IL4 gene polymorphism and previous malaria experiences manipulate anti-Plasmodium falciparum antibody isotype profiles in complicated and uncomplicated malaria

<p>Abstract</p> <p>Background</p> <p>The <it>IL4</it>-590 gene polymorphism has been shown to be associated with elevated levels of anti-<it>Plasmodium falciparum </it>IgG antibodies and parasite intensity in the malaria protected Fulani of West Africa. This study aimed to investigate the possible impact of <it>IL4</it>-590C/T polymorphism on anti-<it>P. falciparum </it>IgG subclasses and IgE antibodies levels and the alteration of malaria severity in complicated and uncomplicated malaria patients with or without previous malaria experiences.</p> <p>Methods</p> <p>Anti-<it>P.falciparum </it>IgG subclasses and IgE antibodies in plasma of complicated and uncomplicated malaria patients with or without previous malaria experiences were analysed using ELISA. <it>IL4</it>-590 polymorphisms were genotyped using RFLP-PCR. Statistical analyses of the IgG subclass levels were done by Oneway ANOVA. Genotype differences were tested by Chi-squared test.</p> <p>Results</p> <p>The <it>IL4</it>-590T allele was significantly associated with anti-<it>P. falciparum </it>IgG3 antibody levels in patients with complicated (<it>P </it>= 0.031), but not with uncomplicated malaria (<it>P </it>= 0.622). Complicated malaria patients with previous malaria experiences carrying <it>IL4</it>-590TT genotype had significantly lower levels of anti-<it>P. falciparum </it>IgG3 (<it>P </it>= 0.0156), while uncomplicated malaria patients with previous malaria experiences carrying the same genotype had significantly higher levels <it>(P </it>= 0.0206) compared to their <it>IL4</it>-590 counterparts. The different anti-<it>P. falciparum </it>IgG1 and IgG3 levels among IL4 genotypes were observed. Complicated malaria patients with previous malaria experiences tended to have lower IgG3 levels in individuals carrying TT when compared to CT genotypes (<it>P </it>= 0.075). In contrast, complicated malaria patients without previous malaria experiences carrying CC genotype had significantly higher anti-<it>P. falciparum </it>IgG1 than those carrying either CT or TT genotypes (<it>P </it>= 0.004, <it>P </it>= 0.002, respectively).</p> <p>Conclusion</p> <p>The results suggest that <it>IL4</it>-590C or T alleles participated differently in the regulation of anti-malarial antibody isotype profiles in primary and secondary malaria infection and, therefore, could play an important role in alteration of malaria severity.</p

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ii CONTENTS Preface..............................................................................................................x Contributors.................................................................................................... xi Abbreviations................................................................................................ xxi PARASITE

IL4-589C/T polymorphism and IgE levels in severe malaria.

Previous studies identified an allelic variant of the IL4 promoter region (IL4-589T) that appears to enhance the transcriptional activity of IL4, and is associated with increased IgE levels. Total serum IgE levels are elevated in malaria endemic regions, and higher in children with severe malaria. Here, we investigated the relationship of the IL4-589C/T polymorphism with severity of the disease in a case-control study of severe malaria in Burkina Faso, West Africa. No association between the IL4-589T and severe malaria was observed. No difference in Plasmodium falciparum-specific IgE was detected between severe and uncomplicated malaria patients. Among children with severe malaria, total IgE levels were significantly elevated in those carrying the IL4-589T allele (P = 0.018). In children with uncomplicated malaria, no significant difference was found. These results raise the possibility that there is a relationship between susceptibility to severe malaria, IgE production and genetic variation in the IL4 region, which merits further investigation in other epidemiological settings

