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From an evolutionary perspective, the gene for celiac disease should have been selected against, but it remains as one of the most prevalent diseases with a strong genetic predisposition. Celiac disease remains an interest to many researchers who are interested in studying how evolutionary biology has an impact on the high prevalence of celiac disease. With the rise in prevalence of celiac disease, its origin and the reasons for its rise in frequency are topics of interest for many scientists. Some researchers believe that although there is a strong genetic predisposition to celiac disease because all patients carry the gene HLA DQ2, there are also strong environmental contributions (Fasano, 2004). Not everyone with the gene display symptoms of celiac disease, and also the age of onset for patients varies greatly (Karsada, 1996). Some studies also looked at the sex as a factor of predisposition to the disease; it was found that girls in Sweden were twice as more likely than boys to be diagnosed with celiac disease (Ivarssaon et al, 2003).
Celiac disease is an autoimmune disorder that affects many individuals in the Western world. It affects 5% to 8% of the United States' population and is also regarded as the third most common disease (Catassi et al., 2010). In the last thirty years, the population of individuals with celiac disease in the United States has doubled every 15 years with a total of 5-fold increase in thirty years, and a similar trend has been observed in other Western countries as well (Catassi et al., 2010). This was due to increasing number of individuals who become immunologically intolerant to gluten as they age (Catassi et al., 2010).
People suffering from celiac disease have adverse reactions to gluten, the protein present in wheat, rye, and barley. Once gluten is ingested, the activated T-cell mediated inflammatory response results in damaged microvilli of the small intestines, which prevents the body from absorbing necessary nutrients for healthy individuals (Fasano, 2004). celiac disease has shown to be clinically highly variable among different individuals and identified as a "multisystemic complex inflammatory disease" (Naluai et al., 2008). Some of the symptoms of celiac disease include anemia, diarrhea, malnutrition, weight loss, vomiting, and weight loss. On the other hand, some individuals are asymptomatic and may never become diagnosed (Nalui et al., 2008). Continued consumption of gluten could lead to more severe health issues. Some people may go years without being diagnosed.
Diagnosing and treating celiac disease as soon as possible is crucial because untreated celiac disease could lead to more genetically vulnerable population developing other autoimmune diseases (Nalui et al., 2008)). Undiagnosed celiac disease is associated with four times the risk of developing other health concerns (Wu et al., 2010). Even young children with celiac disease may develop osteoporosis or osteopenia if they are not on a gluten free diet (GFD) (Matysiak-Budnik et al., 2007).
Because celiac disease is an autoimmune disease with a genetic basis, physicians utilize the serological criteria tests for patients who display more common symptoms of celiac disease (Catassi et al, 2010). These tests measure levels of two different proteins - the IgA anti-tissue transglutaminase antibodies and IgG anti-gliadin antibodies level with IgA deficiency (Catassi et al., 2010; Wu et al., 2010). Being positive for presence of both proteins would indicate that the patient was suffering from celiac disease; this criterion is fairly accurate because the chance of both tests being false positives is very low.
Celiac disease affects 1% of the world population, and there are certain populations that are more vulnerable to celiac disease than others. Similar to other autoimmune diseases, females are more vulnerable to celiac disease than males with a 2:1 ratio (Fabris et al., 2010; Matysiak-Budnik et al., 2007; Marild, Frostell & Ludvigsson, 2010). In a study that looked at seasonal pattern of celiac disease vulnerability for different sexes, it was observed that females had less seasonal effect on celiac disease prevalence than males (Ivarsson, Hernell, Nystrom & Persson, 2003). Thus occurrence of celiac disease among females was mostly due to their genetic predisposition. Also, since celiac disease has some genetic basis, there is a higher prevalence among siblings and twins (Naluai, ascher, Nilsson & Wahlstrom, 2008).
Studies have also shown celiac disease being associated with other autoimmune diseases. One of those diseases is malignant lymphoma, which is frequent among individuals who are diagnosed with celiac disease at an older age (Naluai, Ascher, Nilsson & Wahlstrom, 2008). Also, patients with type 1 diabetes mellitus and hyperthyroid disorder are also more vulnerable (Wu et al., 2010). Although celiac disease is more common among high gluten consuming population (Naluai, Ascher, Nilsson & Wahlstrom, 2008), Saharawi refugees in Africa have the highest population prevalence in the world with 5.6% of the population with celiac disease (Naluai, Ascher, Nilsson & Wahlstrom, 2008). Also, populations among industrialized countries have been observed to have higher frequency of celiac disease. It is possible that in populations that celiac disease is not common, there hasn't been enough exposure to gluten to celiac disease to be widely observed (Wu et al., 2010).
