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Studies Point to Key Deletion Behind Rare Blood Group

NEW YORK (GenomeWeb News) – Two new Nature Genetics studies suggest that mutations affecting a gene called SMIM1 are behind the rare "Vel" blood group — named for the lack of Vel antigen expression on red blood cells of those affected.

Independent research teams took slightly different tacks to identify the Vel blood group culprit. Researchers from the UK, the Netherlands, the US, and Denmark did exome sequencing on several Vel-negative individuals before screening for SMIM1 mutations in dozens more individuals from the blood group. Meanwhile a Swedish-led group relied on array-based SNP typing and transcriptional network data to look for Vel-associated alterations in 20 individuals from the Vel blood group.

The studies mark the first time that a specific gene has been implicated in the blood group, first recognized roughly six decades ago. Estimates since then suggest around one person in every 5,000 is negative for Vel antigens on their red blood cells — a situation that prompts their immune system to raise antibodies against the protein.

Because of this immune response, Vel-negative individuals can have serious or even deadly complications if they receive blood from those with Vel antibodies on their red blood cells, the researchers explained.

That makes simple transfusions a tricky prospect for those in the Vel blood group, given the relative rarity of Vel-negative donors. Studying the genetics behind the blood group has proven difficult, too, in part because of its infrequency.

For the first of the new studies, researchers managed to track down several dozen Vel-negative individuals through blood screening on hundreds of thousands of individuals at sites in the UK, the Netherlands, and Denmark.

That team started by doing whole-exome sequencing on five of the individuals using Illumina's HiSeq 2000 to sequence coding regions of the genome captured with the Roche Nimblegen SeqCap EZ exome kit.

The analysis uncovered a frameshift deletion involving 17 nucleotides within SMIM1, which codes for a small integral membrane protein. Four of the five individuals had the same deletion in both copies of SMIM1, while the fifth person was heterozygous for the frameshift deletion.

Through targeted Sanger sequencing on 64 more individuals lacking the Vel antigen, the researchers found another 59 Vel-negative individuals who were homozygous for the same SMIM1 deletion. Another 19 individuals — all but one of the 20 tested individuals with lower-than-usual Vel expression — were heterozygous for the alteration.

In contrast, population data available for more than 7,500 people from the UK indicated that the overall allele frequency of the frameshift deletion is just 1.6 percent in the population at large.

"Our finding that homozygosity for a low-frequency 17-nucleotide deletion polymorphism underlies Vel-negative status is of direct clinical relevance," the authors of the study noted.

The newly detected alteration "allows the unequivocal identification of Vel-negative blood donors," they explained, "thereby preventing erroneous Vel typing and reducing the risk of severe and sometimes life-threatening destruction if incompatible donor [red blood cells] by antibodies to Vel."

"This is really exciting as it shows how the power of modern genomics technologies can directly benefit patient care," co-senior author Willem Ouwehand, a researcher affiliated with the University of Cambridge and the Wellcome Trust Sanger Institute and who also heads the UK's National Health Service Blood and Transplant group, said in a statement.

Investigators based at the NHS Blood and Transplant Centre and the Netherlands' Sanquin research laboratories are reportedly pursuing a genetic test for the Vel blood group based on the new findings.

As reported in another Nature Genetics study, researchers from Sweden's Lund University and elsewhere unearthed the same 17 base frameshift deletion in SMIM1 using SNP data for Vel-negative individuals, combined with transcriptional network analyses and targeted sequencing.

For the first phase of that study, the team genotyped 20 Vel-negative individuals, including five affected individuals from two families.

From genotyping and allele frequency data on Vel-negative individuals, coupled with data generated for the 1000 Genomes Project, investigators narrowed in on part of chromosome 1 containing SMIM1. They then turned to existing bone marrow gene expression information on almost 2,100 individuals for additional clues on the network of genes with ties to blood-related traits — an analysis that brought SMIM1 to the forefront of candidates in the chromosome 1 region.

SMIM1 gene sequencing in the initial set of individuals led to the homozygous frameshift deletion now believed to characterize the Vel blood group, the researchers explained. Follow-up analyses verified these ties in 15 more Vel-negative individuals and provided clues to the possible functional role of the SMIM1 gene product in blood-related processes.

Consistent with past reports pointing to somewhat higher rates of Vel blood group prevalence in parts of northern Scandinavia, that group estimated that one in every 1,200 individuals from the Swedish population carries the homozygous SMIM1 deletion. Heterozygous carriers appear more common in that population: around one in 17 blood donors screened in that population had the deletion on one of their two SMIM1 alleles.

With the new SMIM1 deletion in hand, that group is keen to start using genotyping for the change as a means of finding matched blood donors for individuals who are Vel-negative.

Authors of the study noted that a regional blood center in Lund, Sweden has already identified individuals with the homozygous deletion through a screening program implemented on the heels of the new research.

"So far, two new homozygotes were found and confirmed serologically as Vel-negative," they noted, "demonstrating how our findings facilitate the procurement of compatible blood for Vel-immunized patients who risk delayed transfusion support and worse outcomes."

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