Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

Weiss, Lauren A.; Abney, Mark; Parry, Rodney; Scanu, Angelo M.; Cook, Edwin H.; Ober, Carole

doi:10.1007/s00439-004-1250-3

Cited by 27 publications

(31 citation statements)

References 48 publications

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“…Previous studies have found association between ITGB3 and whole blood 5-HT levels in males (Weiss et al, 2004(Weiss et al, , 2005a(Weiss et al, , 2005b, but our study is too small to support a sex-specific analysis. Additionally, allelic heterogeneity with regard to 5-HT levels is evident at ITGB3.…”

Section: Discussioncontrasting

confidence: 77%

“…Additionally, allelic heterogeneity with regard to 5-HT levels is evident at ITGB3. The amino-acid polymorphism that we genotyped in this study showed evidence for association with autism in previous studies, but did not show the strongest evidence for association with serotonin level in these studies (Weiss et al, 2005b(Weiss et al, , 2006. A haplotype of two TPH1 polymorphisms was associated with whole blood 5-HT by allele-wise ANOVA (p ¼ 0.046).…”

Section: Discussioncontrasting

confidence: 54%

“…Variation in the integrin b3 gene (ITGB3) has been associated with platelet 5-HT in multiple populations, including probands with autism (Weiss et al, 2004(Weiss et al, , 2005b(Weiss et al, , 2006. Tryptophan hydroxylase 1 (TPH1), which catalyzes the rate-limiting step in 5-HT synthesis in the periphery, could also contain functional variation that would impact 5-HT synthesis.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

Cross

Kim

Weiss

et al. 2007

Neuropsychopharmacol

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Elevated platelet serotonin (5-hydroxytryptamine, 5-HT) is found in a subset of children with autism and in some of their first-degree relatives. Indices of the platelet serotonin system, including whole blood 5-HT, 5-HT binding affinity for the serotonin transporter (K m ), 5-HT uptake (V max ), and lysergic acid diethylamide (LSD) receptor binding, were previously studied in 24 first-degree relatives of probands with autism, half of whom were selected for elevated whole blood 5-HT levels. All subjects were then genotyped for selected polymorphisms at the SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 loci. Previous studies allowed an a priori prediction of SLC6A4 haplotypes that separated the subjects into three groups that showed significantly different 5-HT binding affinity (K m , p ¼ 0.005) and 5-HT uptake rate (V max , p ¼ 0.046). Genotypes at four individual polymorphisms in SLC6A4 were not associated with platelet 5-HT indices. Haplotypes at SLC6A4 and individual genotypes of polymorphisms at SLC6A4, HTR7, HTR2A, ITGB3, and TPH1 showed no significant association with whole blood 5-HT. Haplotype analysis of two polymorphisms in TPH1 revealed a nominally significant association with whole blood 5-HT (p ¼ 0.046). These initial studies of indices of the 5-HT system with several single-nucleotide polymorphisms at loci in this system generate hypotheses for testing in other samples.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussioncontrasting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

Cross

Kim

Weiss

et al. 2007

Neuropsychopharmacol

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“…19 Finally, several recently published studies have described significant SLC6A4 and ITGB3 interactions for both autism risk and 5-HT blood levels, with a male-specific effect. 10,[14][15][16][17]20 Despite these positive findings, several inconsistencies complicate their interpretation, possibly because of clinical and genetic heterogeneity in ASD. In particular, different alleles seem to be associated with autism and/or serotoninemia in independent samples at the ITGB3 and SLC6A4 loci.…”

Section: Introductionmentioning

confidence: 99%

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes

et al. 2010

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The integrin-b 3 gene (ITGB3), located on human chromosome 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for autism spectrum disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P¼0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P¼0.005; odds ratio (OR)¼2.000), at the expense of haplotype H1, which is undertransmitted (HBAT P¼0.018; OR¼0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P-value of 0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P¼0.008). On the other hand, it is SNP rs2317385, located at the 5¢ end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U-test, P¼0.001; multiple regression analysis, P¼0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5¢ and 3¢ ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism. INTRODUCTIONAutism spectrum disorder (ASD) is a complex neurodevelopmental disorder, characterized by different levels of impairment in social interaction and communication, by stereotypies and rigid patterns of behavior, and disease onset before 3 years of age (OMIM 209850). 1 ASD is believed to primarily stem from genetic factors, based on the observation of 60-92% concordance rates in monozygotic twins vs 0-10% in dizygotic twins, with heritability estimated at or above 90%. 2,3 The cause underlying autism in the majority of patients remains unknown, although several known medical conditions account for B10% of cases. 4 ASD, similar to many other complex human disorders, does not show a simple inheritance pattern, as it may involve multiple common variants, each conveying a modest effect in epistatic interaction, rare variants with high penetrance, or perhaps more likely the coincidence of a rare variant acting upon a genetic background rendered vulnerable by a set of common variants. 2-5 Accordingly, familial aggregation of 'endophenotypes' , heritable quantitative traits distributed continuously among ASD patients and first-degree relatives, can promote the search of genetic susceptibility factors in ASD.

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“…En los estudios se ha demostrado un importante carácter hereditario de los niveles de serotonina en plaquetas tanto en individuos sanos como en autistas (23)(24)(25), y los genes SLC6A4 y ITGB3 fueron identificados como loci que tienen efecto sobre los niveles de serotonina en plaquetas (26)(27)(28).…”

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Evidencia de asociación entre el gen SLC6A4 y efectos epistáticos con variantes en HTR2A en la etiología del autismo en población antioqueña

et al. 2012

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Variation in ITGB3 has sex-specific associations with plasma lipoprotein(a) and whole blood serotonin levels in a population-based sample

Cited by 27 publications

References 48 publications

Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

Molecular Genetics of the Platelet Serotonin System in First-Degree Relatives of Patients with Autism

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes

Evidencia de asociación entre el gen SLC6A4 y efectos epistáticos con variantes en HTR2A en la etiología del autismo en población antioqueña

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