ヴァヌアツのマラリア流行島嶼におけるIL4多型とIgE濃度

血中IgE上昇に帰結するIL4プロモーターの遺伝的変異が,マラリアに対する感受性と相関することが最近の研究によって示唆されてきている.本研究においては集団遺伝学的方法を用いヴァヌアツにおけるマラリア流行度が異なる3島嶼において,IL4-590および+33塩基における変異対立遺伝子頻度,血中総IgEおよび熱帯熱マラリア原虫特異的IgE濃度を調べた.3島嶼は中等度の流行が続くMalakula,中等度の流行だが対策が功を奏しているAneityumおよびマラリア流行がないFutunaである.これらの島嶼住民より採取した血液サンプルよりIL4-590および+33についてそれぞれ計878および750サンプルの解析を行った.変異対立遺伝子頻度はこれら3島嶼間においてC-590Tが0.27～0.39,C+33Tが0.39～0.48の範囲で変動した.両対立遺伝子間には顕著な連鎖不均衡が認められた(p<0.001).これら両変異対立遺伝子ともAneityumにおいてはFutunaより高い頻度で認められた(p<0.05).AneityumにおいてはIL4+33位における変異対立遺伝子の存在する群での血中熱帯熱マラリア原虫特異的IgE濃度は有意に上昇していた(p<0.05).しかしながら,これらの関係はMalakulaにおいては認められなかった.本研究はメラネシア住民集団において当該変異遺伝子頻度に関する最初の報告である.見出された変異対立遺伝子頻度はこれまで報告されている,より高いアジア住民集団とより低いヨーロッパ住民集団の中間の値であった.さらにIL4多型が特異的IgEとマラリア病形の関係に関る遺伝的因子の一つであることが示唆された.Recent findings suggest that susceptibility to malaria is associated with genetic variants in the IL4 promoter region, resulting in the up-regulation of serum IgE. In this study, using a population-based approach, we investigated the mutant allele frequencies at positions -590 and +33 of the IL4 gene and total and Plasmodium (P.) falciparum-specific IgE levels on 3 islands with variable malaria endemicities in Vanuatu: Malakula (meso-endemic), Aneityum (meso-endemic with intervention), and Futuna (non-endemic). A total of 878 and 750 samples were typed for -590 and +33 positions, respectively. Variant allele frequencies varied from 0.27 to 0.39 for C-590T and from 0.39 to 0.48 for C+33T among 3 islands. There was a strong linkage disequilibrium between the 2 alleles (p<0.001). For both mutant alleles higher frequencies were detected in Aneityum than in Futuna (p<0.05). In Aneityum there was a significant association between the carriage of C+33T allele and increased levels of P. falciparum-specific IgE (p<0.05). However these relations were not observed in Malakula. This is the first report on IL4 polymorphisms in Melanesian populations. The observed mutant allele frequencies lay between higher values in Asian populations and rather lower values in Caucasians. The data suggest that IL4 promoter polymorphisms may be one of the genetic factors that explain relations between malaria disease and IgE

ヴァヌアツのマラリア流行島嶼におけるIL4多型とIgE濃度

血中IgE上昇に帰結するIL4プロモーターの遺伝的変異が,マラリアに対する感受性と相関することが最近の研究によって示唆されてきている.本研究においては集団遺伝学的方法を用いヴァヌアツにおけるマラリア流行度が異なる3島嶼において,IL4-590および+33塩基における変異対立遺伝子頻度,血中総IgEおよび熱帯熱マラリア原虫特異的IgE濃度を調べた.3島嶼は中等度の流行が続くMalakula,中等度の流行だが対策が功を奏しているAneityumおよびマラリア流行がないFutunaである.これらの島嶼住民より採取した血液サンプルよりIL4-590および+33についてそれぞれ計878および750サンプルの解析を行った.変異対立遺伝子頻度はこれら3島嶼間においてC-590Tが0.27～0.39,C+33Tが0.39～0.48の範囲で変動した.両対立遺伝子間には顕著な連鎖不均衡が認められた(p<0.001).これら両変異対立遺伝子ともAneityumにおいてはFutunaより高い頻度で認められた(p<0.05).AneityumにおいてはIL4+33位における変異対立遺伝子の存在する群での血中熱帯熱マラリア原虫特異的IgE濃度は有意に上昇していた(p<0.05).しかしながら,これらの関係はMalakulaにおいては認められなかった.本研究はメラネシア住民集団において当該変異遺伝子頻度に関する最初の報告である.見出された変異対立遺伝子頻度はこれまで報告されている,より高いアジア住民集団とより低いヨーロッパ住民集団の中間の値であった.さらにIL4多型が特異的IgEとマラリア病形の関係に関る遺伝的因子の一つであることが示唆された.Recent findings suggest that susceptibility to malaria is associated with genetic variants in the IL4 promoter region, resulting in the up-regulation of serum IgE. In this study, using a population-based approach, we investigated the mutant allele frequencies at positions -590 and +33 of the IL4 gene and total and Plasmodium (P.) falciparum-specific IgE levels on 3 islands with variable malaria endemicities in Vanuatu: Malakula (meso-endemic), Aneityum (meso-endemic with intervention), and Futuna (non-endemic). A total of 878 and 750 samples were typed for -590 and +33 positions, respectively. Variant allele frequencies varied from 0.27 to 0.39 for C-590T and from 0.39 to 0.48 for C+33T among 3 islands. There was a strong linkage disequilibrium between the 2 alleles (p<0.001). For both mutant alleles higher frequencies were detected in Aneityum than in Futuna (p<0.05). In Aneityum there was a significant association between the carriage of C+33T allele and increased levels of P. falciparum-specific IgE (p<0.05). However these relations were not observed in Malakula. This is the first report on IL4 polymorphisms in Melanesian populations. The observed mutant allele frequencies lay between higher values in Asian populations and rather lower values in Caucasians. The data suggest that IL4 promoter polymorphisms may be one of the genetic factors that explain relations between malaria disease and IgE