Increased risk of oral submucous fibrosis with increasing number of high-risk genotypes ( P < 0.05) A gene-dose effect is corroborative of a cause-and-effect relation between the genes and the disease. “Dose-response relationship” is one of the causal criteria put forward by Hill ( 1). Finally, they did a trend test to see if the OR increases as the total number of the high-risk genotypes (alleles) increases. They categorized the total number of the high-risk genotypes (alleles) into a number of categories, say, “0 to 2”, “3 to 4”, and “5+”, and they calculated the odds ratios (OR) and the associated confidence intervals (CI) for these categories. They then calculated the total number of the high-risk genotypes (alleles) a subject has for the cases and for the controls in their study. In these studies, the researchers first defined the high-risk genotype (or allele) at each locus. To examine the joint effect of multiple loci on disease risk, many case-control association studies used “gene-dose analyses” (we found 40 articles with gene-dose analysis from January 1998 to May 2005 in six esteemed cancer journals: Cancer Epidemiology Biomarkers and Prevention, Cancer Research, Carcinogenesis, Clinical Cancer Research, International Journal of Cancer, and the Journal of the National Cancer Institute).
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