HLA-C and KIR permutations influence chronic obstructive pulmonary disease risk

Takudzwa Mkorombindo; Thi Tran-Nguyen; Kaiyu Yuan; Yingze Zhang; Jianmin Xue; Gerard J. Criner; Young-il Kim; Joseph M. Pilewski; Amit Gaggar; Michael H. Cho; Frank C. Sciurba; Steven R. Duncan

doi:10.1172/jci.insight.150187

HLA-C and KIR permutations influence chronic obstructive pulmonary disease risk

Takudzwa Mkorombindo,¹ Thi Tran-Nguyen,¹ Kaiyu Yuan,¹ Yingze Zhang,² Jianmin Xue,² Gerard J. Criner,³ Young-il Kim,¹ Joseph M. Pilewski,² Amit Gaggar,¹ Michael H. Cho,⁴ Frank C. Sciurba,² and Steven R. Duncan¹

Published August 31, 2021 - More info

View PDF

Abstract

A role for hereditary influences in the susceptibility for chronic obstructive pulmonary disease (COPD) is widely recognized. Cytotoxic lymphocytes are implicated in COPD pathogenesis, and functions of these leukocytes are modulated by interactions between their killer-cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA)-Class I molecules on target cells. We hypothesized HLA-Class I and KIR inheritance affect risks for COPD. HLA-Class I alleles and KIR genotypes were defined by candidate gene analyses in multiple cohorts of COPD patients (total n=392) and control smokers with normal spirometry (total n=342). Compared to controls, COPD patients had over-representations of HLA-C*07 and activating KIR2DS1, with under-representations of HLA-C*12. Particular HLA-KIR permutations were synergistic; e.g. the presence of HLA-C*07 + KIR2DS1 + HLA-C12^null vs. HLAC*07^null + KIR2DS1^null + HLA-C12 was associated with COPD, especially among HLA-C1 allotype homozygotes (OR=18.5, 95%CI=3.7-90.9, p<0.0001). Cytotoxicity of COPD lymphocytes was more enhanced by KIR stimulation than those of controls (p=0.005) and was correlated with lung function (r=0.44, p=0.004). These data show HLA-C and KIR polymorphisms strongly influence COPD susceptibility and highlight the importance of lymphocyte-mediated cytotoxicity in COPD pathogenesis. Findings here also indicate HLA-KIR typing could stratify at-risk patients and raise possibilities HLA-KIR axis modulation may have therapeutic potential.

HLA-C and KIR permutations influence chronic obstructive pulmonary disease risk

Takudzwa Mkorombindo,¹ Thi Tran-Nguyen,¹ Kaiyu Yuan,¹ Yingze Zhang,² Jianmin Xue,² Gerard J. Criner,³ Young-il Kim,¹ Joseph M. Pilewski,² Amit Gaggar,¹ Michael H. Cho,⁴ Frank C. Sciurba,² and Steven R. Duncan¹

Article tools

Metrics

Go to

HLA-C and KIR permutations influence chronic obstructive pulmonary disease risk

Takudzwa Mkorombindo,1 Thi Tran-Nguyen,1 Kaiyu Yuan,1 Yingze Zhang,2 Jianmin Xue,2 Gerard J. Criner,3 Young-il Kim,1 Joseph M. Pilewski,2 Amit Gaggar,1 Michael H. Cho,4 Frank C. Sciurba,2 and Steven R. Duncan1

Article tools

Metrics

Go to

Sign up for email alerts

Takudzwa Mkorombindo,¹ Thi Tran-Nguyen,¹ Kaiyu Yuan,¹ Yingze Zhang,² Jianmin Xue,² Gerard J. Criner,³ Young-il Kim,¹ Joseph M. Pilewski,² Amit Gaggar,¹ Michael H. Cho,⁴ Frank C. Sciurba,² and Steven R. Duncan¹