Incidence of human breast cancer (HBC) varies geographically, but to date no environmental factor has explained this variation. Previously, we reported a 44% reduction in the incidence of breast cancer in women fully immunosuppressed following organ transplantation (Stewart et al (1995) Lancet346: 796–798). In mice infected with the mouse mammary tumour virus (MMTV), immunosuppression also reduces the incidence of mammary tumours. DNA with 95% identity to MMTV is detected in 40% of human breast tumours (Wang et al (1995) Cancer Res55: 5173–5179). These findings led us to ask whether the incidence of HBC could be correlated with the natural ranges of different species of wild mice. We found that the highest incidence of HBC worldwide occurs in lands where Mus domesticus is thse resident native or introduced species of house mouse. Given the similar responses of humans and mice to immunosuppression, the near identity between human and mouse MTV DNA sequences, and the close association between HBC incidence and mouse ranges, we propose that humans acquire MMTV from mice. This zoonotic theory for a mouse-viral cause of HBC allows testable predictions and has potential importance in prevention. © 2000 Cancer Research Campaign

Background The Global Lipids Genetics Consortium identified 95 common loci that explained 12.2% (LDL-C), 12.1% (HDL-C) and 9.6% (triglycerides [TG]) of total variance in plasma lipid traits in the Framingham Heart Study. Since adiposity is associated with plasma levels of TG and HDL-C, we hypothesized that the predictive value of common risk variants for these lipid traits would differ for obese versus lean subjects. Methods The study population consisted of two independent cohorts of subjects of European de-scent, genotyped on the Affymetrix 6.0 array with 1000G imputation. 1) OBLE: 959 obese/ 869 lean. 2) CC (healthy elderly subjects recruited as con-trols for a CAD study) 830 obese/1,044 lean. A genetic predisposition score was calculated for each individual as a sum across SNPs of the number of risk alleles at that SNP multiplied by the effect size of the SNP. Results In the OBLE cohort, a genetic risk score explained a greater percentage of the total TG variance in obese vs lean (beta GRS=0.154 mmol/L ( p<2e-16) vs 0.094 mmol/L (p=5.8e-10); adjusted R2=0.090 vs 0.042), a finding that was replicated in the CC cohort for obese vs lean (beta GRS=0.153 mmol/L (p=1.5e-7) vs 0.102 mmol/L (p=4.2e-6); adjusted R2=0.044 vs 0.024). A similar but less significant trend was noted for LDL-C. In addition, the genetic risk score predicted variability in TG better than sex/age for obese subjects. In contrast a genetic risk score for HDL-C was a better predictor of this trait in lean versus obese subjects in both the OBLE and CC cohorts. Genetic risk scores for each lipid trait showed no association with BMI (P>0.2) indicating that the above findings are not due to possible overlap between genetic loci for BMI and lipid traits. Conclusions Genetic predisposition to elevated plasma triglycerides and LDL-C and low HDL-C is highly sensitive to extremes of BMI.

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Sir,The letter by Professor Khuder raises several points of potential importance. Our statistical analysis correlating Mus species and human breast cancer (HBC) incidence is described as simplistic, ignoring social, cultural and demographic variables. Thus, it may suffer from ecological bias, due to the effect of hormonal promoters on the development of HBC. The greatest influence would likely be associated with fecundity, which is best reflected in the world statistics on 'total fertility rate' (TFR) (US Bureau of the Census, Report WP/98, World Population Profile (1998) US Government Printing Office: Washington DC, 1999).TFR was evaluated as a potential confounder of the association of M. domesticus geography with human breast cancer incidence. For our sample of 39 countries (less two regions, Hawaii and 'circumpolar Inuit' for want of data), we analysed the reported 1990 (or 1998, where lacking) TFR for correlation with the world age-standardized incidence rate (WASIR) for female breast cancer (as in Stewart et al, 2000). The expected negative correlation of WASIR with TFR [R = -0.327, P = 0.048] was found. However, across Europe there was no difference in TFR between lands of M. domesticus and lands of other mice (mean TFR 1.656 ± SD 0.368, vs 1.657 ± 0.346, P = 0.993).Internationally, excluding Europe, there was a higher reported TFR in M. domesticus lands (TFR 2.875 ± 0.822 vs 2.371 ± 0.971, P = 0.244). Overall, the crude difference in mean WASIR due to M. domesticus lands is +15.6, accounting for 38.3% of the observed variation in this sample. The TFR-adjusted difference in mean WASIR is + 17.4, accounting for 48.4% of variation, both highly statistically significant (P < 0.001). Thus, in addressing Professor Khuder's concern about reproductive factors by adjusting for TFR, the association of WASIR with lands of M. domesticus was strengthened.The report by McCredie et al (1999) on the incidence of HBC in Maori and non Maori women emphasizes that all parameters suggesting a lower incidence of HBC were seen in Maori women in a highly significant fashion, lower educational level, lower socio-economic status, lower age at first full term pregnancy, high parity and longer duration of breast-feeding. Despite this, the incidence of HBC in Maori women before the age of 54 is twice that of non-Maori women in New Zealand. Could this reflect a greater exposure of the Maori to Mus domesticus which occurs in both urban areas and native forests in New Zealand (King, 1982)? In the paper by Chie et al (1995), no data on the incidence of HBC in white women is given in the text. White women form a minuscule proportion of the female population of Taiwan. The use of oral contraceptives in Asian women migrating to the USA, adjusted for age, ethnicity, study area, years since migration,