An update to Kidd blood group system.

Since publication of the original Immunohematology review of the Kidd blood group system in 2015 (Hamilton JR. Kidd blood group system: a review. Immunohematology 2015;31:29-34), knowledge has mushroomed pertaining to gene structure, alleles causing variant and null phenotypes, clinical significance in renal transplant and hemolytic disease of the fetus and newborn, and physiologic functions of urea transporters in non-renal tissues. This review will detail much of this new information.

Blood Management in a Liver Transplant Recipient with Kidd (Jka) and Rhesus (D) Antibodies: A Case Report.

A 67-year-old man presented for urgent liver transplantation (LT). Screening revealed the rare combination of antiRhesus (D) and antiKidd Jk(a) antibodies, requiring antigen-negative red blood cells (RBC) for both phenotypes. This combination has not been reported during LT. Compatible RBCs were initially limited, requiring continued communication between the blood bank/blood supplier to obtain more, including frozen, units. Additional strategies included the use of cell salvage and intentional management of coagulopathy to limit bleeding and RBC requirement. This case highlights blood management during LT when D and Jk(a) antibodies may limit RBC supply and emphasizes the need for effective communication with the blood bank.

Two new JK silencing alleles identified by single molecule sequencing with 20-Kb long-reads.

BACKGROUND: The Kidd blood group gene SLC14A1 (JK) accounts for approximately 20 Kb from initiation codon to stop codon in the genome. In genomic DNA analysis using Sanger sequencing or short-read-based next generation sequencing, it is difficult to determine the cis or trans positions of single nucleotide variations (SNVs), which are occasionally more than 1 Kb away from each other. We aimed to determine the complete nucleotide sequence of a 20-Kb genomic DNA amplicon to characterize the JK allelic variants associated with Kidd antigen silencing in a blood donor. STUDY DESIGN AND METHODS: The Jk(a-b-) phenotype was identified in this donor by standard serological typing. A DNA sample obtained from whole blood was amplified by long-range PCR to obtain a 20-Kb fragment of the SLC14A1 gene, including the initiation and stop codons. The fragment was then analyzed by Sanger sequencing and single-molecule sequencing. Transfection and expression studies were performed in CHO cells using the expression vector construct of JK alleles. RESULTS: Sanger sequencing and single-molecule sequencing revealed that the donor was heterozygous with JK*01 having c.276G>A (rs763262711, p.Trp92Ter) and JK*02 having c.499A>G (rs2298719, p.Met167Val), c.588A>G (rs2298718, p.Pro196Pro), and c.743C>A (p.Ala248Asp). The two JK alleles identified have not been previously described. Transfection and expression studies indicated that the CHO cells transfected with JK*02 having c.743C>A did not express the Jkb and Jk3 antigens. CONCLUSIONS: We identified new JK silencing alleles and their critical SNVs by single-molecule sequencing and the findings were confirmed by transfection and expression studies.

[Analysis of frequency and molecular genetics of Jk (a-b-) phenotype among blood donors from Jining area].

OBJECTIVE: To screen for Jk(a-b-) phenotype among blood donors from Jining area and explore its molecular basis to enrich the rare blood group bank for the region. METHODS: The population who donated blood gratuitously at Jining Blood Center from July 2019 to January 2021 were selected as the study subjects. The Jk(a-b-) phenotype was screened with the 2 mol/L urea lysis method, and the result was confirmed by using classical serological methods. Exons 3 to 10 of the SLC14A1 gene and its flanking regions were subjected to Sanger sequencing. RESULTS: Among 95 500 donors, urea hemolysis test has identified three without hemolysis, which was verified by serological method as the Jk(a-b-) phenotype and demonstrated no anti-Jk3 antibody. The frequency of the Jk(a-b-) phenotype in Jining area is therefore 0.0031%. Gene sequencing and haplotype analysis showed that the genotypes of the three samples were JK*02N.01/JK*02N.01, JK*02N.01/JK-02-230A and JK*02N.20/JK-02-230A, respectively. CONCLUSION: The splicing variant of c.342-1G>A in intron 4, missense variants of c.230G>A in exon 4, and c.647_ 648delAC in exon 6 probably underlay the Jk(a-b-) phenotype in the local population, which is different from other regions in China. The c.230G>A variant was unreported previously.

