Common and Well-Documented HLA Alleles

Common and Well-Documented HLA Alleles Report of the Ad-Hoc Committee of the American Society for Histocompatiblity and Immunogenetics Pedro Cano, William Klitz, Steven J. Mack, Martin Maiers, Steven G.E. Marsh, Harriet Noreen, Elaine F. Reed, David Senitzer, Michelle Setterholm, Anajane Smith, and Marcelo Fernández-Viña ABSTRACT: In histocompatibility testing some genotype ambiguities are almost always resolved into the genotype with the most common alleles. To achieve unambiguous assignments additional unwieldy tests are performed. The American Society for Histocompatibility and Immunogenetics formed a committee to define what human leukocyte antigen (HLA) genotypes do not need to be resolved in external proficiency testing. The tasks included detailed analysis of large datasets of highresolution typing and thorough review of the pertinent scientific literature. Strict criteria were used to create a catalogue of common and well-documented (CWD) alleles. In total, 130, 245, 81, and 143 of the highly polymorphic HLA-A, -B, -C, and DRB1 loci fell into the CWD category; these represent 27%–30% of all alleles recognized. For the loci DRB3/4/5, DQA1, DQB1, and DPB1, a total of 29, 16, 26, and 52 CWD alleles were ABBREVIATIONS ARS antigen recognition site ASHI American Society for Histocompatibility and Immunogenetics CWD common and well-documented GF gene frequency HLA human leukocyte antigen WHO World Health Organization From the University of Texas M. D. Anderson Cancer Center (P.C., M.F.-V.), HLA Typing Laboratory, Houston, Texas; Public Health Institute (W.K.), Oakland, and University of California–Berkeley, Berkeley, California; Children’s Hospital–Oakland Research Institute (S.J.M.), Oakland, California, and Roche Molecular Systems Department of Human Genetics, Alameda, California; National Marrow Donor Program (M.M.,

Human Immunology 68, 392– 417 (2007) © American Society for Histocompatibility and Immunogenetics, 2007 Published by Elsevier Inc.

identified. A recommendation indicated that an acceptable report should only include one possible genotype; multiple genotypes can only be reported if only one of these includes two alleles of the CWD group. Exceptions in which resolution is not necessary are ambiguities involving functional alleles with identical sequences in the antigen recognition site. The criteria were established for proficiency testing, which could be a valuable tool when making clinical histocompatibility decisions. Human Immunology 68, 392– 417 (2007). © American Society for Histocompatibility and Immunogenetics, 2007. Published by Elsevier Inc. KEYWORDS: HLA; common allele; null allele; welldocumented allele; proficiency testing; antigen recognition site; clinical histocompatibility; genotype ambiguity

M.S.), Minneapolis, Minnesota; Anthony Nolan Research Institute (S.M.), Royal Free Hospital, London, United Kingdom; Fairview–University of Minnesota Medical Center (H.M.), Immunology Laboratory, Minneapolis, Minnesota; UCLA Immunogenetics Center (E.F.R.), Department of Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California; City of Hope National Medical Center (D.S.), Duarte, California; Seattle Cancer Care Alliance (A.S.), Clinical Immunogenetics Laboratory, Seattle, Washington. Address reprint requests to: Marcelo Fernández-Viña, Ph.D, University of Texas M. D. Anderson Cancer Center, HLA Typing Laboratory, 8515 Fannin, NAO1.091C, Houston, TX 77054; Tel: (713) 792-2658; Fax: (713) 794-4773; E-mail: [email protected]. Received January 11, 2007; accepted January 17, 2007.

0198-8859/07/$–see front matter doi:10.1016/j.humimm.2007.01.014

Catalogue of HLA Common Alleles

INTRODUCTION The growing number of human leukocyte antigen (HLA) alleles with high sequence homology, and the extensive sharing of the distinguishing sequences with other alleles of the same locus, result in genotype ambiguities when performing molecular tests for HLA typing [1]. The results of many individual high-resolution molecular typing methods, in many instances, correspond to more than one possible genotype, including different allele combinations. Additional tiered tests are performed to exclude some allele combinations and to identify unambiguously, the actual genotype for a given locus [2]. The additional tests are expensive and add a significant burden to the histocompatibility laboratory. Of all possible genotypes corresponding to ambiguous results, the combinations in which both alleles are frequent are more likely to be the actual genotype than genotypes in which both alleles are rare. The likelihood ratio for a given genotype, compared with the occurrence of other possible genotypes, can be estimated based on knowledge of gene frequencies of the alleles included in each possible genotype in the same population from which the individual comes. These estimations apply only to individuals whose parents are not genetically closely related; the accuracy of the likelihood estimates correlates directly with the accuracy of the estimation of gene frequency values. The American Society for Histocompatibility and Immunogenetics (ASHI) formed an ad-hoc committee to summarize the result of studies that analyzed the genetic diversity of the HLA system in various populations, with the objective of determining criteria to establish what HLA genotypes do not need to be resolved when reporting results for external proficiency testing. The accurate estimation of frequencies may be difficult for rare alleles and haplotypes. It has been estimated that at least three examples of a particular allele are needed to obtain an accurate frequency estimate [3]. In clinical histocompatibility practice, it is therefore important to recognize alleles that are observed with a significant frequency, and to distinguish them from alleles of the same locus that may have been observed only in one or a few instances and are not likely to be found again. The Committee proposes to categorize HLA alleles on the basis of their gene frequencies. The distribution of alleles in various populations is different for different HLA loci. For example, the distributions of alleles at DRB1 and DPB1 loci are contrasting in most populations; typically up to 17 DRB1 alleles account for 90% of the alleles in almost all outbred populations. In comparison to this, only eight to ten DPB1 alleles are needed to cover the same proportion of alleles. Therefore, it is

393

easy to distinguish the common alleles from the rare alleles in DPB1; in contrast, the distribution of DRB1 alleles seems to be more a continuum of alleles with intermediate frequencies. It is therefore difficult to determine a cut-off frequency to determine which alleles are rare.

MATERIALS AND METHODS Some operational definitions were established. The committee proposed to define three categories of alleles: 1. Common alleles. Common alleles are those that appear with gene frequencies greater than 0.001 in any reference population. As mentioned above, accurate frequency estimations can be made for alleles observed three or more times; therefore, population studies with a sample size of 1,500 unrelated subjects (2n ⫽ 3,000 chromosomes) could detect with accuracy only allele frequencies of 0.001 or greater. 2. Well-documented alleles. A second category includes those alleles that have been observed in at least three independent unrelated individuals; however, their gene frequencies have not been estimated accurately. Alleles that are found only in isolated populations may have low frequency in any outbred population, and their frequencies are likely to be lower overall than those of most common alleles. 3. Rare Alleles. The remaining alleles are considered rare alleles.These alleles have extremely low frequencies and are not likely to be found again in a significant number of unrelated subjects. Classifying every allele this way may be difficult in some cases, given the lack of systematic studies of all populations, despite large numbers of subjects having been included. In addition, alleles found with intermediate or high frequency in some isolated populations may appear as well-documented or rare alleles in outbred populations with gene flow from those isolated populations. The studies conducted so far vary in sample size and typing resolution. In the United States, the Histocompatibility laboratories serve a diverse population that includes patients and donors from virtually all world populations. This ad-hoc committee proposed to identify the “common” and “well-documented” alleles in all world populations. The committee noted that some databases and studies might include allele level assignments that resulted from intermediate- or low-resolution tests. In these datasets, some of the allele level assignments may be erroneous and could have resulted from spurious reactions of some reagents. Therefore, the determination of allele frequen-

