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Methylenetetrahydrofolate reductase (MTHFR) gene mutations
Since its biochemical characterisation in 19911 and its genetic identification in 1995,2 677C>T allele (T allele) of the 5,10 methylenetetrahydrofolate reductase (MTHFR) gene has been a focus of increasing interest from researchers world wide. The expanding spectrum of common conditions linked with the 677C>T allele now includes certain adverse birth outcomes (including birth defects), pregnancy complications, cancers, adult cardiovascular diseases, and psychiatric disorders
Mutations in the MTHFR gene can affect the body’s ability to process amino acids — namely, homocysteine — which can lead to some adverse health outcomes.
Conditions that researchers have associated with MTHFR gene mutations include:
homocysteinemia, which is the term for abnormally high levels of homocysteine in the blood or urine
ataxia, which is a neurological condition that affects coordination
peripheral neuropathy, which is a neurological condition that damages the nerves
microcephaly, which is a condition present at birth in which the head is smaller than usual
scoliosis, which refers to an abnormal curvature of the spine
anemia, which means that there is a lack of healthy red blood cells in the body
cardiovascular diseases, such as blood clots, stroke, and heart attack
mental health conditions, such as depression
behavior disorders, such as attention deficit hyperactivity disorder
ovarian cancer
breast cancer
skeleton abnormalities, Anencephaly, one of several neural tube defects associated with the MTHFR mutation, in which large parts of the brain are missing and/or a person is missing or has incomplete skull bones
eye problems
Atherosclerosis (hardening of the arteries)
Alzheimer's disease
Microalbuminuria (increased albumin in urine associated with kidney and heart disease)
Alopecia areata, an autoimmune disorder in which the immune system attacks hair follicle roots, causing hair loss
Spina bifida, a birth defect in which the bones of the spinal column do not close completely around the nerves of the spinal cord
Preeclampsia (high blood pressure during pregnancy)
Behavior problems (e.g., attention deficit disorder and hyperactivity)
Digestive issues , including IBS (irritable bowel syndrome)
Autoimmune disease and thyroid issues
Schizophrenia
The distribution of the allele showed marked ethnic and geographical variation The homozygous TT genotype was particularly common in northern China (20%), southern Italy (26%), and Mexico (32%). There was also some evidence for geographical gradients in Europe (north to south increase) and China (north to south decrease). The TT genotype frequency was low among newborns of African ancestry, intermediate among newborns of European origin, and high among newborns of American Hispanic ancestry. Areas at the extremes of the frequency distribution showed deviations from Hardy-Weinberg expectations (Helsinki, Finland, southern Italy, and southern China)
data on 7130 newborns from 16 areas in the Americas, Europe, Russia, China, and Australia. Amplification rates for blood spots by geographical source were the following: Italy, Sicily 89%, Italy, Campania 76%, Italy, Veneto 73%, Spain 69%, France, Strasbourg 78%, Finland, Helsinki 95%, Hungary 95%; Russia, Moscow 95%, Australia, New South Wales 79%, Canada, Alberta 77%, USA, Atlanta 96%. By comparison, a large Irish population based study using newborn blood spots successfully genotyped 85% of collected samples
Prevalence of homozygous TT genotype (two 677C>T alleles) among newborns by area and ethnic background, ICBDMS 2003.
The distribution of the 677C>T allele showed regional and ethnic variations. For example, the prevalence of the homozygous TT genotype was 10–12% in several areas in Europe (for example, Spain, France, and Hungary). However, the prevalence appeared to be lower (4% and 6%, respectively) in Finland, Helsinki and the northern Netherlands, whereas in some areas in southern Europe it was much higher (26% and 20% in Campania and Sicily, respectively). In the Americas, the frequency of the homozygous TT genotype was higher in Mexico (32%), intermediate in Atlanta (11% among whites), and somewhat lower in Alberta (6%). In Australia, TT prevalence was 7.5% among whites.
