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• Re:The genes associated with a high risk of type 1 diabetes are becoming less common
  Wen-Peng You
  Published on: 3 January 2017
• The genes associated with a high risk of type 1 diabetes are becoming less common
  Sarah G Howard
  Published on: 3 January 2017

• Published on: 3 January 2017

  Re:The genes associated with a high risk of type 1 diabetes are becoming less common

  • Wen-Peng You
  • Other Contributors:
    • Maciej Henneberg

  We thank colleagues for their critical comments that help to clarify relationships we have studied. We are not concerned with the frequency of what specific genes, high-risk or not, has increased recently. We are just making a general statement that with relaxed natural selection detrimental mutations may accumulate. The paper by Witas et al. cited by our critics uses the same rationale as we do when suggesting changes in type 1 d...

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  We thank colleagues for their critical comments that help to clarify relationships we have studied. We are not concerned with the frequency of what specific genes, high-risk or not, has increased recently. We are just making a general statement that with relaxed natural selection detrimental mutations may accumulate. The paper by Witas et al. cited by our critics uses the same rationale as we do when suggesting changes in type 1 diabetes (T1D) susceptibility gene frequencies under the operation of natural selection over the last 700 years [1]. For most of that time, excluding the last 100 years or so, natural selection was strong so it eliminated susceptibility genes. Selection only became relaxed in the recent decades. Besides the Human Leukocyte Antigen (HLA) gene group studied in the papers quoted by our critics, we know now that there are some 40-50 alleles located on various chromosomes that may increase susceptibility to type 1 diabetes [2, 3] . Our statements pertain to the genetic susceptibility to T1D that may be caused by all the T1D related genes, not just specific alleles. We argue that T1D related genes may have been accumulated in the whole population rather than in some particular samples. Having studied papers quoted by our critics to support their letter we found a fatal error in their logic. The studies [4-8] cited in the letter used only rather small samples of T1D patients of a limited age range and considered subsets of disease related genes, not all of them. Within those samples of patients, frequencies of alleles considered to confer greatest susceptibility decreased. Meanwhile frequencies of other alleles conferring some T1D susceptibility increased. Without consideration of the frequency of greatest susceptibility alleles, and others, in the total gene pool of the entire population from which limited samples were selected, it is impossible to tell whether the total frequency of susceptibility genes in a population has increased or decreased. The only conclusion that can be drawn from the studies cited by our critics is that frequencies of a limited number of alleles providing different levels of susceptibility to T1D have changed through time among people already suffering from the disease. This tells us nothing about total frequencies of these alleles in a population. A particular study [6] may have shown that a large proportion of T1D patients have no family history of the disease, but this runs counter to the well-known fact that people of different ethnic ancestry (and thus derived from different gene pools) have vastly different prevalence rates of T1D and to the strong correlation of the disease appearance among monozygotic twins. The genetic component of T1D susceptibility is substantial and, as we have already said, provided by scores of genes from various chromosomes. Our critics are also wrong in pointing that our conclusions can be based on the fact that prevalence of T1D increases with increasing GDP. In our statistical analyses we have excluded possible influence of GDP by using partial correlation analysis that stabilizes effects of controlled variables statistically, as if they were of the same magnitude in all analysed countries. The correlation between T1D and Ibs we have observed is independent of the correlation between GDP and T1D prevalence. We are not denying that environmental factors may play some role in increasing prevalence of T1D, we are just pointing, in an appropriately structured statistical analysis of worldwide data, that relaxation of natural selection has an effect on T1D prevalence. Study of relative magnitudes of genetic and environmental influences on T1D increase requires careful quantitative analyses not just rhetorical statements "play much larger role" based on small-scale selective studies. 1. Witas, H., K. J??drychowska???Da??ska, and P. Zawicki, Changes in frequency of IDDM???associated HLA DQB, CTLA4 and INS alleles. International journal of immunogenetics, 2010. 37(3): p. 155-158. 2. Barrett, J.C., et al., Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nature genetics, 2009. 41(6): p. 703-707. 3. Bradfield, J.P., et al., A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS Genet, 2011. 7(9): p. e1002293. 4. Spoletini, M., et al., Temporal Trends of HLA, CTLA-4 and PTPN22 Genotype Frequencies among Type 1 Diabetes in Continental Italy. PloS one, 2013. 8(4): p. e61331. 5. Fourlanos, S., et al., The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes care, 2008. 31(8): p. 1546-1549. 6. Parkkola, A., et al., Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes care, 2013. 36(2): p. 348-354. 7. Patterson, C., et al., Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia, 2001. 44(3): p. B9-B16. 8. Vehik, K., et al., Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care, 2008. 31(7): p. 1392-1396.

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  Conflict of Interest:
  None declared.

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• Published on: 3 January 2017

  The genes associated with a high risk of type 1 diabetes are becoming less common

  • Sarah G Howard, National Coordinator, Diabetes and Obesity Working Group
  • Other Contributors:
    • Timothy G. Howard, PhD

  In the article, "Type 1 diabetes prevalence increasing globally and regionally: The role of natural selection and life expectancy at birth" (You and Henneberg 2016), the authors find a correlation between worldwide type 1 diabetes prevalence and both life expectancy at birth and the "Biological State Index" (Ibs), a measure of population reproductive success. Based on these findings, they argue that "the correlation of Ibs to the...