394

cies must be based on high-quality data from highresolution tests that have been reviewed thoroughly. Because of the limitations in the studies conducted so far, the committee proposed to identify the alleles that have relevance in clinical histocompatibility practice. For practical purposes, “common and well-documented alleles” (CWD alleles) are grouped together, distinguishing them from the “rare alleles.” The assignment of alleles to these categories should be reviewed periodically. The CWD alleles are identified as those found with accurate gene frequency estimates of at least 0.001 in any reference population, or the alleles that have been identified unambiguously by a single laboratory when performing high-resolution tests in at least three unrelated individuals, or alleles that have been reported to IMGT/ HLA Database in three unrelated individuals. HLA alleles are reported to the World Health Organization (WHO) Nomenclature Committee for Factors of the HLA System systematically via the IMGT/HLA Database (Immunogenetics Project) [58]. In the compilation of the list of CWD alleles, a thorough review of the scientific literature was conducted. [3–72]. In addition, the following unpublished or non–peer-reviewed sources of data were reviewed by the members of the committee, high-resolution HLA typing results generated in individual clinical histocompatibility laboratories (more than 25,000 subjects were investigated); thoroughly reviewed high-resolution HLA typing results from donors listed in the National Marrow Donor Program; high-resolution HLA genotype data from the Anthropology Components of the 13th and 14th International Histocompatibility Workshops (listed in “dbMHC-Anthropology” dbMHC National Center for Biotechnology Information. 2006) and alleles that have been reported to IMGT/HLA Database. Information of the two latter sources is available online: 1. “dbMHC-Anthropology” dbMHC National Center for Biotechnology Information. 2006: http://www. ncbi.nlm.nih.gov/projects/mhc/ ihwg.cgi?cmd⫽page&page⫽AnthroMain 2. The IMGT/HLA Database: http://www.ebi.ac.uk/ imgt/hla/ [58] RESULTS After establishing criteria to categorize the HLA alleles according to the frequencies in which they are found in different populations, the Committee elaborated a list of HLA alleles to be provided to the Scientific Affairs Committee and to the Accreditation Review Board of ASHI, which includes alleles with their corresponding

P. Cano et al.

TABLE 1 Number of common and well-documented HLA alleles Locusa

CWD allelesb

HLA allelesc

Percentaged

HLA-A HLA-B HLA-C HLA-DRB1 HLA-DQB1 HLA-DRB3/4/5 HLA-DQA1 HLA-DPB1

130 245 81 143 26 29 16 52

489 830 266 463 78 74 34 125

26.6% 29.5% 30.5% 30.9% 33.3% 39.2% 47.1% 41.6%

a HLA locus in chromosome 6. HLA-DRB3, HLA-DRB4, and HLA-DRB5 are considered here as a single locus. b Number of common and well-documented (CWD) HLA alleles. c HLA alleles described until October 2006. d Percentage of described alleles that are common or well documented.

full names or four-, six-, or eight-digit names as assigned by WHO. Table 1 shows the number of CWD alleles currently defined by this Committee, and the number of HLA alleles currently recognized by the WHO Nomenclature Committee for Factors of the HLA System (release 2.15, available at the IMGT/HLA Database; 10/06/2006). Approximately 27% to 30% of the currently recognized HLA alleles, at the most polymorphic loci (HLA-A, -B, -C, and -DRB1), are considered as CWD alleles. It is likely that the number of WHO-recognized alleles will increase significantly over time, whereas the number of CWD alleles will remain relatively constant. Table 1 also shows that a higher proportion of all the alleles described so far in the less polymorphic HLADRB3, -DRB4, and -DRB5, as well as -DQA1, -DQB1, and -DPB1 loci are defined as Common and Welldocumented alleles. The alleles at DRB3, DRB4, and DRB5 were grouped together as DRB3/4/5 because operationally the alleles at these three loci behave virtually as alleles of single locus with mutually exclusive segregation. Approximately one third to one half of all alleles of the less polymorphic loci have been found in several instances (three or more times) when analyzing multiple populations. Tables 2 through 9 show the CWD alleles identified by the Committee based on the criteria presented above at each HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci (alleles that are common in the US are also identified). The corresponding allele groups for alleles with identical nucleotide sequence in exons 2 and 3 of the HLA-A, -B, and -C loci (Table 10) or in exon 2 of DRB1, DRB3/4/5, DQA1, DQB1 and DPB1 loci (Table 11) are also shown. The HLA class I alleles that are identical in the ␣-1 and ␣-2 domain share identical structure in the antigen recognition site (ARS) and likely they present similar or

Catalogue of HLA Common Alleles

395

TABLE 2 Well-documented alleles in HLA-A Locus

Namea

4 Digits

Common in the USb

A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A

01010101 0102 0103 0104N 02010101 020104 0202 020301 0204 0205 020601 0207 0208 0209 0210 0211 0212 0213 0214 0216 021701 0219 022001 0222 0224 0225 0227 0230 0233 023501 0238 0245 0253N 0260 0264 03010101 03010103 030102 030103 0302 0305 110101 110201 1103 1104 1105 2301 2302 24020101 24020102L 240301 2405 2406 2407 2408 2409N 2410 2411N 2413

0101

Yes Yes Yes

0201 0201

Yes

0203 0206

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Exon 2–3 sequence groupsc

Among CWDd

Aⴱ010101g

Yes

Aⴱ010101g Aⴱ020101g

Yes Yes

Aⴱ0207g Aⴱ020101g

Yes

Aⴱ0211g

Yes 0217

Yes

0220

Yes Aⴱ0222g

0235

0301 0301 0301 0301

Yes

Aⴱ030101g Aⴱ030101g

Yes Yes

Yes 1101 1102

2402 2402 2403

Yes Yes

Aⴱ110101g

Yes

Aⴱ2301g

Yes

Aⴱ240201g Aⴱ240201g Aⴱ240301g

Yes Yes Yes

Aⴱ240201g

Yes

Aⴱ240201g

Yes

Yes Yes Yes

396

P. Cano et al.

TABLE 2 (Continued) Locus

Namea

A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A

2414 2417 2420 2421 2422 2423 2425 2428 2433 2435 250101 2502 260101 2602 2603 2605 260702 2608 2609 2612 2615 29010101 290201 2903 2910 300101 300201 3003 3004 3007 3009 3010 310102 3102 3104 3106 3111 3201 3202 3204 3206 3301 330301 3305 3401 3402 3405 3601 3603 4301 6601 6602 6603 680101 680102 6802 680301 6804 6805

