Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe

Abstract

We obtained eight collections of DNA samples from ethnically matched systemic lupus erythematosus (SLE) patients and controls from five European countries totaling 783 patients and 1210 controls. A highly significant cline in the frequency of the PD1.3 A allele was found among controls but not among SLE patients. The frequency of the PD1.3 A allele increased from the Northeast to the Southwest of Europe. The cline was clearly apparent (P ¼ 1.2 Â 10 À6 ) when data from controls of other five SLE susceptibility studies were included in the analysis. This variation has severely biased SLE association studies owing to the lack of parallel changes in SLE patients. As a consequence, the PD1.3 A allele was more common in SLE patients than in controls in the Northeast and Center of Europe, similar to controls in Southeast Europe, and less frequent than in the controls in the Southwest of the Continent. This dissociation in allele frequencies between SLE patients and controls in different subpopulations indicated that programmed cell death 1 variation and disease susceptibility are not independent but the type of relationship is currently unclear. As allele frequency clines are common in other polymorphisms their impact in genetic epidemiology studies should be carefully considered.

Analysis of the functional relevance of a putative regulatory SNP of PDCD1, PD1.3, associated with systemic lupus erythematosus

“…2,3 However, most posterior studies have failed to replicate the PD1.3-SLE genetic association. In some studies, there was not association, 4,5 in others association was only with specific subsets of SLE patients, or association was with other polymorphisms in the PDCD1 gene 3,[6][7][8] or with the opposite allele of the PD1.3 single nucleotide polymorphism (SNP). 9 These contradictory results could be related to an allele frequency cline in PD1.3, which introduces a bias in association studies depending on the population explored.…”

“…9 These contradictory results could be related to an allele frequency cline in PD1.3, which introduces a bias in association studies depending on the population explored. 5 As a consequence of the discordant results, it is still unclear if genetic variation in PDCD1, either PD1.3 or another polymorphism, plays any role in SLE susceptibility. This is very relevant because SLE has a clear genetic component, recurrence sibling ratio of 20-40, and few genetic factors identified.…”

Opposed independent effects and epistasis in the complex association of IRF5 to SLE

“…Most of these samples have been already described; 26,27 new collections were from Corunna in Spain, Martin in Slovakia and Groningen in the Netherlands. Significant heterogeneity and lack of HWE in several SNPs among controls led to the exclusion from further study of samples from the Czech Republic.…”

PDCD1single nucleotide genes polymorphisms confer susceptibility to juvenile-onset systemic lupus erythematosus

“…A few more reports of nonassociation of this SNP in other populations also exist [4,27]. In contrast, PD1.3 SNP with a G to A transition at +7146 position, located in an enhancer-like domain in PD-1 intron 4, has been previously shown to affect SLE pathogenesis in Caucasian, European American, Mexican, Swedish, Icelandic and Greek populations, as well as the European population in the Northeast and Center of Europe [4,8,14,15,27,28]. Similarly, the results of the investigation conducted by Velazquez-Cruz et al supported the association of the PD1.3 A SNP to susceptibility of JSLE in Mexican population [3].…”