Genotype varied by ethnicity as well as by geographical location. For example, TT homozygosity was more common among newborns from Mexico or those born in Atlanta of Hispanic origin, intermediate among newborns of European ancestry (for example, in Europe and North America), and lower among newborns of African ancestry (for example, in Atlanta and Veneto, Italy). However, a range of genotype frequencies was evident even within broad ethnic groups. For example, TT homozygosity among whites ranged from as low as 6% in Alberta (Canada), to 7.5% in New South Wales (Australia), to 11% in Atlanta (USA), to the high values already noted for Italy. For other ethnic and racial groups, such estimates are more unstable because of the smaller number of specimens, but it is worth noting an apparently low frequency of TT homozygosity among newborns of Asian origin from Australia and Atlanta.
The several fold variation in the prevalence of the TT homozygous genotype across the study areas (fig 1) was also consistent, in some areas, with the presence of geographical gradients. In Europe, for example, the prevalence of the TT genotype increased in a roughly southerly direction, from low values in the north (4–7% in Finland, Helsinki, northern Netherlands, and Russia), to intermediate values (8–10%) in France and Hungary, to higher values in southern Europe (12–15% in Spain and northern Italy), peaking in southern Italy (20–26% in Campania and Sicily). In North America, the frequency of TT homozygotes increased from western Canada (Alberta) to south eastern United States (Atlanta) and peaked in Mexico.
Ethnic variation was apparent among and within geographical areas. In metropolitan Atlanta, for example, TT homozygosity was common among newborns of Hispanic origin (15%), intermediate among those of European origin (11%), and low among African-American newborns (3%). These data are consistent with the high prevalence of TT homozygosity among newborns from Mexico in this study and with published data from the population based sample of babies of Mexican ancestry from California.14 The low prevalence among US blacks is similar to that reported in pooled estimates of five studies on US blacks and three studies from sub-Saharan Africa3 as well as in later studies from South Africa and Zimbabwe.15,16 The intermediate prevalence among whites in Atlanta is consistent with similar rates observed in several European areas in this and several other studies.3
The high frequency of TT homozygotes observed in this study among newborns from Mexico, northern China, and southern Italy was notable. These findings confirm and extend those previously reported from Mexico19 and southern Italy.20 Why such high rates of TT homozygosity occur in these regions is unclear, given the apparently limited ethnic, genetic, or environmental commonalities among such areas. Researchers have suggested the possibility of heterozygote advantage with respect to the risk for neural tube defects.21 However, such a hypothesis remains unconfirmed. Nevertheless, further exploration of gene-gene and gene-environment interaction might help to identify the evolutionary pressures favoring a high prevalence of this gene variant in certain areas and ethnic groups.
The impact of such geographical and ethnic variation on the distribution of disease in the population is unclear. For example, one would predict high rates of neural tube defects, whose risk appears to be increased nearly two-fold in the presence of 677C>T homozygosity3 in those geographical areas or ethnic groups with a high frequency of this genotype. The evidence supporting such relations is mixed. For example, the data are consistent for Mexico and northern China, which not only have a very high frequency of the TT genotype but also high rates of neural tube defect.22,23 Furthermore, within China, rates of neural tube defect are higher in the north (where the TT homozygous genotype is more common) than in the south.23 In the United States, the rates of neural tube defects historically have been higher among Hispanics, intermediate among non-Hispanic whites, and lower among African-Americans, a trend that follows the relative frequency of the TT homozygous genotype.
There are, however, notable exceptions. In southern Italy, for example, the TT genotype is common, but the rate of neural tube defects is not particularly high.22 Nevertheless, such exceptions are not entirely unexpected, because environmental and nutritional factors are likely to modulate considerably the genetic risk for neural tube defects. In fact, these exceptions might prove particularly valuable when investigating the aetiological heterogeneity and the role of interactions in the occurrence of neural tube defects.
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