4 Digits

Common in the USb

Exon 2–3 sequence groupsc

Among CWDd

Yes

Aⴱ240301g

Yes

2501

Yes

2601

Yes

Aⴱ2601g

2607 Yes

2901 2902

Yes Yes

3001 3002

Yes Yes

Aⴱ2901

Yes

3101

Yes

Yes

3303

Yes Yes Yes Yes Yes Yes Yes Yes

6801 6801 6803

Yes Yes Yes Yes Yes

Aⴱ680102g

Yes

Catalogue of HLA Common Alleles

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TABLE 2 (Continued) Locus

Namea

A A A A A A A A A A A A

6806 6807 6811N 6812 6815 6817 6820 6901 7401 7402 7403 8001

4 Digits

Common in the USb

Yes Yes

Exon 2–3 sequence groupsc

Among CWDd

Aⴱ680102g

Yes

Aⴱ7401g Aⴱ7401g

Yes Yes

Yes

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

identical peptide binding and immunologic characteristics. The ␣-1 and ␣-2 domains are encoded by the exons 2 and 3. Operationally, some laboratories and transplant programs consider that subjects carrying alleles with identical sequences in these exons as HLA matched at the corresponding HLA locus. Similarly, alleles of the HLA class II loci, DRA, DQA1, DPA1, with identical amino acid sequence in the ␣-1 domain and alleles of DRB1, DRB3/4/5, DQB1, and DPB1 loci that have identical amino acid sequence in the ␤-1 domain are considered equivalent. Therefore, subjects with HLA class II alleles, with identical sequences in the exon 2, may be considered as matched by many clinical programs. HLA class I alleles that have identical nucleotide sequence in exons 2 and 3 are shown in Table 10, and HLA class II alleles that have identical nucleotide sequences in exon 2 are shown in Table 11. In both of these tables, options for naming groups of alleles with identical sequences in the exons that encode for the domains of the ARS are also provided. These groups of alleles are named with the first four or six digits of the allele in the group that was described first, not necessarily the most common one, followed by the letter “g” and are meant to remain constant regardless of changes in the official nomenclature of HLA alleles. The Committee also provided a table (not shown) including the reduction to the four-digit names of HLA alleles. Tables 2 through 9 include columns with reduction to four-digit names of the alleles with six or eight digits. The tables are also available at http://hla. mdanderson.org under the section “A Catalogue of HLA alleles.”

DISCUSSION This catalogue of CWD alleles represents the allelic diversity of the HLA system in almost all world populations. When considered together, CWD alleles probably account for more than 99% of all genes of each HLA locus in each population studied so far. It is possible that some of the alleles not included in the CWD list may eventually be recognized as “well-documented” alleles after performing high-resolution typing, but the chances for finding each one of them are extremely low. Given this possibility however, the importance of testing for all alleles presently recognized by the World Health Organnization Nomenclature Committee for HLA factors cannot be overstated. The high-resolution tests should include reagents that allow for the appropriate resolution level that can recognize “rare” alleles in the event that those alleles are found again. In most instances, the assignment of the so-called rare alleles should be performed without ambiguity, or if ambiguous the possible genotypes should include combinations with only one CWD allele, the second allele being rare in all possible genotypes. Evaluation of Proficiency Testing The Committee recommends the use of the CWD allele list (Tables 2–11) to evaluate the reports of laboratories performing proficiency tests. It is recommended that an acceptable result is the one that includes only one unambiguously assigned possible genotype, or multiple ambiguous genotypes in which only one genotype includes two alleles of the list of CWD HLA alleles, whereas the other

398

P. Cano et al.

TABLE 3 Common and well-documented HLA-B alleles Locus

Namea

B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B

070201 070204 0703 0704 070501 0706 0707 0709 0710 0712 0714 0720 0732 080101 0802 0804 0809 0812 1301 130201 1303 1304 1309 1310 1401 140201 1403 1405 15010101 15010102N 1502 1503 1504 1505 1506 1507 1508 1509 1510 151101 1512 1513 1514 1515 1516 15170101 1518 1520 1521 1523 1524 1525 1527 1528 1529 1530 1531

4 Digits 0702 0702 0705

Common in the USb

Exon 2–3 sequence groupsc

Yes

Bⴱ070201g

Yes Yes Yes

Bⴱ070501g Bⴱ070501g

Among CWDd

Yes Yes

Yes

0801

Yes

1302

Yes Yes

1402

Yes Yes

1501 1501N

Yes Yes Yes

1511

1517

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

Yes

Bⴱ080101g

Bⴱ150101g Bⴱ150101g Bⴱ1503g

Bⴱ1512g

Yes Yes

Catalogue of HLA Common Alleles

399

TABLE 3 (Continued) Locus

Namea

B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B

1532 1533 1534 1535 1537 1538 1539 1540 1546 1547 1548 1552 1554 1558 1586 180101 180102 1802 1803 1804 2701 2702 2703 270401 270502 270503 2706 2707 2708 2709 2712 2714 350101 350201 3503 350401 3505 3506 350801 350901 350902 3510 3511 3512 3513 351401 3516 3517 3518 3519 3520 3521 3522 3523 3524 3527 3528 3530 3531

4 Digits

Common in the USb

Exon 2–3 sequence groupsc

Yes Yes Yes Yes

1801 1801

Yes

Bⴱ180101g

Yes Yes Yes

2704 2705 2705

Yes Yes Yes Yes

Bⴱ270502g

Yes Yes Yes

3501 3502

Yes Yes Yes

3504 Yes 3508 3509 3509

Yes

Yes Yes Yes Yes Yes Yes

Bⴱ350101g

Among CWDd

400

P. Cano et al.

TABLE 3 (Continued) Locus

Namea

B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B

3541 3543 370101 3702 380101 380201 380202 39010101 390201 390202 3903 3904 3905 390601 390602 3908 3909 3910 3911 3912 391301 3914 3915 3920 3924 400101 400102 400201 4003 4004 4005 40060101 4007 4008 4009 4010 4011 4012 4016 4020 4022N 4023 4027 4030 4040 4101 4102 4103 4106 4201 4202 44020101 440301 440302 4404 4405 4406 4407 4408

4 Digits

Common in the USb

3701

Yes Yes

3801 3802 3802 3901 3902 3902

Exon 2–3 sequence groupsc

Among CWDd

Bⴱ3543g

Yes Yes Yes Yes Yes

3906 3906

Yes Yes Yes

3913

Yes Yes

4001 4001 4002

4006

Yes Yes Yes

Bⴱ400101g Bⴱ400101g Bⴱ400201g

Yes Yes

Bⴱ440201g

Yes

Yes Yes Yes Yes

Yes Yes Yes Yes

4402 4403 4403

Yes Yes Yes Yes Yes Yes Yes

Catalogue of HLA Common Alleles

401

TABLE 3 (Continued) Locus

Namea

B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B B

4409 4410 4415 4420 4423N 4427 4429 4441 4501 4601 47010101 4702 4703 4705 4801 4802 4803 4804 4805 4807 4901 5001 5002 510101 510102 510201 510202 5103 5104 5105 5106 5107 5108 5109 5111N 5113 5114 5119 5121 5122 5123 520101 520102 530101 5302 5401 550101 550201 5504 5601 5602 5603 5604 570101 5702 570301 5704 5705 5801