Analysis of frequency and molecular genetics of Jk (a-b-) phenotype among blood donors from Jining area / 中华医学遗传学杂志

OBJECTIVE@#To screen for Jk(a-b-) phenotype among blood donors from Jining area and explore its molecular basis to enrich the rare blood group bank for the region.@*METHODS@#The population who donated blood gratuitously at Jining Blood Center from July 2019 to January 2021 were selected as the study subjects. The Jk(a-b-) phenotype was screened with the 2 mol/L urea lysis method, and the result was confirmed by using classical serological methods. Exons 3 to 10 of the SLC14A1 gene and its flanking regions were subjected to Sanger sequencing.@*RESULTS@#Among 95 500 donors, urea hemolysis test has identified three without hemolysis, which was verified by serological method as the Jk(a-b-) phenotype and demonstrated no anti-Jk3 antibody. The frequency of the Jk(a-b-) phenotype in Jining area is therefore 0.0031%. Gene sequencing and haplotype analysis showed that the genotypes of the three samples were JK*02N.01/JK*02N.01, JK*02N.01/JK-02-230A and JK*02N.20/JK-02-230A, respectively.@*CONCLUSION@#The splicing variant of c.342-1G>A in intron 4, missense variants of c.230G>A in exon 4, and c.647_ 648delAC in exon 6 probably underlay the Jk(a-b-) phenotype in the local population, which is different from other regions in China. The c.230G>A variant was unreported previously.

Development of anti-Jk3 associated with silenced Kidd antigen expression and a novel single nucleotide variant of the JK gene.

Anti-Jk3 is a rare alloantibody to a high-prevalence antigen primarily seen in individuals of Polynesian descent and is associated with a handful of well-established variants of the SLC14A1 gene. We report a case of the Jknull phenotype, associated with formation of anti-Jk3, in a patient of non-Polynesian descent. This patient, a 51-year-old woman self-described as of Jamaican and Scottish ancestry, presented to our hospital for oncologic care. The patient's blood sample typed as blood group A, D+. All screening and panel reagent red blood cells showed reactivity, ranging from 2 to 4+; autocontrol and direct antiglobulin test were both negative. Antigen phenotyping revealed Jk(a-b-), leading to suspicion for anti-Jk3, which was subsequently confirmed by our immunohematology reference laboratory. Given her reported familial background, testing of the SLC14A1 gene was performed, revealing that the patient was heterozygous for the single nucleotide variant (SNV) at c.838G>A in exon 8 and therefore carries both JK*01 and JK*02 alleles that encode Jka and Jkb, respectively. However, the patient was found to be heterozygous for several additional SNVs: c.28G>A in exon 3; c.191G>A, c.226G>A, and c.303G>A in exon 4; and c.757T>C in exon 7. The patient's Jk(b-) phenotype can be explained by coinheritance of c.838A with c.191G>A, which defines null allele JK*02N.09. Coinheritance of SNVs c.28G>A and c.838G with rare SNV c.757C that is predicted to cause a non-conservative amino acid change (p.S253P) likely accounts for the complete serologic absence of Jka and the ability to form anti-Jk3 in this case. This finding would represent a new JK*01 null allele. This evaluation illustrates the importance of genetic analysis in identifying the factors preventing a high-prevalence antigen from being expressed, particularly when discovered outside of an expected racial or ethnic group.Anti-Jk3 is a rare alloantibody to a high-prevalence antigen primarily seen in individuals of Polynesian descent and is associated with a handful of well-established variants of the SLC14A1 gene. We report a case of the Jknull phenotype, associated with formation of anti-Jk3, in a patient of non-Polynesian descent. This patient, a 51-year-old woman self-described as of Jamaican and Scottish ancestry, presented to our hospital for oncologic care. The patient's blood sample typed as blood group A, D+. All screening and panel reagent red blood cells showed reactivity, ranging from 2 to 4+; autocontrol and direct antiglobulin test were both negative. Antigen phenotyping revealed Jk(a­b­), leading to suspicion for anti-Jk3, which was subsequently confirmed by our immunohematology reference laboratory. Given her reported familial background, testing of the SLC14A1 gene was performed, revealing that the patient was heterozygous for the single nucleotide variant (SNV) at c.838G>A in exon 8 and therefore carries both JK*01 and JK*02 alleles that encode Jka and Jkb, respectively. However, the patient was found to be heterozygous for several additional SNVs: c.28G>A in exon 3; c.191G>A, c.226G>A, and c.303G>A in exon 4; and c.757T>C in exon 7. The patient's Jk(b­) phenotype can be explained by coinheritance of c.838A with c.191G>A, which defines null allele JK*02N.09. Coinheritance of SNVs c.28G>A and c.838G with rare SNV c.757C that is predicted to cause a non-conservative amino acid change (p.S253P) likely accounts for the complete serologic absence of Jka and the ability to form anti-Jk3 in this case. This finding would represent a new JK*01 null allele. This evaluation illustrates the importance of genetic analysis in identifying the factors preventing a high-prevalence antigen from being expressed, particularly when discovered outside of an expected racial or ethnic group.

