Association studies of genetic polymorphisms and complex disease

Gambano, Giovanni; Anglani, Franca; D’Angelo, Angela

doi:10.1016/s0140-6736(99)07202-5

Cited by 168 publications

(108 citation statements)

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“…Other possibilities include genuine locus or allele heterogeneity among different populations and differences in risk-allele frequencies among studies (46)(47)(48). Substantial differences in IL1RN VNTR frequencies have been reported among different ethnic groups (9,10,25,41,49).…”

Section: Discussionmentioning

confidence: 99%

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

Maksymowych¹,

Reeve²,

Reveille³

et al. 2003

Arthritis & Rheumatism

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Objective. To examine single-nucleotide polymorphisms (SNPs) in the 3 region of the IL1RN gene in a large Caucasoid case-control series and in ankylosing spondylitis (AS) families from Western Canada by use of high-throughput MassArray matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry SNP typing.Methods. An association analysis was performed in a case-control cohort of 394 AS cases and 500 controls. Family-based association analysis was performed in 58 simplex and 13 multiplex families. Three SNPs located in the 3 region of the IL1RN gene (T/C at position 27810 in exon 4, T/C at position 30735 in exon 6, and G/C at position 31017 in exon 6) were examined by high-throughput MassArray MALDI-TOF mass spectrometry. Haplotype inference software programs were used to infer the most likely haplotypes and to compare haplotype frequencies, which were then further analyzed in family-based association studies by transmission disequilibrium tests.Results. The frequency of allele C at SNP position 30735 in exon 6 was significantly increased in AS cases (35.1%) versus controls (27.8%), as was the phenotype frequency (61.7% versus 48.6%). A significantly increased frequency of SNP allele G at position 31017 in exon 6 in cases (32.9%) versus controls (28.3%) was also noted. A highly significant difference in the overall distribution of haplotype frequencies was evident between cases and controls, with significant increases in the frequencies of the 27810C/30735C/31017C and 27810C/30735T/31017G haplotypes, but a significant reduction in the estimated frequency of the 27810C/ 30735T/31017C haplotype, in the AS cases. Estimation of haplotype frequencies based on 2 SNP markers indicated a highly significant increase in the 30735C/ 31017C haplotype and a highly significant decrease in the 30735T/31017C haplotype in cases compared with controls. Preliminary evidence for reduced transmission of the 27810C/30735T/31017C 3-marker haplotype was also found in family-based association analyses. Conclusion. Our data establish a highly significant disease association with markers in the IL1RN gene. In the absence of nonsynonymous coding sequence substitutions, it is possible that the primary diseaseassociated locus regulates gene expression. Association with specific haplotypes raises the possibility that the primary disease locus is in linkage disequilibrium with a specific combination(s) of markers in the IL1RN gene.Genetic modeling studies in twins have suggested that 97% of the population variance for developing ankylosing spondylitis (AS) can be explained by additive genetic effects, while comparison of disease concordance in identical twins (75%) versus HLA-B27-concordant dizygotic twins (27%) points to an important Dr. Maksymowych is a Senior Scholar with the Alberta

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Section: Discussionmentioning

confidence: 99%

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

Maksymowych¹,

Reeve²,

Reveille³

et al. 2003

Arthritis & Rheumatism

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“…Among patients with no history of previous myocardial infarction, there were significantly greater numbers of patients with determined genotypes compared with the numbers of patients with myocardial infarction, thus suggesting a protective action for patients with such genotypes. These types of studies must be interpreted with criticism, because they are subject to a potentially high risk of bias, as discussed in the review by Gambaro et al 27 However, this example is of particular interest, because the individuals identified who were protected against ischemic disease were asymptomatic and had no history of myocardial infarction, although they were at high risk for developing it-documented coronary atherosclerosis-and were not just normal, healthy individuals (although the study included a control group of healthy participants). Thus, there was a greater opportunity to find true protective factors rather than simply the absence of disease, which would be expected in a group of healthy individuals with a normal population risk.…”

