Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer's disease.

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.

High-resolution characterization of allelic and haplotypic HLA frequency distribution in a Spanish population using high-throughput next-generation sequencing.

Next-generation sequencing (NGS) at the HLA-A, -B, -C, -DPA1, -DPB1, -DQA1, -DQB1, -DRB1 and -DRB3/4/5 loci was performed on 282 healthy unrelated individuals from different major regions of Spain. High-resolution HLA genotypes defined by full sequencing of class I loci and extended coverage of class II loci were obtained to determine allele frequencies and also to estimate extended haplotype frequencies. HLA alleles were typed at the highest resolution level (4-field level, 4FL); with exception of a minor deviation in HLA-DPA1, no statistically significant deviations from expected Hardy Weinberg Equilibrium (HWE) proportions were observed for all other HLA loci. This study provides new 4FL-allele and -haplotype frequencies estimated for the first time in the Spanish population. Furthermore, our results describe extended haplotypes (including the less frequently typed HLA-DPA1 and HLA-DQA1 loci) and show distinctive haplotype associations found at 4FL-allele definition in this Spanish population study. The distinctive allelic and haplotypic diversity found at the 4FL reveals the high level of heterozygosity and specific haplotypic associations displayed that were not apparent at 2-field level (2FL). Overall, these results may contribute as a useful reference source for future population studies, for HLA-disease association studies as a healthy control group dataset and for improving donor recruitment strategies of bone marrow registries. HLA genotyping data of this Spanish population cohort was also included in the 17th International Histocompatibility and Immunogenetics Workshop (IHIW) as part of the study of HLA diversity in unrelated worldwide populations using NGS.

In-Out-Test: A New Paradigm for Sorting the Wheat from the Chaff in Prodromal Alzheimer's Disease.

BACKGROUND: Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks. OBJECTIVE: To assess the validity of the In-out-test in identifying prodromal Alzheimer's disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers. METHODS: A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture. RESULTS: Internal consistency was demonstrated using Cronbach Alpha (r = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r = 0.57 (p = 0.57). ICC between the In-out-test and FCSRT r = 0.87 (p = 0.001). ICC between the In-out-test and Aß42 and P-tau/Aß42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aß42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44. CONCLUSIONS: The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD.

Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

Description of the new HLA-A*11:288 allele found in a healthy individual from the Canary Islands.

A new HLA-A allele, A*11:288, was characterized in a Spanish individual from the Canary Islands.

Butyrylcholinesterase, ApoE and Alzheimer's disease in a population from the Canary Islands (Spain).

AIM: Cholinergic dysfunction is a major neurochemical feature in Alzheimer's disease (AD), accountable for many cognitive dysfunctions and some psychiatric symptoms. Butyrylcholinesterase (BChE) is one of the cholinesterases with increased activity in the brain of Alzheimer's patients. Several mutations code for different BChE, such as the K variant, which is the most common and is capable of reducing BChE activity by 30%. We studied the relationship between this K variant and Alzheimer's disease in our population from the Canary Islands (Spain). PATIENTS AND METHODS: We used DNA PCR-RFLP techniques to compare 282 patients who had been diagnosed with probable Alzheimer's disease--according to NINCS-ADRDA criteria--with 312 control subjects confirmed to be free of cognitive impairment as assessed by using the CAMDEX cognitive subscale CAMCOG. RESULTS: In our population the K variant of BChE is linked to the age of diagnosis of Alzheimer's disease, since AD individuals with this allele presented the disease at a later stage. No other susceptibility relations are exposed in this study. In addition, the BChE allelic frequencies in our population are higher than those previously reported.

Utilidad del índice aterogénico en la predicción de enfermedad coronaria prematura / Coronary heart disease. Cardiovascular risk factors. Lipids. Atherogenic index. Triglycerides. HDL

