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Thread: Lactase Persistence and the LCT 22018A gene

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    Lactase Persistence and the LCT 22018A gene

    Jean M posted about the different mutations for lactase persistence which are currently known. 13910T has been observed in Europe and other Eurasian populations (i.e. the Indian subcontinent) prompting a correlation with the distribution of Indo-European languages.

    22018A is another mutation which seems to code for lactase persistence. To try and understand the distribution and origins of this mutation through this thread, current literature will be shared and discussed. Inferences/summaries are included below the studies cited. Jean has already stated elsewhere much of the conclusions of what is stated here, although it is useful to view the source material.

    A study on genetic test of lactase persistence in relation to milk consumption in regional groups of India.
    Baadkar SV, Mukherjee MS, Lele SS. Genet Test Mol Biomarkers. 2012 Dec;16(12):1413-8. doi: 10.1089/gtmb.2012.0191. Epub 2012 Oct 3.
     

    ... The two SNPs were present in a strong linkage disequilibrium. LP prevalence varied in these Indian regional groups. The LP frequency was highest for North Indians and lowest for Parsis (p=0.03 CC vs. CT+TT, p=0.008 GG vs. GA+AA). South Indians had a lower LP frequency compared to North Indians (p=0.07 for each SNP). The milk consumption pattern varied in these Indian subgroups, with the Gujaratis exhibiting the highest milk intake and Parsis the lowest (p=0.04).
    CONCLUSION:
    Our study indicates that the milk intake in Indians might be influenced by their dietary habits in addition to their ancestral history. An overall correlation, however, between milk consumption and LP genotypes was not observed.

    13910T and 22018A are strongly linked with one another and the overall frequency of lactase persistence was higher in north India rather than the south. As the two were lumped together it isn't possible to tell whether one predominated over the other, but their "strong linkage disequilibrium" makes this a moot point.


    Correlation of G/A -22018 single-nucleotide polymorphism with lactase activity and its usefulness in improving the diagnosis of adult-type hypolactasia among North Indian children.
    Kuchay RA, Anwar M, Thapa BR, Mahmood A, Mahmood S. Genes Nutr. 2013 Jan;8(1):145-51. doi: 10.1007/s12263-012-0305-7. Epub 2012 Jul 5.
     

    ... There was a significant correlation between lactase activity and different genotypes of G/A -22018 SNP. Children with G/G -22018 genotype had low lactase activity. With a reference value of <10 U/g protein (lactase activity) to be indicative of AtH, the sensitivity and specificity of genetic test based on G/A -22018 SNP was 94.4 and 94.1 %, respectively. Furthermore, the consumption of milk was lower in children with G/G -22018 genotype. Flatulence was the only symptom significantly more frequent among the children with G/G -22018 genotype compared to those with G/A and A/A -22018 genotypes. However, most of the children with G/G -22018 genotype seem to tolerate small amounts of milk without any significant difference in gastrointestinal symptoms from those with G/A and A/A -22018 genotypes.

    This paper also implies a connection between 13910T and 22018A, although it states 22018A is "strongly, but not completely" related to lactase persistence. North Indian children found to carry the A/C allele mutation on 22018 were, for all intents and purposes, lactose tolerant. Those who were homozygous for G/T had low lactase activity and reported flatulence compared to the other groups, although some still could "tolerate small amounts of milk". As a medical student I imagine this has something to do with intestinal gut flora converting the lactose themselves rather than the in-situ presence of lactase in the body.


    Frequency of LCT -13910c/T And LCT - 22018 G/A Single Nucleotide Polymorphisms Associated with Adult-Type Hypolactasia /Lactase Persistence Among Israelis of Different Ethnic Groups.
    Raz M, Sharon Y, Yerushalmi B, Birk R. Gene. 2013 Feb 12. pii: S0378-1119(13)00122-4. doi: 10.1016/j.gene.2013.01.049. [Epub ahead of print]
     

    Primary lactase deficiency (PLD), the physiological decline of lactase, is associated with the LC-13910C/T and LCT-22018G/A polymorphisms. PLD is the most common phenotype in humans and varies widely as a function of ethnicity. Israel is a multiethnic country. We analyzed the genetic frequencies of PLD in different Israeli ethnicities. Ethnicity-related frequencies were analyzed in 439 Israelis: Ashkenazi (n=96), Iraqi-(n= 96) and Moroccan (n=96) Jews and Bedouin-Arabs (n=151). DNA was extracted from leukocytes; LCT-13910C/T , -22018G/A and -13915 T/G(in Bedouin-Arabs) polymorphisms were analyzed by PCR-restriction fragment length polymorphism analysis. There was a significant association between ethnicity and genotype in both polymorphic LCT SNPs (-13910C/T and -22018). Prevalence of the CC (LCT-13910C/T) genotype associated with adult hypolactasia was 97%, 93%, 83% and 82% among Bedouin-Arabs and Iraqi, Ashkenazi and Moroccan Jews, respectively. The prevalence of the GG (LCT-22018G/A) adult hypolactasia genotype among those groups was identical to that of the CC genotype in each group, except for Iraqi-Jews, of which only 83% carried the GG genotype. The prevalence of heterozygous and homozygous genotypes associated with lactase persistence (CT , TT for -13910C/T and GA, AA for -22018G/A) were 3%, 7%, 17% and 18% and 3%, 17%, 17% and 18% for Bedouin-Arabs, Ashkenazi, Iraqi and Moroccan Jews, respectively. A significant correlation between SNPs was found. PLD prevalence is high among different ethnic groups in Israel and varies between ethnicities. The prevalence of the -13915*G allele, indicative of lactose persistence in African and Arab populations, was 41% in the Bedouin-Arabs group. Lactase persistence genotype prevalence was found to vary between Israeli ethnicities (4-18%). SNPs (-13910C/T and -22018) showed significant correlation in detecting genotype prevalence in Israeli Jews. We suggest adjusting nutritional recommendations accordingly.

    Once more 13910T and 22018A are connected. These mutations were found in a small minority of Israeli populations (Bedouin Arab, Ashkenazi, Iraqi Jewish, Moroccan Jewish) on average ascending from 3% to 18% respectively for both alleles. This indicates Bedouin Arabs in Israel who are lactose tolerant are so due to different genes. 22018A has almost the exact same distributive range as 13910T in this part of the Middle-East, again solidifying the statement of "strong linkage disequilibrium" from the first study.

    The -22018A allele matches the lactase persistence phenotype in northern Chinese populations.
    Xu L, Sun H, