RESUMEN
BACKGROUND AND PURPOSE: Taking advantage of low genetic variations in northern Sweden, we performed a genome-wide linkage scan to investigate the susceptibility loci for common forms of stroke. METHODS: Fifty-six families, containing multiple cases of stroke and whose data had been previously used to replicate linkage to the phosphodiesterase 4D locus on chromosome 5q, were genotyped in a genome-wide scan. Fine mapping was performed, and subsequently 53 additional families from the same region were genotyped over the candidate regions. RESULTS: Linkage calculations were performed by using 3 different disease models, from a very broad (all stroke cases defined by World Health Organization MONICA criteria) to a narrower (ischemic stroke only) stroke phenotype. With all models, nonparametric multipoint linkage analysis yielded allele-sharing log of the odds (LOD) scores >1.2 at 9 locations: 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, and 20q13. The highest allele-sharing LOD scores were obtained on chromosomes 5q (previously reported), 1p (LOD=2.09), and 18p (LOD=2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q (previously reported) and 9q22 (LOD=1.56), but all others decreased. Combining these initial results with a subsequent analysis of 53 additional families, we obtained the highest allele-sharing LOD scores on chromosomes 5q, 13q, and 18p, although none reached the initial genome-wide allele-sharing LOD scores. CONCLUSIONS: Genetic analysis of stroke in families from northern Sweden did not identify any new major stroke loci. This indicates that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5 could contribute to the disease.
Asunto(s)
Mapeo Cromosómico/métodos , Predisposición Genética a la Enfermedad/genética , Genoma Humano/genética , Accidente Cerebrovascular/genética , Anciano , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 18/genética , Cromosomas Humanos Par 5/genética , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/epidemiología , Pruebas Genéticas , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Accidente Cerebrovascular/epidemiología , Suecia/epidemiologíaRESUMEN
BACKGROUND AND PURPOSE: Recent Icelandic studies have demonstrated linkage for common forms of stroke to chromosome 5q12 and association between phosphodiesterase4D (PDE4D) and ischemic stroke. Using a candidate region approach, we wanted to test the validity of these findings in a different population from northern Sweden. METHODS: A total of 56 families with 117 affected individuals were included in the linkage study. Genotyping was performed with polymorphic microsatellite markers with an average distance of 4.5 cM on chromosome 5. In the association study, 275 cases of first-ever stroke were included together with 550 matched community controls. Polymorphisms were tested individually for association of PDE4D to stroke. RESULTS: Maximum allele-sharing lod score in favor of linkage was observed at marker locus D5S424 (lod score=2.06; P=0.0010). Conditional logistic regression calculations revealed no significant association of ischemic stroke to the defined at-risk allele in PDE4D (odds ratio, 1.1; 95% confidence interval, 0.84 to 1.45). A protective effect may though be implied for 2 of the polymorphisms analyzed in PDE4D. CONCLUSIONS: Using a candidate region approach in a set of stroke families from northern Sweden, we have replicated linkage of stroke susceptibility to the PDE4D gene region on chromosome 5q. Association studies in an independent nested case-control sample from the same geographically located population suggested that different alleles confer susceptibility/protection to stroke in the Icelandic and the northern Swedish populations.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/genética , Cromosomas Humanos Par 5 , Frecuencia de los Genes/genética , Algoritmos , Alelos , Estudios de Casos y Controles , Mapeo Cromosómico , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Complicaciones de la Diabetes/genética , Exones , Salud de la Familia , Ligamiento Genético , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Islandia , Isquemia , Desequilibrio de Ligamiento , Escala de Lod , Repeticiones de Microsatélite , Modelos Estadísticos , Oportunidad Relativa , Polimorfismo Genético , Análisis de Regresión , Factores de Riesgo , Accidente Cerebrovascular/genética , SueciaRESUMEN
We have identified a large family in the northern part of Sweden with multiple cases of autoimmune diseases, namely type 1 diabetes (T1D), Graves' disease (GD) and Hashimoto's thyroiditis (HT). The family members affected by any of these diseases share a region of 2.4 Mb that comprises among others the CTLA4 gene. We determined that all affected members of the family shared the HLA susceptibility haplotype (DR4-DQA1*0301-DQB1*0302). Analysis of genetic interaction conditioning for HLA haplotype provided strong evidence that the critical region which includes the CTLA4 gene acts together with the HLA locus on the etiology of disease (lodscore 4.20 (theta=0.0). The study of this family allowed us to: (1) reinforce a number of reports on linkage and association of the CTLA4 region to T1D and AITD; (2) demonstrate that a single haplotypic variant in this region constitutes an etiological factor to disease susceptibility in T1D, GD and HT; (3) reveal a strong genetic interaction of the CTLA4 and HLA loci in the genetic architecture of autoimmune disease; (4) emphasise the value of large pedigrees drawn from isolated populations as tools to single out the effect of individual loci in the etiology of complex diseases.