PD1.3A allele has been associated with SLE susceptibility in Swedish, Mexican and European American cohorts,6,7
whereas it has been shown to be protective for SLE among a Spanish cohort,15
and not associated with SLE susceptibility among a biethnic (African American and Caucasian) US cohort.9
The PD1.3A allele has also been positively associated with susceptibility to LN among Swedish Europeans7,8
and negatively associated with APLA presence.9
As it appears that PD1.3A does not explain all the PDCD1
associations in SLE, we evaluated additional polymorphisms within PDCD1
for susceptibility to SLE and clinical sub-phenotypes.
We have analyzed a total of 15 SNPs, covering on average one SNP per 670 bp of the PDCD1 gene. We examined the distribution of these SNPs and their haplotypes in several populations (data not shown). We find that the size of the LD blocks in PDCD1 is rather small (1–2 kb), suggesting that in order to identify susceptibility variants in this gene, a very dense SNP map is required. We also identified five SNPs that can provide non-redundant information about haplotypes in any population and can be used as ‘tags’ for association studies.
In the current study, using family-based association methods, we detected a weak association for the PD1.3A allele among European American families (P = 0.08, dominant model; P = 0.11, additive model). In addition, the 5-marker haplotype containing PD1.3A showed an even stronger association with SLE risk (P = 0.01, additive model). The fact that we have not detected any other associations indicates that there may be no other disease variants of similar frequency/relative risk within this gene in Europeans, but it does not exclude the possible existence of additional rare, weak and/or recessive mutations that we were not able to detect using the current data set.
We can exclude PD1.3A as a significant disease variant in non-European populations because of its extreme rarity and acknowledge that additional studies will be needed to clarify the contribution of PDCD1 to disease in these populations using both families and case/control analyses. However, we did observe an association between two other PDCD1 SNPs (PD1.6A and PD1.7T) and SLE susceptibility among Hispanic families. To our knowledge this is a novel finding and should encourage others to evaluate these variants in Hispanic populations.
In our evaluation of PDCD1
and SLE sub-phenotypes, we have identified several haplotypic associations. Notably, Haplotype 5 containing the PD1.1A allele located in the promoter region of the gene (position −531 from the translation start) was much more frequent among the Asian American patients, and it conferred a protective effect for LN in this subgroup. This haplotype has also been recently demonstrated to be associated with decreased levels of tumor necrosis factor alpha.16
Haplotype 4 was positively associated with arthritis among Asian Americans and with APLA among African American patients, whereas it was negatively associated with dsDNA antibodies among the Hispanic American patients. Among the Caucasian patients, Haplotype 3 was marginally associated with APLAs. These novel findings should be viewed as specific hypotheses to be confirmed in independent cohorts.
Although strengths of the current study include the ethnically diverse cohort and the relatively large number of non-Caucasians overall, we still had reduced power to detect genetic associations among the smaller ethnic subgroups and for the less frequent alleles/haplotypes. Another strength of the study is the family-based design, which minimizes problems with population admixture.
In conclusion, we have carefully evaluated 15 SNPs in the PDCD1 gene to further define its role in SLE risk and disease expression. The knowledge of haplotype structure in different populations allowed us to select five SNPs that can be used as ‘tags’ for association studies in any population. We have used these ‘tags’ to study a large multi-ethnic set of SLE families. We have shown that a 5-marker haplotype containing PD1.3A is associated with SLE in European Americans using family-based association methods. We also identified haplotypic associations for clinical SLE subphenotypes among Asian Americans, African Americans and Hispanic Americans.
The new haplotypic associations identified herein provide further evidence that PDCD1 is an important gene for expression of SLE. The associations suggest either a true haplotypic effect or alternatively, indicate that another polymorphism within or near PDCD1 may be causal for disease apart from PD1.3A. The fact that haplotype associations are stronger than allele associations and that the haplotype associations vary by ethnic group, suggest there may be additional causal variants that have not yet been identified.