Currently, the only treatment option for celiac disease is placing patients on a gluten-free diet (GFD), which had been implemented since the 1950s (Zhernakova et al., 2010). As of now, permanent intolerance of gluten requires a life long gluten free diet (Matysiak-Budnik et al., 2007). There have been studies to show that reintroduction of gluten after GFD has shown feasible for certain individuals. It isn't very successful, because it takes 8- 30 years for normal mucosa to be reestablished (Matysiak-Budnik et al., 2007). Unsuccessful reintroduction of gluten could cause further villous atrophy, which would lead to increased risk of osteopenia and osteoporosis (Matysiak-Budnik et al., 2007). However, there is a dilemma between suggesting GFD and nutrition deficiency, especially for young children and adolescents, because of the pros and cons for both diets (Matysiak-Budnik et al., 2007). New research shows that patients on GFD for few years during childhood may reduce severity of celiac disease at adulthood (Matysiak-Budnik et al., 2007). At the same time, being on a GFD may lead to nutrition deficiency, stunted growth, and immunological imbalance (Matysiak-Budnik et al., 2007; Pinier, Fuhrmann, Verdu & Leroux, 2010). At this time, there are no conclusive studies performed on a large population to draw any concrete conclusions about the GFD diet.
Because the gluten free diet is restrictive for many patients and may pose problems for sufficient nutrient intake, there is strong motive to explore other treatment options. Since adverse symptoms of celiac disease are triggered by ingesting gluten, chemically modifying gluten via microbial transglutaminase may decrease T-cell mediated inflammatory response (Pinier, Fuhrmann, Verdu & Leroux, 2010). Another option is developing a tablet containing the exogenous enzyme prolyl endopeptidases (PEP) that would target gluten and completely digest it, which would completely detoxify gluten peptides and prevent gliadin uptake (Pinier, Fuhrmann, Verdu & Leroux, 2010). Because PEP has only been studied in vitro, further research is necessary to observe its in vivo effects before it can be considered a viable treatment option.
In order to develop more effective treatment plans, it is crucial to understand the origin and the possible causes of celiac disease. As previously mentioned, celiac disease is an autoimmune disease with a strong genetic predisposition. The genes associated with celiac disease are genes that express human leukocyte agent (HLA) DQ 2 heterodimers and HLA DQ 8 heterodimers. 90% those with celiac disease test positive for HLA DQ 2 and almost all those who are negative for HLA DQ 2 are positive for HLA DQ8 (Naluai, Ascher, Nilsson & Wahlstrom, 2008). This evidence suggests that HLA DQ 2 gene is a stronger indicator of celiac disease predisposition than HLA DQ 8 (Fabris et al., 2010). There is evidence to show that this gene is population specific because HLA DQ 8 is more frequent among southern European population (Romnaos et al., 2008).
In addition to HLA DQ 2 and HLA DQ 8 genes increasing predisposition to celiac disease, additional studies show that there are new loci of the genome being discovered that may contribute to other genetic factors that contribute to the disease. This particular research shows that non-HLA genes may be more influential than previously thought (Ivarsson, Persson, Nystrom & Hernell, 2002). Romanos et al. predict that "60% of the genetic heritability" is due to non-HLA genes and "each of which is estimated to contribute only a small risk effect" (2008). These eight loci discovered are believed to contribute to immune response (Romanos et al., 2008). Because this study concentrated on the southern European population, the authors speculated that there may be a population difference in genetic predisposition to celiac disease (Romanos et al., 2008).
More recently, numerous studies have been conducted to find more celiac disease associated genes. One of those gene sequences is the14-base pair (bp) insertion allele in the HLA-G gene has been observed to occur more frequently among individuals with celiac disease than in normal population (Fabris et al., 2010). The study showed that 14-bp allele followed a recessive genetic model and it was "significantly more frequent in celiac disease patients than in healthy controls"(Fabris et al., 2010). There was no difference in genotype frequencies between men and women for the HLA-G 14-bp insertion pattern (Fabris et al., 2010). The study also looked at individuals with the 14-bp insertion in addition to the HLA DQ 2 heterodimer presence. Fabris et al. concludes that individuals with both genes had higher predisposition to celiac disease compared to the individuals with just the HLA DQ-2 gene (2010). Fabris et al. also believe that increased level of HLA-G among celiac disease patients may be due to HLA-G's role in "restoring tolerance toward dietary gluten (2010). It's important to keep in mind that genetics alone cannot be used to predict risk population because of complex genetic inheritance pattern due to linkage and association analysis on phenotype (Fabris et al., 2010).