Jknull alleles in two patients with anti-Jk3.

BACKGROUND: As of publication, a total of 41 null alleles have been acknowledged by the International Society of Blood Transfusion (ISBT) to cause the rare Jknull phenotype, but none have been discovered in Austria thus far. MATERIALS AND METHODS: Two patients with anti-Jk3 were serologically identified by a positive antibody screening and typed as Jk(a-b-). The initial genotyping using an SSP-PCR method for the common 838A/G polymorphism indicated a JK*02/02, or JK*01/02 genotype, respectively. To find the disruptive mutations, Sanger sequencing was performed and results were compared to the reference sequence. The patient's antibodies were characterized with a monocyte monolayer assay (MMA) for their potential clinical significance. RESULTS: Three novel null-mutations of the SLC14A1 gene were found in two patients. Patient 1 was homozygous for a 10bp deletion in exon 4 (c.157_166del on JK*02). Testing of her family members revealed Mendelian inheritance of the deletional allele. The other patient was compound heterozygous for two mutations: one allele carrying a single base deletion in exon 4 (c.267delC on JK*01) and the other a splice site mutation in intron 3 (c.152-1g>a on JK*02). The MMA results suggest high clinical significance of the anti-Jk3 in both patients. DISCUSSION: The detected mutations led to Jknull phenotypes and are the first description of JKnull alleles in the Austrian population.

Diversity of variant alleles encoding Kidd, Duffy, and Kell antigens in individuals with sickle cell disease using whole genome sequencing data from the NHLBI TOPMed Program.

BACKGROUND: Genetic variants in the SLC14A1, ACKR1, and KEL genes, which encode Kidd, Duffy, and Kell red blood cell antigens, respectively, may result in weakened expression of antigens or a null phenotype. These variants are of particular interest to individuals with sickle cell disease (SCD), who frequently undergo chronic transfusion therapy with antigen-matched units. The goal was to describe the diversity and the frequency of variants in SLC14A1, ACKR1, and KEL genes among individuals with SCD using whole genome sequencing (WGS) data. STUDY DESIGN AND METHODS: Two large SCD cohorts were studied: the Recipient Epidemiology and Donor Evaluation Study III (REDS-III) (n = 2634) and the Outcome Modifying Gene in SCD (OMG) (n = 640). Most of the studied individuals were of mixed origin. WGS was performed as part of the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program. RESULTS: In SLC14A1, variants included four encoding a weak Jka phenotype and five null alleles (JKnull ). JKA*01N.09 was the most common JKnull . One possible JKnull mutation was novel: c.812G>T. In ACKR1, identified variants included two that predicted Fyx (FY*X) and one corresponding to the c.-67T>C GATA mutation. The c.-67T>C mutation was associated with FY*A (FY*01N.01) in four participants. FY*X was identified in 49 individuals. In KEL, identified variants included three null alleles (KEL*02N.17, KEL*02N.26, and KEL*02N.04) and one allele predicting Kmod phenotype, all in heterozygosity. CONCLUSIONS: We described the diversity and distribution of SLC14A1, ACKR1, and KEL variants in two large SCD cohorts, comprising mostly individuals of mixed ancestry. This information may be useful for planning the transfusion support of patients with SCD.

Genotyping and serotyping profiles showed weak Jka presentation for previously typed as Jknull donors.

BACKGROUND AND OBJECTIVES: Kidd blood group system consists of two major antigens: Jka and Jkb . Both the antigens are absent in individuals typed as Jknull and may develop clinically significant anti-Jk3 antibody. Screening donors for provision of Jknull blood is an ongoing task for blood centres with Jknull blood units kept frozen for specific requirements. In 2016, we discovered a previously typed Jknull donor to be Jka weak positive. Therefore, a study was conducted for our donors to verify Jknull status and to reinforce our typing protocol. MATERIALS AND METHODS: In this experiment, donors previously typed and screened as Jknull were tested with four antisera of Jka and Jkb , and each with gel card for serology testing. Sequence analysis was performed for SLC14A1 gene for the detection of JKnull and weak alleles for genetic testing. RESULTS: Among the 30 samples, four were serologically identified as Jk(a+w ) and genotypically identified as heterozygous for the JK*01W.01 allele. The other 26 were confirmed to be Jknull with JK*02N.01 as the most frequent allele. None of JK*B weak alleles were detected, but three were identified as false positives in the tube method. Gel card gave great accuracy for Jkb detection, but failed to give consistent results for weak Jka . CONCLUSION: By combining the tube method and gel card method in serology, along with complementary genetic testing, the possibility of misinterpreting weak Jka expression was eliminated, and we were able to provide Jknull blood for safe clinical transfusion.

