RESUMO
INTRODUCTION: Genome-wide association studies (GWAS) are fundamental for identifying loci associated with diseases. However, they require replication in other ethnicities. METHODS: We performed GWAS on sporadic Alzheimer's disease (AD) including 539 patients and 854 controls from Argentina and Chile. We combined our results with those from the European Alzheimer and Dementia Biobank (EADB) in a meta-analysis and tested their genetic risk score (GRS) performance in this admixed population. RESULTS: We detected apolipoprotein E ε4 as the single genome-wide significant signal (odds ratio = 2.93 [2.37-3.63], P = 2.6 × 10-23 ). The meta-analysis with EADB summary statistics revealed four new loci reaching GWAS significance. Functional annotations of these loci implicated endosome/lysosomal function. Finally, the AD-GRS presented a similar performance in these populations, despite the score diminished when the Native American ancestry rose. DISCUSSION: We report the first GWAS on AD in a population from South America. It shows shared genetics modulating AD risk between the European and these admixed populations. HIGHLIGHTS: This is the first genome-wide association study on Alzheimer's disease (AD) in a population sample from Argentina and Chile. Trans-ethnic meta-analysis reveals four new loci involving lysosomal function in AD. This is the first independent replication for TREM2L, IGH-gene-cluster, and ADAM17 loci. A genetic risk score (GRS) developed in Europeans performed well in this population. The higher the Native American ancestry the lower the GRS values.
Assuntos
Doença de Alzheimer , Azidas , Estudo de Associação Genômica Ampla , Humanos , Chile , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genéticaRESUMO
Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Doença de Alzheimer/etnologia , Doença de Alzheimer/genética , Glicoproteínas de Membrana/genética , Fosfolipase C gama/genética , Receptores Imunológicos/genética , Idoso , Idoso de 80 Anos ou mais , Argentina/etnologia , População Negra/genética , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Indígenas Norte-Americanos/genética , Masculino , Pessoa de Meia-Idade , População Branca/genéticaRESUMO
The incidence of melanoma is increasing rapidly, and in many cases the primary tumor is excised after metastatic spreading. In 80 percent of the cases, the first metastatic site is in regional lymph nodes (AJCC Stage III). After excision of these nodes, the patient is clinically disease-free, but the chances of recurrency vary between 40-80 percent. Thirty patients with stage III melanoma were treated in a non-randomized Phase II adjuvant trial with a vaccine consisting of a mixture of three allogeneic cell lines: IIB-MEL-J, IIB-MEL-LES and IIB-MEL-IAN (5 x 10(6) cells each). The cells were irradiated (5,000cGy) and BCG was used as nonspecific stimulant. Before each vaccination (72 hr) the patients received cyclophosphamide (300 mg/sqm). The untreated control group was composed of 24 Stage III melanoma patients. Vaccination started within 60 days after surgery, and patients received 4 vaccinations, one every 21 days and then 1 every two months during the 1st year; 1 every three months during the 2nd year, and 1 every 6 months during the 3rd, 4th and 5th years. The treated group was composed by 19 men (63.3 percent) and 11 women (36.7 percent); average age: 47.6 + 14.1 years (range: 16-70 yr). The control group was composed by 18 men (75 percent) and 6 women (25 percent); average age 49.8 + 14.2 yr (range:26-73 yr). The median disease free survival (DFS) calculated according to Kaplan-Meier was 7.0 months in the control group vs 20.0 months in the treated group (p < 0.001). The results of this clinical trial suggest that treatment with allogeneic cell vaccines increases DFS in stage III melanoma patients.