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

CTLA-4 polymorphisms and anti-malarial antibodies in a hyper-endemic population of Papua New Guinea

In malaria endemic areas, people naturally acquire an age-related immunity to malaria. Part of this immunity involves anti-malarial specific antibodies. Acquisition of these malaria-specific antibodies depends not only on exposure to malaria parasites but also on the human genetic predisposition. CTLA-4 is a costimulatory molecule that delivers an inhibitory signal to suppress T-cell as well as B-cell responses. We investigated associations between malaria-specific antibody levels and CTLA-4 polymorphisms in 189 subjects living in a hyper-endemic area of Papua New Guinea (PNG), where both P. falciparum and P. vivax are prevalent. We determined P. falciparum/ P. vivax specific IgG/IgE levels (Pf-IgG, Pv-IgG, Pf-IgE, Pv-IgE) and polymorphisms in the CTLA-4 gene at position -1661 promoter region (A/G), the +49 exon 1 non-synonymous mutation (A/G), and the +6230 3‘-UTR (A/G). All quantified antibody levels were significantly higher in subjects > 5 years (n = 150) than in subjects 5 years of age (n = 39). In children 5 years old, significant associations were detected between CTLA-4 +49 (GG/AG vs. AA) and Pv-IgG (median 18.7 vs. 13.7 Μg/ml, P = 0.017) and Pv-IgE (266.6 vs. 146.5 pg/ml, P = 0.046). No significant difference was observed in subjects > 5 years old. These results suggest that the CTLA-4+49 polymorphism influenced Pv-IgG and Pv-IgE levels among children less than five years old in the studied population, which may regulate the age- and species-specific clinical outcomes of malaria infection