Human NCR3 gene variants rs2736191 and rs11575837 influence susceptibility to the longitudinal development of pediatric severe malarial anemia

Author:

Onyango Clinton O.1,Cheng Qiuying2,Munde Elly O.3,Raballah Evans4,Anyona Samuel B.1,McMahon Benjamin H.5,Lambert Christophe G.2,Onyango Patrick O.1,Schneider Kristan A.6,Perkins Douglas J.2,Ouma Collins1

Affiliation:

1. Maseno University

2. University of New Mexico

3. Kirinyaga University

4. Masinde Muliro University of Science and Technology

5. Los Alamos National Laboratory

6. University of Applied Sciences Mittweida

Abstract

Abstract Background Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb) < 5.0g/dL] is the most common clinical manifestation of severe malaria in such regions. Although innate immune response genes are known to influence the development of SMA, the role of natural killer (NK) cells in malaria pathogenesis remains largely undefined. As such, we examined the impact of genetic variation in the gene encoding a primary NK cell receptor, natural cytotoxicity-triggering receptor 3 (NCR3), on the occurrence of malaria and SMA episodes over time. Methods Susceptibility to malaria, SMA, and all-cause mortality was determined in carriers of NCR3 genetic variants (i.e., rs2736191:C > G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children (n = 1,515, aged 1.9–40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya. Results Poisson regression modeling, controlling for anemia-promoting covariates, revealed an increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114–2.129, P = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009–1.597, P = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030–1.393, P = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had an additive effect for protection against SMA (IRR = 0.823, 95% CI = 0.711–0.952, P = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030–1.581, P = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018–1.372, P = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality. Conclusions Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria.

Publisher

Research Square Platform LLC

Reference61 articles.

1. WHO. World Malaria Report 2021.

2. Indicators of life-threatening malaria in African children;Marsh K;NEJM,1995

3. The Clinical Profile of Severe Pediatric Malaria in an Area Targeted for Routine RTS,S/AS01 Malaria Vaccination in Western Kenya;Akech S;Clin Infect Dis,2019

4. Assessment of malaria infection among pregnant women and children below five years of age attending rural health facilities of Kenya: A cross-sectional survey in two counties of Kenya;Okoyo C;PLoS ONE,2021

5. Paton RS, Kamau A, Akech S, Agweyu A, Ogero M, Mwandawiro C, et al. Malaria infection and severe disease risks in Africa. Science (New York. 2021;373(6557):pp. 926–31.

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3