB1*0201. The frequency of DQB1*0302 and DQB1*0201 and of the high-risk genotype DQB1*0302/DQB1*0201 did not differ significantly between diabetic relatives and those remaining nondiabetic. On follow-up, progression to IDDM was not statistically different for relatives with or without the DQB1*0302/DQB1*0201 genotype. However, those relatives with the DQB1*0302/DQB1*0201 genotype had a tendency to develop diabetes at an earlier age (log-rank P = 0.02). We found DQB1*0602 in 8 of 72 (11.1%) ICA+ relatives. Relatives with DQB1*0602 did not develop diabetes or show any decline of FPIR versus 28 of 64 DQB1*0602- relatives who developed IDDM (log-rank P = 0.006; Wilcoxon's P = 0.02). The protective allele DQB1*0602 is found in ICA+ relatives who have minimal risk of progression to IDDM. Therefore, DQB1*0602 is associated with protection from IDDM both in population studies and among relatives with evidence of autoimmunity who should not enter prevention trials.

Adolescent↗
PubMed1994

Common major histocompatibility complex class II markers in clinical variants of cicatricial pemphigoid.

Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease affecting multiple mucous membranes derived from stratified squamous epithelium and occasionally the skin. CP has a wide spectrum of disease manifestations. Patients with oral pemphigoid (OP) have a benign self-limited disease in which pathological changes are restricted to the oral mucosa. On the other hand, patients with ocular cicatricial pemphigoid (OCP), a chronic condition marked with relapses and remissions, have ocular involvement and also perhaps involvement of other mucous membranes. All clinical subsets are characterized by the presence of a similar anti-basement zone autoantibody. The factors that determine the development of one form of CP or the other are not known. In a previous study, we described the association between OCP and the DQB1*0301 allele (P = 0.006). In this study, we have analyzed 22 Caucasian patients with OP and their family members for major histocompatibility complex DRB generic, DQA1, and DQB1 allele associations by PCR-sequence-specific oligonucleotide probe hybridization. The results were compared to those obtained from 17 Caucasian patients with OCP and to control Caucasian alleles and haplotypes. The DQB1*0301 allele frequency was 38.6% in OP, 52.9% in OCP, and 17.8% in controls. Statistically significant associations were detected between the DQB1*0301 allele and both OP (P = 0.0047) and OCP (P < 0.0001). In addition, DRB1*04 showed a statistically significant association (P = 0.005) with OCP when compared to controls. Analysis of major histocompatibility complex class II haplotypes showed significant statistical associations between both OCP and OP and the HLA-DRB1*04, DRB4*0101, DQA1*03, DQB1*0301 haplotype (P < 0.0001 and P = 0.0012, respectively). Our results indicate that DQB1*0301 is a marker of both oral and ocular forms of CP. The analysis of the amino acid sequence of the DQB1 alleles present in both OP and OCP suggested that amino acid residues at position 57 and positions 71-77 may also be markers of CP.

DNA Probes↗
PubMed1994

Polymorphic Hh genes in the HLA-B(C) region control natural killer cell frequency and activity.

We demonstrated earlier that individuals homozygous for conserved major histocompatibility complex (MHC)-extended haplotypes have low natural killer (NK) activity as measured by cytolysis of the K562 tumor cell lines. In the present study, we investigated the segregation and MHC linkage of NK activity in families in which MHC haplotypes of human histocompatibility leukocyte antigens (HLA)-A, -C, and -B, complotype, and DR specificities are known. In two informative families, low activity was inherited as a recessive trait linked to the MHC. By using individuals homozygous for specific fragments of extended haplotypes or for HLA-B alleles, we found that the HLA-C and -B and not the complotype or HLA-DR region contains genes controlling NK activity. The majority of the unrelated individuals with low NK activity were homozygous or doubly heterozygous for HLA-B7 (Cw7), B8 (Cw7), B44 (Cw5), B18, or B57 (Cw6). Thus, these alleles form one complementation group designated NKB1. Another less frequent group, NKB2, was also identified, and consisted of individuals homozygous for B35 (Cw4). NK activity was correlated with the number of circulating NK (CD16+ CD56+) cells. Individuals homozygous for the NKB complementation groups have fewer circulating NK cells than individuals heterozygous for these alleles and alleles of other complementation groups, possibly explaining the low activity of cells in these subjects. These findings suggest that during the maturation of NK cells there is NK cellular deletion in donors homozygous for NKB genes resulting in low NK cell numbers and activity.

Adult↗
PubMed1994

The paternally inherited insulin gene B allele (1,428 FokI site) confers protection from insulin-dependent diabetes in families.

Several polymorphisms of the insulin gene and its flanking regions (INS region) are in linkage disequilibrium and confer susceptibility to insulin-dependent diabetes (IDDM). We have analysed INS AA and AB-BB genotypes at the 1,428 FokI site (3' of the insulin gene) in 217 patients with IDDM, 402 non-diabetic first degree relatives negative for insulin (IAA) and islet cell autoantibodies (ICA), and 116 autoantibody positive (for ICA or IAA, or both) relatives of whom 39 became diabetic on follow-up. Most IDDM patients (83.4%, 181/217) had the AA genotype vs. 50% (25/50) of the controls (P < 10(-6)). Only 16.6% (36/217) of IDDM patients carried the AB genotype and none was BB homozygous, suggesting a protective effect of the B allele. By segregation analysis of the B allele in the IDDM offspring of informative families (only one AB parent) from the United States, the maternal B allele was inherited by 19/35 (54.2%) of the IDDM offspring. In contrast, only 4/26 (15.3%) of the IDDM offspring inherited the paternal B allele (P = 0.001), suggesting maternal imprinting of the INS region. Therefore, the INS B allele may be protective only when paternally inherited. Among the 39 of 116 autoantibody positive relatives who developed IDDM on follow-up, only five of them had the B allele. The frequency of the B allele in this group was much lower (12.8%, 5/39) than that observed in non-diabetic autoantibody positive relatives (32.5%, 25/77, P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The immunoglobulin heavy chain and disease association: application to pemphigus vulgaris.

Genes involved in the immune response are generally encoded from a complex cluster of gene segments. Studies of the association of diseases with such genes require well-defined genetic markers throughout the selected region. A set of 15 polymorphic loci that span 1500 kb of the immunoglobulin heavy chain (IGH) complex, 8 in the variable (VH) region and 7 in the constant (CH) region, were selected for the study of disease association. We present a protocol for the use of multiple immunoglobulin heavy chain (IGH) polymorphisms for general application in disease association studies. No microsatellite repeat markers are available for this region. To demonstrate the applicability of this approach, we have examined these IGH polymorphisms in families with individuals affected with pemphigus vulgaris (PV), an autoimmune dermatologic disease. Allele frequencies in 12 patients with PV were compared with those found in their spouses, and with those in a white Canadian control population. A significant difference was found between PV patients and both control groups for the presence of the VH gene VH3f-R4, and possibly for the absence of VH3f-R3, suggesting the possibility of susceptibility factors in these regions. Examination of the frequencies of the IGH region C gamma-haplotypes of PV patients indicated that, while the patients did not differ significantly from their spouses (chi 2 = 1.79), both groups were found to differ significantly from the white Canadian control group (chi 2 = 10.10), emphasizing the importance of matching the ethnic background of controls with that of the patient test group in disease association studies. Unexpectedly, two patients had large deletions of genes in the IGH constant region, which could play a role in the development of PV and require further investigation.

Alleles↗