Section: Studies In Individuals Potentially Protected From Developingmentioning

confidence: 99%

“…47 Finally, some histocompatibility antigen alleles have been linked in case-control studies with a decreased susceptibility to lung carcinoma, 48 melanoma, 49 and renal cell carcinoma, 50 and even homozygotic women for determined polymorphic alleles of the BRCA-1 gene have been associated with a decreased risk of breast carcinoma. 51 The ambiguous and clinically not very relevant results of some of these studies may be explained by flaws in methodology, as detailed elsewhere, 27 but also may be related in part to an inadequate selection of the study populations. Compared with the former studies, in which individuals were selected by a very characteristic phenotype-a definite protection against developing HIV or myocardial infarction-the latter studies compared the risk of patients who have developed disease with a control group formed by normal control participants.…”

Section: Studies In Individuals Potentially Protected From Developingmentioning

confidence: 99%

The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research

Perez-Gracia

Ruiz-Ilundáin

García-Ribas

et al. 2002

Cancer

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The investigation of genetic alterations that may be related to the prognosis of patients with malignant disease has become a frequently used strategy in recent years. Although some conclusions have been reached in certain studies, the complexity and the multifactorial nature of most neoplastic diseases makes it difficult to identify clinically relevant information, and the results of some studies have been of borderline significance or have been conflicting. In contrast, the identification and the study of patients or families with very characteristic phenotypes have yielded outstanding results in the identification of the genetic characteristics underlying such phenotypes. Although, in most cases, the individuals who are selected for these types of studies are characterized by a negative phenotype (i.e., individuals who are at increased risk for developing a specific disease), a few studies have been directed toward individuals with phenotypes that imply an unusually good prognosis (i.e., individuals who present with a decreased risk for developing specific diseases despite an important exposure to well-known risk factors). Therefore, it seems logical to develop this strategy further as a valid methodology for the study of other diseases, such as cancer. The study of individuals with phenotypes that imply an extremely good prognosis, such as long-term survivors of theoretically incurable malignancies or individuals who seem to be protected against a certain neoplastic disorder despite having a markedly increased risk for its development, may unveil genetic alterations that explain such characteristic phenotypes and may provide potentially useful therapeutic targets against these diseases. Cancer 2002;95:1605-10.

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“…Often, results are published that do not later replicate in other studies. 14,19,23,32,82,91 There are multiple factors that render it difficult for these studies to produce reliable results, such as the high rate of false positives due to multiple testing, 73 population structure, 64 and the presence of confounding factors or limitations in the clinical data.…”

Section: Introductionmentioning

confidence: 99%

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

et al. 2008

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The search for genetic factors associated with disease is complicated by the complexity of the biological pathways linking genotype and phenotype. This analytical complexity is particularly concerning in diseases historically lacking reliable diagnostic biological markers, such as schizophrenia and other mental disorders. We investigate the use of functional magnetic resonance imaging (fMRI) as an intermediate phenotype (endophenotype) to identify physiogenomic associations to schizophrenia. We screened 99 subjects, 30 subjects diagnosed with schizophrenia, 13 unaffected relatives of schizophrenia patients, and 56 unrelated controls, for gene polymorphisms associated with fMRI activation patterns at two locations in temporal and frontal lobes previously implied in schizophrenia. A total of 22 single nucleotide polymorphisms (SNPs) in 15 genes from the dopamine and serotonin neurotransmission pathways were genotyped in all subjects. We identified three SNPs in genes that are significantly associated with fMRI activity. SNPs of the dopamine beta-hydroxylase (DBH) gene and of the dopamine receptor D4 (DRD4) were associated with activity in the temporal and frontal lobes, respectively. One SNP of serotonin-3A receptor (HTR3A) was associated with temporal lobe activity. The results of this study support the physiogenomic analysis of neuroimaging data to discover associations between genotype and disease-related phenotypes.

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Association studies of genetic polymorphisms and complex disease

Cited by 168 publications

References 10 publications

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

High‐throughput single‐nucleotide polymorphism analysis of the IL1RN locus in patients with ankylosing spondylitis by matrix‐assisted laser desorption ionization‐time‐of‐flight mass spectrometry

The role of extreme phenotype selection studies in the identification of clinically relevant genotypes in cancer research

Physiogenomic Analysis of Localized fMRI Brain Activity in Schizophrenia

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