Phenotype frequencies of Rh (C, c, E, e), M, Mia and Kidd blood group systems among ethnic Thai blood donors from the north-east of Thailand.

We here report the first study of antigen and phenotype frequencies of Rh (C, c, E, e), M, Mia and Kidd antigens in north-east Thai blood donors. Blood transfusion services aim to ensure availability of adequate and safe blood to minimize the development of transfusion reactions. For pre-transfusion testing, the most important blood group systems are ABO and RhD. The transfusion of ABO-compatible otherwise unknown phenotype blood may result in alloimmunization, especially in multi-transfused patients. Extended red blood cell (RBC) phenotyping and selection of blood negative for specific antigens reduce post-transfusion complications and allow for effective blood transfusion regimens to be achieved. A total of 13,567 regular repeated, voluntary Thai blood donors were included for red-cell antigen typing of Rh (D, C, E, c, e). Samples from 12,768, 9,389 and 13,059 donors were typed for Kidd, M and Mia antigens, respectively. Amongst Rh antigens, e was the most common (96.80%) followed by C (95.50%), c (34.40%) and E (32.20%) with CCDee (60.00%) being the most common phenotype. For Kidd phenotypes, Jk(a+b+) was the most common (46.73%) and Jk(a-b-) was rare (0.07%). For the M and Mia antigen, M(+) was most frequently found (94.96%) and Mia (+) was found in 17.97% of individuals. Knowledge of red-cell antigen phenotype frequencies in a population is helpful for creating a phenotype database of blood donors which can provide antigen-negative compatible blood to patients with multiple alloantibodies. Moreover, provision of antigen-matched blood can prevent alloimmunization in multi-transfused patients.

A Caucasian JK*A/JK*B woman with Jk(a+b-) red blood cells, anti-Jkb, and a novel JK*B allele c.1038delG.

The Kidd blood group on the red blood cell (RBC) glycoprotein urea transporter-B has a growing number of weak and null alleles in its gene SLC14A1 that are emerging from more widespread genotyping of blood donors and patients. We investigated a 64-year-old Caucasian woman of Polish-Czech descent who developed anti-Jkb detected in solid-phase RBC adherence testing within 12 days after 7 units of RBCs were transfused. Her RBCs subsequently typed Jk(a+b­) by licensed reagents and human antisera. Nevertheless, in RBC genotyping (BioArray HEA BeadChip, Immucor, Warren, NJ) performed in our transfusion service on all patients with alloantibodies, her Kidd typing was JK*A/JK*B based on the Jka/Jkb single nucleotide polymorphism in exon 9 (c.838G>A, p.Asp280Asn). Genomic analysis and cDNA sequencing of her JK*B allele revealed a novel single-nucleotide deletion of c.1038G in exon 11, predicting a frameshift and premature stop (p.Thr346Thrfs*5) after translation of nearly 90 percent of the expressed exons 4­11. This allele has been provisionally named JK*02N.14, subject to approval by the International Society of Blood Transfusion Working Party. The site of this variant is closer to the C-terminus than that of any allele associated with the Jk(a­b­) phenotype reported to date. Routine genotyping of patients with RBC alloantibodies can reveal variants posing potential risk of alloimmunization. Continuing investigation of Kidd variants may shed light on the structure of Kidd antigens and the function of urea transporter-B.

Profile of Rh, Kell, Duffy, Kidd, and Diego blood group systems among blood donors in the Southwest region of the Paraná state, Southern Brazil.