As previously mentioned, females in general are more vulnerable to autoimmune disorders, and celiac disease is no exception (Ivarsson, Hernell, Nystrom & Persson, 2003; Ivarsson, Hernell, Nystrom & Persson, 2002). When frequency of celiac disease among girls and boys was observed in the pre- and post- epidemic period in Sweden, the 2:1 frequency ratio of girls to boys remained relatively constant (Ivarsson, Hernell, Nystrom & Persson, 2002).
Although genetic predisposition is almost required for celiac disease, there are individuals who have the genes for celiac disease yet never show any symptoms or have the disease. This phenomenon has led the scientists to believe that environmental factors also play a large role in celiac disease. Although there is a strong association between individuals with the HLA DQ 2 and 8 genes with celiac disease, there are individuals in the healthy population who also have the genes (Nalui, Ascher, Nilsson &Wahlstrom, 2008). This led the researchers to believe that that about 40-50% of celiac disease is due to environmental causes (Fabris et al., 2010).
To show that environmental causes contribute greatly to development of celiac disease, there is evidence to support that seasonal pattern and its variable exposure to certain factors. One particular study looked at sunlight exposure as well as different temperature of the seasons as factors that could affect celiac disease occurrence (Ivarsson, Hernell, Nystrom & Persson, 2003). For children who were diagnosed before the age of 2 years, the frequency of celiac disease was higher for the children born in the summer (Ivarsson, Hernell, Nystrom & Persson, 2003). Researchers believe that this is due to the seasonal effect on immune system and to the variations of infectious and non-infectious exposure level between seasons (Ivarsson, Hernell, Nystrom & Persson, 2003). For example, the infants born in the summer were in utero during the winter when mothers are more vulnerable to infections (Ivarsson, Hernell, Nystrom & Persson, 2003). It is possible that interactions with adenoviruses, which are upper respiratory infections such as common colds, contribute to celiac disease development due to immunological cross reactivity between the virus and A-gliadin, a protein that's present in the body and responsible for gluten formation (Ivarsson, Hernell, Nystrom & Persson, 2003). These evidences are the basis of the viral hypothesis, which will be further explored later in the paper.
Another possible environmental factor is the effect of nutrient intake of the infant's diet. Researchers predict that about half of celiac disease is due to the individual's infant dietary pattern (Ivarsson, Hernell, Nystrom & Persson, 2003). Studies have shown that delayed introduction of gluten in an infant's diet could reduce the possibility of celiac disease (Matysiak-Budnik, 2007). Since changes in infant feeding practices vary with the season, infant's diet is also affected seasonally. Since it is a common practice among the mothers to wean their infants off breast milk and introduced them to gluten during the winter, celiac disease is more common among infants born in the summer (Ivarsson, Hernell, Nystrom & Persson, 2003). It has been noted that the highest rate of breastfeeding among children with celiac disease more so than other enteritis diseases (Decker et al., 2010).
Researchers also studied maternal stress during pregnancy as a contributing factor to celiac disease occurrence in their infants. One particular study shows that celiac disease in the offspring due to maternal stress to be almost negligible (Marild, Frostell & Ludvigsson, 2010). The study looked at parental stress level after birth until their offspring were 2.5 years of age. Three different categories of psychological stresses among parents were analyzed: exposure to serious life events such as death, parenting stress such as social isolation, and parental worries to create "composite measure of psychological stress at age 2.5, " such as worries that the child will get sick or don't develop normally (Marild, Frostell & Ludvigsson, 2010). The study failed to establish a meaningful correlation between psychological stress of parents and occurrence of celiac disease among their infants (Marild, Frostell & Ludvigsson, 2010). This may be due to the fact that the study was based on only a few subjects.