Introducción. La presentación prematura de la enfermedad coronaria es relativamente frecuente, pero sus factores predictores todavía no se conocen bien. Método. Analizamos los factores de riesgo en varones canarios: 515 pacientes menores de 51 años, con enfermedad coronaria documentada, y 436 controles mayores de 56 años, sin enfermedad. Resultados. La serie presenta una elevada prevalencia de factores de riesgo; el 98% de los pacientes y el 93% de los controles tenían al menos un factor de riesgo cardiovascular (p < 0,001). Encontramos diferencias significativas (p < 0,001) en la frecuencia de antecedente familiar de enfermedad prematura (35% pacientes y 15% controles), tabaquismo (85% pacientes y 76% controles) y dislipemia (78% pacientes y 53% controles) superior en pacientes. La hipertensión arterial resultó el factor más prevalente en controles (51% pacientes y 66% controles; p < 0,001). Pese al tratamiento con estatinas, los pacientes presentaban índices aterogénicos (triglicéridos/colesterol unido a lipoproteínas de alta densidad [cHDL]) más elevados que los controles (promedio 5,39 pacientes y 4,10 controles; p < 0,001). La enfermedad coronaria se adelantaba 2 años en pacientes con índices aterogénicos superiores a 5,5 (48,2 años con índice bajo y 46,6 años con índice aterogénico alto; p < 0,013). El análisis multivariante de pacientes normotensos seleccionó índice aterogénico superior a 4 (p < 0,004; odds ratio (OR) = 1,263-3,617), antecedentes familiares de enfermedad coronaria prematura (p < 0,013; OR = 1,154-3,980) y dislipemia (p < 0,001; OR = 1,936-5,346), como principales predictores de enfermedad coronaria prematura. Conclusiones. A pesar de su juventud, la prevalencia de factores de riesgo en pacientes canarios masculinos es muy elevada. El índice aterogénico resulta una herramienta muy útil y relativamente independiente de las estatinas, para detectar los sujetos con riesgo de presentar enfermedad coronaria prematura (AU)

Introduction. Although premature coronary heart disease (CHD) is relatively frequent, the factors predicting its development are still poorly defined. Method. We analyzed risk factors and lipid profiles in a series of men from the Canary Islands (Spain): 515 patients aged less than 51 years with documented CHD and 436 elderly controls aged more than 56 years without CHD. Results. Most patients and controls had at least one major risk factor (98% of patients and 93% of controls; P<.001). We found significant differences (P<.001) in the prevalence of a family history of premature CHD (35% of patients and 15% of controls), smoking (85% of patients and 76% of controls), and dyslipidemia (78% of patients and 53% of controls). Only hypertension was more common among controls (51% of patients and 66% of controls; P<.001). Despite statin therapy, patients showed a higher atherogenic index (triglycerides/high density lipoprotein HDL-cholesterol [HDL-c] ratio) than controls, the mean index being 5.39 in patients and 4.10 in controls (P<.001). In normotensive patients the multivariate analysis shows as the major predictors of premature coronary disease: atherogenic index higher than 4 (P<.004, OR = 1.154-3.980), and dislypidemia (P<.001, OR = 1.936-5.346). Conclusion. Despite their youth, male patients with CHD in the Canary Islands have a very high prevalence of risk factors. The atherogenic index is a highly useful tool and is relatively independent of the effects of statin therapy in detecting individuals at risk for premature CDH (AU)

Genetic basis of the latex-fruit syndrome: association with HLA class II alleles in a Spanish population.

BACKGROUND: The latex-fruit syndrome is a well-defined disorder whose genetic background has not been elucidated. OBJECTIVE: To study the genetic basis of the latex-fruit syndrome. METHODS: In a case-control study, we have investigated a carefully selected group of patients allergic to latex, searching for association between latex-fruit allergy and HLA class I and II genes, HLA-DR functional groups, and markers IL4-R1 and FcepsilonRI-betaca . RESULTS: Seventy-eight patients allergic to latex without spina bifida, 33% of them also allergic to fruits, were included in our protocol. Skin prick test results with both a commercial latex extract and purified hevein were significantly greater in patients allergic to latex and fruit than in patients allergic to latex and not fruit. A cutoff point of >7 mm for commercial latex skin prick test diagnosed latex-fruit allergy with a sensitivity of 66.7% (95% CI, 41.0-86.6) and a specificity of 83.3% (95% CI, 68.6-93.0) in our series of patients. No significant differences were found regarding HLA class I, IL4-R1 , or FcepsilonRI-betaca allele distributions. However, comparison of HLA class II allelic frequencies between patients allergic to latex and fruit and patients allergic to latex and not fruit showed significant associations of latex-fruit allergy with DQB1 *0201 (corrected P value, .001; odds ratio, 7.3; 95% CI, 2.6-20.0), as well as with HLA-DR functional group E (corrected P value, .028; odds ratio, 16.0; 95% CI, 1.9-134.1). When comparing allelic distribution among different subgroups of patients allergic to latex, additional significant associations of latex-fruit allergy with DRB1 *0301 and *0901, and of latex and not fruit allergy with DQB1 *0202, DRB1 *0701 and *1101, were demonstrated. CONCLUSIONS: Latex-fruit allergy is associated with HLA-DQB1 *0201, DRB1 *0301, and *0901, as well as with HLA-DR functional group E, whereas latex-not-fruit allergy is associated with DQB1 *0202, and with both DRB1 *0701 and *1101 alleles.