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  In the article, "Type 1 diabetes prevalence increasing globally and regionally: The role of natural selection and life expectancy at birth" (You and Henneberg 2016), the authors find a correlation between worldwide type 1 diabetes prevalence and both life expectancy at birth and the "Biological State Index" (Ibs), a measure of population reproductive success. Based on these findings, they argue that "the correlation of Ibs to the type 1 diabetes prevalence rate has been observed, compatible with suggestion (sic) that lower opportunity for selection allows accumulation of unfavorable genes," and that, "reduced natural selection (Ibs) may be the major contributor to the increasing prevalence of type 1 diabetes worldwide with special regard to European countries." We do not agree with the conclusion that natural selection is playing a role in these correlations, particularly in light of an existing body of evidence that has already examined the question of whether or not the high-risk genes associated with type 1 diabetes have increased over the past decades--evidence that the authors failed to cite.
  
  The existing body of evidence shows that the high-risk genes associated with type 1 diabetes have actually decreased over time, while more people with low-risk genes are now developing the disease. For example, Hermann et al. (2003) found that the high risk genotypes were lower, and protective genotypes were higher, in Finnish type 1 diabetes patients diagnosed more recently (between 1990 and 2001) as compared to those diagnosed between 1939 and 1965. Resic-Lindehammer et al. (2008) found that the high-risk type 1 diabetes genotypes were decreasing over time, and the lower-risk genotypes were increasing in Swedes diagnosed in three time periods between 1986 and 2005. Gillespie et al. (2004) compared the frequency of high- risk genes in UK patients diagnosed with type 1 diabetes more than 50 years ago compared to those more recently diagnosed (1985-2002). They found that, "The proportion of high- risk susceptibility genotypes was increased in the earlier cohort, especially in those diagnosed at age 5 years or younger, which is consistent with the hypothesis that the rise of type 1 diabetes is due to a major environmental effect." The strongest correlations found by You and Henneberg (2016) were in Europe, where these studies were conducted.
  
  Outside of Europe, the patterns are the same. Steck et al. (2011) found that in two large cohorts representing multiple populations, the high-risk genotypes associated with type 1 diabetes decreased between 1965 and 2004-6. Fourlanos et al. (2008) analyzed the genotypes of Australians diagnosed with type 1 diabetes between 1950 and 2005 and found that, "The rising incidence and decreasing age at diagnosis of type 1 diabetes is accounted for by the impact of environment on children with lower-risk ... genes, who previously would not have developed type 1 diabetes in childhood." Vehik et al. (2008) genotyped Colorado youth with type 1 diabetes (diagnosed from 1978-1988, as compared to 2002-4), and found that "high-risk... genotypes are becoming less frequent over time in youth with type 1 diabetes of non-Hispanic white and Hispanic origin. This temporal trend may suggest that increasing environmental exposure is now able to trigger type 1 diabetes in subjects who are less genetically susceptible."
  
  Witas et al. (2010) compared the DNA from bones from the 11th-14th centuries to those of today. They found that, "Contrary to the initial assumptions, genetic predisposition towards type 1 diabetes... is much lower contemporarily than it was approximately 700 years before present."
  
  Moreover, the vast majority of people who develop type 1 diabetes have no family history of the disease. Even when taking into account both first and second degree relatives, the number of people diagnosed with type 1 diabetes without a family history approaches 80% (Parkkola et al. 2013).
  
  Aside from natural selection, there are other reasons that could explain why reproductive success and life expectancy are associated with worldwide type 1 diabetes prevalence, such as the availability of insulin (which the authors do acknowledge) and other medications, technologies, and health care opportunities that are more available in countries with higher life expectancies and reproductive success. Numerous additional environmental factors that are positively associated with GDP, which the authors found was even more strongly associated with type 1 diabetes prevalence than the Biological State Index, could also explain these patterns (Patterson et al. 2001).
  
  The authors' conclusion that "reduced natural selection (Ibs) may be the major contributor to the increasing prevalence of type 1 diabetes worldwide" is not supported by the existing scientific evidence. The studies that have examined this hypothesis via genetic analyses show the genetic risk of type 1 diabetes actually declining over time, and that people with lower genetic risk profiles are now developing type 1 diabetes more often than they did in the past. These patterns suggest that environmental factors play a much larger role than natural selection in the increasing rates of type 1 diabetes.
  
  References Cited
  
  Fourlanos S, Varney MD, Tait BD, Morahan G, Honeyman MC, Colman PG et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 2008; 31(8):1546-1549.
  
  Gillespie KM, Bain SC, Barnett AH, Bingley PJ, Christie MR, Gill GV et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 2004; 364(9446):1699-1700.
  
  Hermann R, Knip M, Veijola R, Simell O, Laine AP, Akerblom HK et al. Temporal changes in the frequencies of HLA genotypes in patients with Type 1 diabetes-- indication of an increased environmental pressure? Diabetologia 2003; 46(3):420-425.
  
  Parkkola A, Harkonen T, Ryhanen SJ, Ilonen J, Knip M. Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes Care 2013; 36(2):348-354.
  
  Patterson CC, Dahlquist G, Soltesz G, Green A. Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates. Diabetologia 2001; 44 Suppl 3:B9-16.
  
  Resic-Lindehammer S, Larsson K, Ortqvist E, Carlsson A, Cederwall E, Cilio CM et al. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk. Acta Diabetol 2008; 45(4):231-235.
  
  Steck AK, Armstrong TK, Babu SR, Eisenbarth GS. Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years. Diabetes 2011; 60(3):1045-1049.
  
  Vehik K, Hamman RF, Lezotte D, Norris JM, Klingensmith GJ, Rewers M et al. Trends in high-risk HLA susceptibility genes among Colorado youth with type 1 diabetes. Diabetes Care 2008; 31(7):1392-1396.
  
  Witas HW, Jedrychowska-Danska K, Zawicki P. Changes in frequency of IDDM-associated HLA DQB, CTLA4 and INS alleles. Int J Immunogenet 2010; 37(3):155-158.
  
  You WP, Henneberg M. Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. BMJ Open Diabetes Res Care 2016; 4(1):e000161.

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  Conflict of Interest:
  None declared.

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