Another method of analyzing the causes of celiac disease would be to study celiac disease within the evolution context. Adaptationists would ask if having celiac disease is not a positive trait, then why does the disease still exist? Because predisposition for celiac disease is highly suggested to be genetic, natural selection should have selected against this gene. Because celiac disease is a frequently occurring disorder today, one hypothesis would be that celiac disease may have a protective effect. There is evidence to show that having celiac disease is a form of protection from bacterial infections (Zhernakova et al., 2010). This study explores SH2B3 as a locus that is associated with having a protective effect from diseases (Zhernakova et al., 2010). Research shows that the SH2B3 gene plays a significant role in cytokines response by increasing cytokines response and thus associated with various autoimmune and metabolic disorders (Zhernakova et al., 2010). This gene could be selected for possibly 1200-1700 years ago due to greater mortality from an infectious disease (Zhernakova et al., 2010). Research shows that SH2B3 gene was under positive selection and could have resulted in "population differences in selective pressure resulting in global allele frequency variations (Zhernakova et al., 2010).
Another hypothesis that supports the prevalence of HLA DQ 2 gene is the hypothesis that HLA DQ 2 is a "wildtype" gene and not having the gene is recessive (Naluai, Ascher, Nilsson & Wahlstrom, 2008). Although having a celiac disease is not optimal, the HLA DQ 2 gene has been passed on because individuals with celiac disease live to reproduce (Naluai, Ascher, Nilsson & Wahlstrom, 2008). One study shows that having the HLA DQ 2 gene could be advantageous if an individual lacks some other HLA molecules since HLA DQ 2 plays a role in inflammation response with procytokine functions (Nalui, Ascher, Nilsson & Wahlstrom, 2008). Therefore, having this gene could be a benefit in terms of protection from infections.
Another hypothesis suggests a mismatch in dietary patterns between our ancestors and today's humans. Studies show that in the early days of agriculture the amount of gluten present in wheat was lower than that of today (Nalui, Ascher, Nilsson & Wahlstrom, 2008). This is possible due to manipulating genetic components of crops due to the advent of technology. It is possible that in the diet of our ancestors, there wasn't enough gluten in the wheat to produce a result (Nalui, Ascher, Nilsson & Wahlstrom, 2008). It has been previously mentioned that in populations where gluten is more substantial part of the population's diet, there is a greater prevalence of celiac disease. Due to variations in diet, climate and pathogen load, population differences in selective pressure result in global allele frequency variations where one population has a greater frequency of one gene than the other (Nalui, Ascher, Nilsson & Wahlstrom, 2008).
Another hypothesis that falls into the category of novel environment hypothesis is the advent of sophisticated medicine. One particular study examined Cesarean delivery contributing to celiac disease due to alterations of intestinal microflora among infants born by Cesarean delivery. The study showed that Cesarean delivery influences postnatal bacterial colonization in the infants' intestines (Decker et al., 2010). There are noted differences in microbial flora and impaired priming of the enteric epithelial surface for babies born via Cesarean section. (Decker et al., 2010). Alterations of flora composition and anatomic localization at the epithelial lining could make children born via Cesarean section more vulnerable to intestinal complications, including celiac disease (Decker et al., 2010). In the last decade, specifically between the years 1991 to 2007, the rate of C-section increased by 15% to 30% (Decker et al., 2010). With this increase was also an increased rate of celiac disease and irritable bowel disorders (Decker et al., 2010). Enhanced permeability of the mucosal barrier during the pathogenesis occur significantly earlier in life in patients with celiac disease, which would leave these individuals more vulnerable to infections and viruses (Decker et al., 2010).
Although it may seem that Cesarean section is a valid explanation for the recent rise in prevalence of celiac disease, it may be possible that the reason for the increase in Cesarean section is that women with celiac disease usually deliver via Cesarean section (Decker et al., 2010). There is also evidence to suggest that there is some transmission of maternal intestinal flora to the fetus from the mother (Decker et al., 2010). Therefore, children of the mothers with celiac disease are more likely to also be affected by celiac disease.
Celiac disease is still a relatively new disorder that deserves further attention in what causes the disorder. This paper attempts to provide some proximate causes that describe the biophysical nature of the diseases and puts great emphasis on the genetics contribution to the disease and some environmental factors that may or may not contribute to the disease. Because the research on the disease is fairly recent and compared to other chronic disorders there is not much information about celiac disease, the evolutionary explanation for the disease is still in its preliminary phases. There are only a couple possible explanations as to why the disorder exists. However, there are many aspects of the disease that is still unexplored. Why there is an upward trend of diagnoses being later in life is still not sufficiently explained.
The need to explain why and how celiac disease has persisted rises from finding a way to treat and possibly prevent the disorder from occurring within our population. As of now, celiac disease is only managed by following a gluten free diet. This is a relatively restrictive diet that has unfavorable side effects such as nutrient deficiency. It is crucial to be able to find a less evasive and more patient friendly treatment plan.