The aim of this study was to assess the distribution of alleles and genotypes of the blood group systems Rh, Kell, Duffy, Kidd, and Diego in 251 regular blood donors registered in the hemotherapy unit of the Southwestern region of Paraná, Southern Brazil. The frequencies were obtained by direct counting on a spreadsheet program and statistical analyses were conducted in order to compare them with other Brazilian populations using chi-squared with Yates correction on OpenEpi software. The frequencies of RHD* negative, RHCE*c/c and RHCE*e/e were higher than expected for the Caucasian population. A difference was also observed for FY alleles, FY*01/FY*01 genotype and FY*02N.01 -67T/C (GATA Box mutation). Two homozygous individuals were defined as a low frequency phenotype K + k- (KEL*01.01/KEL*01.01) and, for Diego blood group system the rare DI*01 allele was found in ten blood donors, of which one was DI*01/DI* 01 (0.4%). The allele and genotype frequencies of Kidd blood group system were similar to expected to Caucasians. The results showed the direction in which to choose donors, the importance of extended genotyping in adequate blood screening and the existence of rare genotypes in Brazilian regular blood donors.

Molecular genetic analysis of the Jk(a-b-) phenotype in Chinese: A novel silent recessive JK allele.

The Jk(a-b-) phenotype, referred to as Jknull, is rare in most populations. This blood type is characterized by the absence of Kidd glycoprotein on the surface of red blood cells (RBCs) and moderately reduced ability to concentrate urine. The molecular basis for Jknull phenotype includes splice-site mutations, missense mutations, and a partial gene deletion in the JK(SLC14A1) gene that encodes the human urea transporter protein. In this study, we have analyzed 10 Chinese Jknull samples to determine their molecular bases. In addition to the well known Polynesian Jknull allele, three Jknull alleles were detected including one novel Jknull allele: JKA (130A, 220G).

Kidd blood group system: a review.

The Kidd blood group system has been recognized as clinically important in red blood cell (RBC) serology since its identification in 1951. Forty years later, the JK glycoprotein was determined to be a product of SCL14A1 and was identical to the urea transport protein UT-B produced by HUT11A. The functional role of the protein as a urea transporter in RBC and kidney has been well documented. The polymorphism responsible for the antithetical anigens Jk(a) and Jk(b) was identified in 1994 as c.838G>A (p.Asp280Asn). Recent discoveries have expanded the system to include 23 variant alleles recognized by the International Society of Blood Transfusion that silence the protein expression and 7 variant alleles presumably producting weak or partia JK antigens. Null phenotypes have been identified in individuals of several populations including those of African, Indian, and Chinese decent, in addition to the well-documented findings in the Polynesian and Finnish populations. This review will examine the historical information about the anigens and antibodies of the JK system as well as catalog the variations of the JK gene.

A novel missense mutation nt737T>G of JK gene with Jk(a-b-) phenotype in Chinese blood donors.

OBJECTIVES: The aim of this study was to investigate the molecular mechanism of the JK-null phenotype in the Chinese population. BACKGROUND: The Jk(a-b-) phenotype is vanishingly rare and the molecular basis differs between ethnic groups. The information regarding the molecular basis of JK-null alleles in the Chinese population is limited. MATERIALS AND METHODS: Three unrelated Jk(a-b-) phenotype donors were selected from 52 260 randomly blood samples through the urea lysis test and serological analysis. The JK gene-coding regions were amplified by the polymerase chain reaction and the products were sequenced directly. RESULTS: Sequencing results revealed that one sample of JK(*) B alleles carried the well-known Polynesian Jk(a-b-) mutation IVS5-1g>a. Another null allele, also on the JK(*) B background, presented with two heterozygous missense mutation, including nt222C>A(Asn74Lys) in exon 5 and nt896G>A(Gly299Glu) in exon 9. The third null allele carried two heterozygous missense mutations, nt222C>A and a novel allele nt737T>G(Leu246Arg) in exon 8. The family investigation revealed that the proband was JK(*) A(737T>G)/JK(*) B(222C>A). CONCLUSION: The Jk(a-b-) phenotype in the Chinese population shows several different molecular mechanisms. A novel missense mutation nt737T>G of JK gene was found as associated with Jk(a-b-) phenotype.

Clinical aspects of urea transporters.

Jk antigens, which were identified as urea transporter B (UT-B) in the plasma membrane of erythrocytes, and which determine the Kidd blood type in humans, are involved in transfusion medicine, and even in organ transplantation. The Jk(a-b-) blood type is a consequence of a silent Slc14A1 gene caused by various mutations related to lineage. In addition, the specific mutations related to hypertension and metabolic syndrome cannot be ignored. Genome-wide association studies established Slc14A1 as a related gene of bladder cancer and some genotypes are associated with higher morbidity. This chapter aims to introduce the clinical significance of urea transporters.