RESUMO
The contribution of genetic ancestry on chronic obstructive pulmonary disease (COPD) predisposition remains unclear. To explore this relationship, we analyzed the associations between 754,159 single nucleotide polymorphisms (SNPs) and risk of COPD (n = 214 cases, 193 healthy controls) in Talca, Chile, considering the genetic ancestry and established risk factors. The proportion of Mapuche ancestry (PMA) was based on a panel of 45 Mapuche reference individuals. Five PRDM15 SNPs and two PPP1R12B SNPs were associate with COPD risk (p = 0.05 to 5×10-4) in those individuals with lower PMA. Based on linkage disequilibrium and sliding window analyses, an adjacent PRDM15 SNPs were associated with COPD risk in the lower PMA group (p = 10-3 to 3.77×10-8). Our study is the first to report an association between PPP1R12B and COPD risk, as well as effect modification between ethnicity and PRDM15 SNPs in determining COPD risk. Our results are biologically plausible given that PPP1R12B and PRDM15 are involved in immune dysfunction and autoimmunity, providing mechanistic evidence for COPD pathogenesis and highlighting the importance to conduct more genome wide association studies (GWAS) in admixed populations with Amerindian descent.
RESUMO
BACKGROUND: Genome-wide association studies (GWAS) have accelerated our understanding of the genetic underpinnings of chronic obstructive pulmonary disease (COPD); however, GWAS populations have typically consisted of European descent, with â¼1% of Latin American ancestry. OBJECTIVE: To overcome this limitation, we conducted a GWAS in a rural Chilean population with increased COPD risk to investigate genetic variation of COPD risk in this understudied minority population. METHOD: We carried out a case-control study of 214 COPD patients (defined by the GOLD criteria) and 193 healthy controls in Talca, Chile. DNA was extracted from venous blood and genotyped on the Illumina Global Screening Array (n = 754,159 markers). After exclusion based on Hardy-Weinberg equilibrium (p ≤ 0.001), call rates (<95%), and minor allele frequencies (<0.5%) in controls, 455,564 markers were available for logistic regression. RESULTS: PRDM15 rs1054761 C allele (p = 2.22 × 10-7) was associated with decreased COPD risk. Three PRDM15 SNPs located on chromosome 21 were significantly associated with COPD risk (p < 10-6). Two of these SNPs, rs1054761 and rs4075967, were located on a noncoding transcript variant region of the gene. CONCLUSION: PRDM15 overexpression may play a role in the B-cell dysregulation in COPD pathogenesis. To the best of our knowledge, the association between PRDM15 and COPD risk was not previously found in GWAS studies in largely European populations, highlighting the importance of investigating novel variants associated with COPD risk among ethnically diverse populations.