4 Digits

Exon 2–3 sequence groupsc

Among CWDd

Yes

Bⴱ440201g

Yes

Yes Yes Yes

Bⴱ4501g

Yes

Bⴱ4801g

Common in the USb Yes

4701

Yes

5101 5101 5102 5102

Yes Yes Yes Yes

Bⴱ510101g

Yes

Bⴱ510101g

Yes

Yes

Yes Yes Yes Yes

5201 5201 5301

Yes Yes Yes

5501 5502

Yes Yes Yes

Bⴱ520101g

Yes

5701 5703

Yes Yes Yes Yes

Bⴱ5801g

402

P. Cano et al.

TABLE 3 (Continued) Locus

Namea

B B B B B B B B B B B

5802 5811 5901 670101 6702 7301 7801 780202 8101 8201 8202

4 Digits

Common in the USb

Exon 2–3 sequence groupsc

Among CWDd

Yes 6701

Yes Yes Yes Yes

7802 Yes Yes

Bⴱ8101g

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

alternative genotypes do not include any allele of this list. In other words, reporting multiple genotypes is allowed when the results include NO more than one genotype with two alleles of the list of CWD alleles. Tests results in which multiple genotypes include different CWD alleles are not acceptable; additional tests are needed to exclude some genotypes and leave only one genotype with two CWD alleles or to leave a single genotype with a pair of alleles of any category (CWD, rare, or novel). Single genotypes that include a pair composed by one CWD and one rare allele, or two rare alleles, or a new allele paired with a CWD allele or a rare allele are acceptable. Examples of these scenarios, the resolution and actions to be taken are shown in Table 12. This table includes hypothetical cases with results of single genotype and with two or more genotypes, including alleles of the CWD list or rare or new alleles. Occasionally the proficiency samples, as occurs in the clinical samples, may include novel alleles that have not been described previously and not recognized by the WHO Nomenclature Committee for HLA factors. When novel alleles are described, their identification should be noted and reported; it is recommended that a brief description of the structural characteristics of the novel allele be provided. Alleles with Identical Sequences in Exons That Encode the Domains of the ARS An exception to the recommendations described above is indicated for reports that include multiple genotypes that list alleles with identical sequences in these ARSencoding exons (exons 2 and 3 of class I loci, exon 2 of class II loci). It is recommended to accept reports that

may include more than one possible genotype in which common alleles differ in segments of the gene that are not likely to be functionally relevant or that can be assessed by other methodologies (e.g., serologic testing to rule out null alleles, expression assays including flow cytometry, etc.). Table 13 lists possible scenarios including multiple genotypes with alleles of the same ARS group. The rationale for this recommendation is similar to the scenarios shown in Table 12 and in this situation the alleles of the same group are considered as a single allele and could be reported as such. Testing for Sequence-Related Alleles with Deleterious Mutations (Null Alleles) The ad-hoc committee recommends that the alleles of HLA-A, B and C loci that differ outside exons 2 and 3, and the alleles of the HLA-DR, DQ and DP loci that differ outside exon 2, do not need to be distinguished by laboratories performing molecular typing proficiency tests. Tables 10 and 11 include alleles that do not need to be distinguished in external proficiency testing with exception of the common alleles Cwⴱ0409N, DRB4ⴱ01030102N and DRB5ⴱ0108N that occur with high frequency (gene frequencies of more than 0.001 in at least one population living in the United States). It has been recognized that the alleles Cwⴱ0401 and Cwⴱ0409N can both be found in haplotypes bearing the allele Bⴱ4403 [53]. Both HLA-C alleles, Cwⴱ0401 and Cwⴱ0409N, are common and are not distinguished by molecular methods that test only exons 2 and 3, because these alleles differ by the deletion of one nucleotide in exon 7. Cwⴱ0409N does not appear to associate with any other allele of HLA-B; since subjects carrying Bⴱ4403

Catalogue of HLA Common Alleles

403

TABLE 4 Well-documented alleles in HLA-C Locus

Namea

4 Digits

Common in the USb

Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw

010201 0103 020201 020202 0203 0205 0207 0210 030201 030202 030301 030304 030401 030402 0305 0306 0307 0308 0309 0310 0314 0316 0319 04010101 0403 040401 040402 0406 0407 0409N 0413 050101 0502 0505 0507N 0509 0510 0602 0604 070101 07020101 070401 0705 0706 0710 0712 0718 0719 0722 0726 080101 0802 0803 0804 0806 120202 120203 120301

0102

Yes

0202 0202

Yes

0302 0302 0303 0303 0304 0304

0401

Exon 2–3 sequence groupsc

Among CWDd

Yes Yes Yes Yes Yes Yes Yes Yes

Cwⴱ030301g

Yes Yes

Cwⴱ040101g

Yes

Yes Yes

Cwⴱ040101g

Yes

Yes

Cwⴱ050101g

0404 0404

0501

Yes Yes 0701 0702 0704

0801

1202 1202 1203

Yes Yes Yes

Cwⴱ070101g

Yes

Cwⴱ070101g

Yes

Yes

Cwⴱ070101g

Yes

Yes Yes Yes Yes Yes Yes Yes

Yes

Cwⴱ070401g

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P. Cano et al.

TABLE 4 (Continued) Locus

Namea

4 Digits

Common in the USb

Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw Cw

120402 1205 1209 1213 140201 140203 1403 1404 150201 1503 1504 150501 1506 1507 1509 1511 160101 1602 160401 1701 1703 1801 1802

1204

Yes

1402 1402

Yes

Exon 2–3 sequence groupsc

Among CWDd

Yes 1502

Yes

1505

Yes Yes Yes

1601 1604

Yes Yes Yes Yes Yes Yes

Cwⴱ150201g

Cwⴱ1701g Cwⴱ1701g Cwⴱ1801g Cwⴱ1801g

Yes Yes Yes Yes

a This column includes common and well documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

could carry either the expressed allele Cwⴱ0401 or the null allele Cwⴱ0409N, it is indicated to resolve the HLA-C ambiguity Cwⴱ0401/0409N when the allele Bⴱ4403 is present. The mismatch between subjects carrying Cwⴱ0401 and Cwⴱ0409N could result in allo-recognition. A similar example of common null alleles is observed for alleles at DRB4 and DRB5. The class II alleles DRB4ⴱ01030102N and DRB4ⴱ0101 and DRB4ⴱ0130101 have identical sequence in exon 2 and associate with DRB1ⴱ0701; therefore subjects carrying DRB1ⴱ0701 and listed with the ambiguity DRB4ⴱ0101/DRB4ⴱ01030101/01030102N could carry different either the expressed or null allele [73]. A similar example of a pair of common alleles with identical sequence in exon 2 in which one of the alleles is null, is represented by the ambiguity DRB5ⴱ0102/0108N. Both DRB5 alleles associate with DRB1ⴱ1502 in some Asian populations [74]; therefore, subjects carrying DRB1ⴱ1502 could carry either the expressed allele DRB5ⴱ0102 or the null allele DRB5ⴱ0108N. Even though alleles with identical sequences in exons 2 and 3 for class I or in exon 2 for class II do not need to

be distinguished in external proficiency testing, the committee recognizes their importance and the possible need in laboratory practice of testing other segments of the HLA genes. The grouping of alleles just described, for instance, does not account for distinction of null alleles from expressed alleles. Some null alleles are found with significantly high frequencies (DRB4ⴱ01030102N, DRB5ⴱ0108N, Cwⴱ0409N) or have been observed with several instances (Aⴱ0104N, Aⴱ2409N, Aⴱ2411N, etc.). These null alleles are identical in exon 2 of the class II genes and in exons 2 and 3 of the class I genes to some alleles included in the catalogue of CWD alleles. It is suggested to the laboratories performing clinical histocompatibility testing that they adopt typing strategies that identify or rule out the presence of null alleles. Suggested strategies could involve testing of expression by serologic methods or testing the segments of the gene where the deleterious mutations occur. When doing genomic testing only, the strategy to identify null alleles should take advantage of our knowledge of the linkagedisequilibrium blocks and the identification of haplotypes where the null alleles appear in. In these scenarios, the performance of ad-hoc additional tests is indicated to

Catalogue of HLA Common Alleles

405

TABLE 5 Well-documented alleles in HLA-DRB1 Locus

Namea

4 Digits

DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1

010101 010102 010201 0103 0107 030101 030102 030201 030202 0303 0304 0306 0307 0322 0315 040101 0402 040301 040302 0404 040501 040601 040701 0408 0409 0410 0411 0412 0413 0414 0415 0416 0417 0418 0426 0435 0438 0440 070101 080101 080201 080302 080401 080402 080404 0806 0807 0809 0810 0811 0813 0814 0818 090102 100101 110101 110102 110103 110201 1103

0101 0101 0102

Common in the USb Yes Yes Yes

0301 0301 0302 0302

Yes

0401

Yes Yes Yes

0403 0403 0405 0406 0407

Yes

Yes Yes Yes Yes Yes Yes Yes

Yes 0701 0801 0802 0803 0804 0804 0804

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

0901 1001 1101 1101 1101 1102

Yes Yes Yes Yes Yes Yes

Exon 2 sequence groupc

Among CWDd

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TABLE 5 (Continued) Common in the USb

Locus

Namea

4 Digits

DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1

110401 110402 1105 110601 1107 1109 1110 111101 111201 1113 111401 1115 1117 1118 111901 112701 1134 1139 1142 1145 120101 120201 120202 130101 130103 130201 130301 130302 1304 130501 1306 130701 130702 1310 1311 1312 1313 131401 1315 1316 1318 1320 1329 1331 1336 1356 140101 1402 140301 1404 140501 1406 140701 1408 1409 1410 1411 1412 1413 1414

1104 1104

Yes

1106

Yes

Exon 2 sequence groupc

Among CWDd

Yes Yes 1111 1112 1114

Yes Yes Yes

1119 1127

1201 1202 1202 1301 1301 1302 1303 1303 1305

Yes Yes

DRB1ⴱ120101g

Yes Yes Yes Yes Yes

1307 1307 Yes

1314

1401 1403 1405 1407

Yes Yes Yes Yes Yes Yes Yes

DRB1ⴱ140101g

Yes

Catalogue of HLA Common Alleles

407

TABLE 5 (Continued) Locus

Namea

DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1 DRB1

1415 1416 1417 1418 1420 1421 1424 1425 1448 1454 150101 150201 150202 1503 1504 1506 1510 160101 160201 1604 160501 1607

4 Digits

Common in the USb

Exon 2 sequence groupc

Among CWDd

DRB1ⴱ140101g

Yes

Yes

1501 1502 1502

Yes Yes Yes Yes Yes

1601 1602

Yes Yes

1605

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

be performed in samples with HLA genotypes associated with the presence of the common null alleles (e.g. rule out DRB4ⴱ01030102N in DRB1ⴱ0701 haplotypes; rule out the presence of Cwⴱ0409N in Bⴱ4403 haplotypes or determine the presence of Cwⴱ0401 by performing additional tests). Testing of other segments of the HLA genes may become of importance in anthropologic studies and in other evaluations in which the HLA derived peptides may be presented as alloantigens by the indirect presentation pathway and as minor-histocompatibility antigens. Examples of Acceptable and Unacceptable Results The catalogue of CWD alleles should be used in the evaluation of laboratory performance in external proficiency testing. Participating laboratories should rule out multiple genotypes with alleles of this list leaving only one genotype in their answer that includes one or two alleles of the list of CWD alleles. For clarification, we present examples of acceptable and unacceptable high-resolution results.

Unacceptable High-Resolution Results Several possible genotypes that have identical “sequencebased heterozygous typing” include common alleles in more than one genotype combination. The result that follows is not acceptable: “B*3501, B*4901” or “ B*5001, B*5301” The alleles of both genotypes are included in the list of CWD alleles. Additional tests are therefore needed and only one genotype, e.g., “(Bⴱ3501, Bⴱ4901),” is acceptable. Acceptable High-Resolution Results Laboratories could report multiple genotypes with alleles not included in the CWD allele list. For instance, the following result is acceptable: “B*3501, B*4601” or “ B*3562, B*4606” Only the alleles of first genotype (Bⴱ3501, Bⴱ4601) are included in the list of CWD alleles and neither of the alleles of the second genotype (Bⴱ3562 and Bⴱ4608) is included in this list.

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TABLE 6 Well-documented alleles in HLA-DRB3/4/5 Locus

Namea

DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5 DRB3/4/5

B3ⴱ01010201 B3ⴱ01010202 B3ⴱ0201 B3ⴱ020201 B3ⴱ0203 B3ⴱ0206 B3ⴱ0207 B3ⴱ0209 B3ⴱ0210 B3ⴱ0211 B3ⴱ0216 B3ⴱ0217 B3ⴱ030101 B3ⴱ0303 B4ⴱ01010101 B4ⴱ0102 B4ⴱ01030101 B4ⴱ01030102N B4ⴱ010303 B4ⴱ0201N B4ⴱ0301N B5ⴱ010101 B5ⴱ010102 B5ⴱ0102 B5ⴱ0103 B5ⴱ0108N B5ⴱ0110N B5ⴱ0202 B5ⴱ0203

4 Digits B3ⴱ0101 B3ⴱ0101 B3ⴱ0202

Common in the USb

Yes

B4ⴱ0101

Yes Yes Yes Yes

B5ⴱ0108N B5ⴱ0110N B5ⴱ0202 B5ⴱ0203

Among CWDd

DRB4ⴱ010101g

Yes

DRB4ⴱ010101g DRB4ⴱ010101g

Yes Yes

DRB5ⴱ0102g

Yes

DRB5ⴱ0102g

Yes

Yes Yes Yes Yes Yes

B3ⴱ0301

B4ⴱ0103 B4ⴱ0103N B4ⴱ0103 B4ⴱ0201N B4ⴱ0301N B5ⴱ0101 B5ⴱ0101

Exon 2 sequence groupc

Yes Yes Yes

Yes Yes

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

Acceptable High-Resolution Results Laboratories could report multiple genotypes that include class I alleles differing outside exons 2 and 3 and genotypes that include class II alleles that differ outside exon 2. The result shown below is acceptable: “B*0705, B*1502 ” or “ B*0706, B*1502” The alleles Bⴱ070501 and Bⴱ0706 differ only in one substitution in the first nucleotide of codon 281 located in exon 5. Notice that the second allele of both genotypes is the same Bⴱ1502; there may be instances in which both alleles of the genotype have identity in exons 2 and 3 with other alleles of the locus. The list of class I alleles with identical sequences in exon 2 and 3 and of class II alleles with identical sequence in exon 2 is provided in Table 10.

Suggested Use of the CWD Allele List in Clinical Histocompatibility Practice The Committee suggests that each laboratory performing clinical histocompatibility typing should define, in agreement with their physicians, the boundaries of resolution of ambiguities according to the population of patients and donors that they serve. The expertise of the histocompatibility consultant is crucial to define the criteria for resolution of ambiguities. It is acknowledged that differences in criteria of resolution of ambiguities may arise when performing tests for less diverse populations and for different transplant types. Similarly, the criteria for resolution of ambiguities may be different when evaluating related and unrelated donors, as well as when performing HLA typing of newly recruited donors for bone marrow registries and cord blood banks. It is recommended that all possible

Catalogue of HLA Common Alleles

409

TABLE 7 Well-documented alleles in HLA-DQA1 Locus

Namea

4 Digits

DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1 DQA1

010101 010102 010201 0103 010401 0105 0201 030101 0302 0303 040101 050101 0503 0505 0509 060101

0101 0101 0102

Common in the USb

Exon 2 sequence groupc

Among CWDd

Yes

DQA1ⴱ010101g DQA1ⴱ010101g

Yes Yes

DQA1ⴱ010101g DQA1ⴱ010101g

Yes Yes

DQA1ⴱ030101g DQA1ⴱ030101g DQA1ⴱ030101g

Yes Yes Yes

DQA1ⴱ050101g DQA1ⴱ050101g DQA1ⴱ050101g DQA1ⴱ050101g

Yes Yes Yes Yes

0104 0301 0401 0501

0601

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

genotypes resulting from the performance of one or more tests are included in the laboratory reports. If frequency data are obtained in studies performed locally or published in scientific journals, and with ethnicity similar to the one the sample typed, the likelihood ratio of common genotypes could also be reported. The report should include the possible genotypes resulting from heterozygous ambiguities if no tests ruling out multiple genotypes were performed. For instance, in the presence of the ambiguity shown below: “B*3501, B*4601” or “ B*3562, B*4608” both possible genotypes should be reported and the following comment could be included: “The genotype (Bⴱ3501, Bⴱ4601) is at least ⬎1000/1 times more likely than the genotype (Bⴱ3562, Bⴱ4608).” For alleles differing in segments not tested, the report should similarly include all possible genotypes if no tests ruling out multiple genotypes were performed. For instance, in the presence of the ambiguity shown below: “共B*0705, B*1502兲” or “ 共B*0706, B*1502兲” both genotypes should be reported and the following comment could be included: “Alleles Bⴱ0705 and Bⴱ0706 differ by one amino acid substitution at residue 281 located in the trans-membrane region. This difference is not likely to be immunologically relevant.”

An alternative way of reporting the possible highresolution result could include high-resolution NMDP for the possible results “(Bⴱ0705, Bⴱ1502) or (Bⴱ0706, Bⴱ1502),” the report could include the results as follows: “共B*07EH, B*1502兲” A comment describing the meaning of the code should be included in the report: “Bⴱ07EH indicates that the assignment may be either Bⴱ0705 or Bⴱ0706. The alleles Bⴱ0705 and Bⴱ0706 differ by one amino acid substitution trans-membrane region. This difference is not likely to be immunologically relevant.” The list of CWD HLA alleles provided could be a useful tool for HLA laboratories performing clinical histocompatibility typing. It is expected that more than 98.5% of the subjects of any population of the world will carry genotypes including two alleles of the list. The committee suggests that when the HLA laboratories performing clinical histocompatibility typing find a rare allele, that is, an allele not included in the list of CWD HLA alleles, the HLA type should be confirmed by performing additional tests in the subject or in family relatives bearing the same haplotype. Principles used to define the criteria for resolution of ambiguities. The criteria for resolution of ambiguities were established from principles of population genetics, in which genotype frequencies can be estimated as the double product of the gene frequencies of individual alleles of particular genotype. In the example shown

410

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TABLE 8 Well-documented alleles in HLA-DQB1 Common in the USb

Exon 2 sequence groupc

Among CWDd

0201

Yes Yes

DQB1ⴱ020101g DQB1ⴱ020101g

Yes Yes

0301 0302 0303

Yes Yes Yes Yes Yes

DQB1ⴱ030101g

Yes

DQB1ⴱ030101g DQB1ⴱ030101g

Yes Yes

Locus

Namea

4 Digits

DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1 DQB1

020101 0202 0203 030101 030201 030302 0304 030501 0309 0319 0401 0402 050101 050201 050301 0504 060101 060102 0602 0603 060401 0608 0609 0610 061101 061102 0619

0305

0501 0502 0503 0601 0601 0604

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

0611 0611

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

below; the estimated genotype frequency of the genotype I including the alleles X1 and X2 from locus X can be calculated as follows Genotype f I ⫽ 2 x Gf (X1) x Gf (X2) The frequency of several genotypes can be added to estimate the overall frequency of all alternative genotypes to a genotype including two common alleles. For example, the genotypes: “Cwⴱ0602, Cwⴱ070101g,” “Cwⴱ0604, Cwⴱ0722,” and “Cwⴱ0611, Cwⴱ0709” have identical heterozygous sequencing based typing pattern. The frequency of this ambiguous heterozygous pattern can be estimated as the sum of all possible genotype frequencies: Frequency of pattern ⫽ Genotype f I ⫹ Genotype f II ⫹ Genotype f III where Genotype f I ⫽ 2 x Gf (Cw*0602) x Gf (Cw*070101g)

Genotype f II ⫽ 2 x Gf (Cw*0604) x Gf (Cw*0722) Genotype f III ⫽ 2 x Gf (Cw*0611) x Gf (Cw*0709) The odds ratio of the occurrence of particular genotype (e.g., Cwⴱ0602, Cwⴱ070101g) in subjects carrying this ambiguity can be estimated as:) Odds ’ Cw*0602, Cw*070101g ’ ⫽ Genotype f I ⁄ (Genotype f II ⫹ Genotype f III) To calculate the odds ratio of the genotype “Cwⴱ0602, Cwⴱ070101g” we used data from study of 643 unrelated Caucasian subjects typed unambiguously using sequence-based typing methods combined with other procedures (Burdett and Fernandez-Vina, unpublished observation). In this study, 1,286 genes of HLA-C were analyzed; the alleles Cwⴱ0602 (n ⫽ 110) and Cwⴱ070101g (n ⫽ 210) were observed in numerous examples, whereas the alleles Cwⴱ0604, Cwⴱ0611, Cwⴱ0709, and Cwⴱ0722 were not observed. In order to

Catalogue of HLA Common Alleles

411

TABLE 9 Well-documented alleles in HLA-DPB1 Locus

Namea

4 Digits

DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1 DPB1

010101 010102 020102 0202 030101 0302 040101 0402 0501 0601 0602 0901 1001 110101 1301 1401 1501 1601 1701 1801 1901 200101 2101 2201 2301 260101 2701 2801 2901 3001 3101 3301 3401 3501 3601 3801 3901 4001 4501 4601 4701 5001 5101 5501 5901 6301 6901 7201 7801 8101 8501

0101 0101 0201 0301 0401

1101

2001

Common in the USb

Exon 2 sequence groupsc

Among CWDd

Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

DPB1ⴱ030101g DPB1ⴱ0402g

Yes

DPB1ⴱ0402g

Yes

DPB1ⴱ1301g

DPB1ⴱ1901g

Yes 2601

Yes

Yes

Yes

a This column includes common and well-documented (CWD) alleles. The names of the alleles were assigned by the World Health Organization Nomenclature committee for HLA factors. b The alleles that are found frequently in subjects living in the US are indicated. c The names of the allele groups that have identical sequence in the exons encoding for the antigen recognition site (ARS) are shown in this column. The name of the allele group was assigned on the basis of the allele of the group that was recognized at the earliest date. d The information in this column indicates that other alleles of the same ARS group are present among the CWD alleles.

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P. Cano et al.

TABLE 10 HLA class I allele groups identical sequence when only exons 2 and 3 are tested Allele 1

Allele 2

Aⴱ0101 Aⴱ0201 Aⴱ0207 Aⴱ0211 Aⴱ0222 Aⴱ0301 Aⴱ1101 Aⴱ2301 Aⴱ24020101 Aⴱ240301 Aⴱ260101

Aⴱ0104N Aⴱ0209 Aⴱ0215N Aⴱ0269 Aⴱ9204 Aⴱ0320 Aⴱ1121N Aⴱ2307N Aⴱ24020102L Aⴱ2433 Aⴱ2624

Aⴱ29010101 Aⴱ680102 Aⴱ7401 Bⴱ070201 Bⴱ0705 Bⴱ0801 Bⴱ15010101 Bⴱ1503 Bⴱ1512 Bⴱ180101 Bⴱ270502 Bⴱ350101 Bⴱ3543 Bⴱ400101 Bⴱ4002 Bⴱ44020101 Bⴱ4501 Bⴱ4801 Bⴱ510101 Bⴱ520101 Bⴱ5801 Bⴱ8101 Cwⴱ030301 Cwⴱ040101 Cwⴱ0501 Cwⴱ070101 Cwⴱ070401 Cwⴱ150201 Cwⴱ1701

Aⴱ29010102N Aⴱ6811N Aⴱ7402 Bⴱ0744 Bⴱ0706 Bⴱ0819N Bⴱ15010102N Bⴱ9503 Bⴱ1519 Bⴱ180103 Bⴱ270504 Bⴱ350103 Bⴱ3567 Bⴱ400102 Bⴱ4056 Bⴱ44020102S Bⴱ4507 Bⴱ4809 Bⴱ510105 Bⴱ5207 Bⴱ5811 Bⴱ8102 Cwⴱ030303 Cwⴱ040102 Cwⴱ0503 Cwⴱ070102 Cwⴱ0711 Cwⴱ1513 Cwⴱ1702

Cwⴱ1801

Cwⴱ1802

Allele 3 Aⴱ0243N

Allele 3

Allele 4

Allele 5

Allele 6

Aⴱ0266

Aⴱ0275

Aⴱ0283N

Aⴱ0289

Aⴱ240210

Aⴱ2409N

Aⴱ2411N

Aⴱ2440N

Aⴱ0321N Aⴱ240203 Aⴱ2626 Aⴱ2901

Bⴱ9502

Bⴱ9504

Bⴱ1817N Bⴱ2713 Bⴱ3540N

Bⴱ3542

Bⴱ3557

Bⴱ4055 Bⴱ4419N

Bⴱ4427

Bⴱ5111N

Bⴱ5130

Bⴱ5132

Cwⴱ0320N Cwⴱ0409N Cwⴱ0706

Cwⴱ0718

Cwⴱ1703

Bⴱ5130

Bⴱ5132

Suggested name to report Aⴱ0101/0104N Aⴱ020101g Aⴱ0207/Aⴱ0215N Aⴱ0211/0269 Aⴱ0222g Aⴱ030101g Aⴱ1101/1121N Aⴱ2301/2307N Aⴱ240201g Aⴱ2403/2433 Aⴱ2601/2624/ 2626 Aⴱ2901 Aⴱ6801/6811N Aⴱ7401/7402 Bⴱ0702/0744 Bⴱ0705/0706 Bⴱ0801/0819N Bⴱ150101g Bⴱ1503/9503 Bⴱ1512/1519 Bⴱ1801/1817N Bⴱ270502g Bⴱ350101g Bⴱ3543g Bⴱ4001g Bⴱ4002/4056 Bⴱ440201g Bⴱ4501/4507 Bⴱ4801/4809 Bⴱ510101g Bⴱ5201/5207 Bⴱ5801/5811 Bⴱ8101/8102 Cwⴱ0303/0320N Cwⴱ0401/0409N Cwⴱ0501/0503 Cwⴱ070101g Cwⴱ0704/0711 Cwⴱ1502/1513 Cwⴱ1701/1702/ 1703 Cwⴱ1801/1802

Alternative Aⴱ010101g Aⴱ020101g Aⴱ0207g Aⴱ0211g Aⴱ0222g Aⴱ030101g Aⴱ110101g Aⴱ2301g Aⴱ240201g Aⴱ240301g Aⴱ2601g Aⴱ680102g Aⴱ7401g Bⴱ070201g Bⴱ0705g Bⴱ0801g Bⴱ150101g Bⴱ1503g Bⴱ1512g Bⴱ180101g Bⴱ270502g Bⴱ350101g Bⴱ3543g Bⴱ4001g Bⴱ4002g Bⴱ440201g Bⴱ4501g Bⴱ4801g Bⴱ510101g Bⴱ520101g Bⴱ5801g Bⴱ8101g Cwⴱ030301g Cwⴱ040101g Cwⴱ050101g Cwⴱ070101g Cwⴱ070401g Cwⴱ150201g Cwⴱ1701g Cwⴱ1801g

In each row alleles of the HLA class I locus that have identical nucleotide sequence in exons 2 and 3. Possible names for grouping alleles with identical sequences in the exons that encode for the domains of the antigen recognition site (ARS) are provided in the last two columns. The last column indicates the suggested name for groups of alleles; the groups are named with the first four or six digits of the allele in the group that was described first followed by the letter g.

calculate the odds ratio for the occurrence of the common genotype we gave values of 1 or 3 to the unobserved alleles. With these values we estimated ratios ranging 11,500/1 to 1283/1 for the genotype “Cwⴱ0602, Cwⴱ070101g” versus “Cwⴱ0604, Cwⴱ0722” or “Cwⴱ0611, Cwⴱ0709.” In this example the alleles and Cwⴱ0602 and Cwⴱ070101g are included in the group of CWD, whereas none of the alleles included in the alternative genotypes (Cwⴱ0604, Cwⴱ0611, Cwⴱ0709, and Cwⴱ0722) belong to the CWD list. The genotype with

two alleles of CWD is at least 1,000 times (and possibly 10,000) more likely than other alternative genotype. The use of the CWD list would also indicate that this ambiguity does not need to be resolved. In most population studies the rare alleles are not observed at all, their maximal gene frequency could be estimated assuming that those could have been observed once for a particular sample size. Then the minimal odds ratio for the likelihood of the occurrence of a genotype including two common alleles versus the occurrence of

Catalogue of HLA Common Alleles

413

TABLE 11 HLA class II allele groups identical sequence when only exon 2 is tested Allele 1

Allele 2

Allele 3

Allele 3

Allele 4

Allele 5

Allele 6

Suggested name to report

DPB1ⴱ0301 DPB1ⴱ0502

DPB1ⴱ0301/ 0502 DPB1ⴱ0402 DPB1ⴱ0602 DPB1ⴱ0402/ 0602 DPB1ⴱ0802 DPB1ⴱ1901 DPB1ⴱ0802/ 1901 DPB1ⴱ0902 DPB1ⴱ1301 DPB1ⴱ0902/ 1301 DQA1ⴱ0101 DQA1ⴱ0104 DQA1ⴱ0105 DQA1ⴱ0101/ 0104/0105 DQA1ⴱ0301 DQA1ⴱ0302 DQA1ⴱ0303 DQA1ⴱ03 DQA1ⴱ0501 DQA1ⴱ0503 DQA1ⴱ0505 DQA1ⴱ0506 DQA1ⴱ0507 DQA1ⴱ0508 DQA1ⴱ0509 DQA1ⴱ05 DQA1ⴱ0601 DQA1ⴱ0602 DQA1ⴱ06 DQB1ⴱ0201 DQB1ⴱ0202 DQB1ⴱ0204 DQB1ⴱ0201/ 0202/0204 DQB1ⴱ0301 DQB1ⴱ0309 DQB1ⴱ0319 DQB1ⴱ0301/ 0309/0309 DRB1ⴱ1201 DRB1ⴱ1206 DRB1ⴱ1210 DRB1ⴱ120101/ 1206/1210 DRB1ⴱ1401 DRB1ⴱ1454 DRB1ⴱ140101/ 1454

Alternative DPB1ⴱ030101g DPB1ⴱ0402g DPB1ⴱ1901g DPB1ⴱ1301 DQA1ⴱ0101g DQA1ⴱ0301g DQA1ⴱ050101g DQA1ⴱ0601g DQB1ⴱ0201g DQB1ⴱ0301g DRB1ⴱ120101g DRB1ⴱ140101g

In each row are alleles of the HLA class II loci that have identical nucleotide sequence in exon 2. Possible names for grouping alleles with identical sequences in the exons that encode for the domains of the antigen recognition site (ARS) are provided in the last two columns. The last column indicates the suggested name for groups of alleles; the groups are named with the first four or six digits of the allele in the group that was described first followed by the letter g.

TABLE 12 Possible results to be reported in external proficiency tests and their resolution Single genotype results 1) 2) 3) 4) 5) Multiple genotype results 6) 7) 8) 9) 10) 11)

Genotypesa

1st Allele

2nd Allele

a a a a a

CWD1b CWD1 Rare1 CWD1 Rare1

CWD2 Rare1c Rare2 New New

a b c a b a b a b a b a b

CWD1 Rare1 Rare3 CWD1 CWD3 CWD1 CWD3 CWD1 CWD2 CWD1 Rare2 Rare1 Rare3

CWD2 Rare2 Rare4 CWD2 CWD4 CWD2 Rare1 Rare1 Rare2 Rare1 Rare3 Rare2 Rare4

Resolution

Action

Acceptable Acceptable Acceptable Acceptable Acceptable

Complete Complete Complete Complete Complete

Acceptable

Complete

Not acceptable

Perform additional tests

Not acceptable

Perform additional tests

Not acceptable

Perform additional tests

Not acceptable

Perform additional tests

Not acceptable

Perform additional tests

a Genotypes ⫽ genotypes composed by the combination of two alleles (first (1st) and second (2nd)) allele. The alleles may fall into three categories: common and well documented (CWD); rare; and new (allele newly recognized, not listed in the World Health Organization Nomenclature Report). The possible genotypes are indicated with letters a, b, and c. The resolution as acceptable or not acceptable is based on the possible alternatives as described in the text. b CWD ⫽ common and well-documented allele. The numbers after “CWD” denote different alleles of the locus reported. c Rare ⫽ rare allele. The numbers after “rare” denote different alleles of the locus reported.

414

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TABLE 13 Possible results involving groups of alleles that differ outside the exons encoding for antigen recognition site (ARS) Multiple genotype results including alleles of the same group

1) 2) 3) 4) 5)

Genotype

1st Allele

2nd Allele

A B A B A B A B C A B C

CWD gi CWD gi CWD gi CWD gi CWD gi CWD gi CWD gi CWD gi CWD2 CWD gi CWD gi CWD1

CWD1 CWD1 CWD gf CWD gf Rare1 Rare1 CWD1 CWD1 CWD3 CWD gf CWD gf CWD2

Category

Resolution

Acceptable

Report one allele and one group

Acceptable

Report two groups

Acceptable

Report one allele and one group

Not acceptable

Perform additional tests

Not acceptable

Perform additional tests

Genotypes ⫽ genotypes composed by the combination of one group of alleles (CWD g: 1st and 2nd allele). The alleles and allele groups may fall into three categories: common and well-documented (CWD); rare; and new (allele newly recognized, not listed in the World Health Organization Nomenclature Report). The possible genotypes are indicated with letters a, b, and c. The resolution as acceptable or not acceptable is based on the possible alternatives as described in the text. b CWD g ⫽ group including one or more alleles listed as common and well documented (see Tables 10 and 11). The subindex i, f indicates different allele groups. c CWD ⫽ common and well-documented allele. The numbers after “CWD” denote different alleles of the locus reported. d Rare ⫽ rare allele. The numbers after “rare: denote different alleles of the locus reported. a

any remaining genotypes including rare alleles can be estimated with confidence assuming that the gene frequencies are at best the inverse number of all genes tested. In this scenario odds ratio for the likely occurrence of a particular genotype including two common alleles (since the gene frequencies of each allele are factored to calculate the frequency of the genotype) are extremely high when compared with alternative including genotypes composed by two rare alleles. The tables of CWD do not include gene frequencies; however, one can assume that the genotypes including two alleles of this list have high frequency, whereas the genotypes composed by two alleles not included in this list are rare. The odds ratios for other possible multiple genotype combinations shown in Tables 12 and 13 may be lower. The Committee took a conservative position to recommend that the genotype ambiguities with likely intermediate odds ratios need to be resolved. Through this recommendation, the Accreditation Review Board of ASHI should be able to evaluate with accuracy the ability of individual laboratories to perform high-resolution testing in a scenario similar to the tests done in clinical histocompatibility practice. ACKNOWLEDGMENTS The authors acknowledge Lynn Benson from the M. D. Anderson Cancer Center for excellent secretarial assistance, and Kimberly Glenn for coordination of the activities of the committee. The committee members also acknowledge Kelly Buck and Jane Kempenich from the National Marrow Donor Program for the thorough review of HLA phenotypes in the NMDP

database. The encouragement from Drs. Peter Nickerson, Karen Nelson, Carol Pancoska, Deborah Crowe, Marilyn S. Pollack, Ms. Doreen Jezek, and Dr. David Eckels is also recognized.

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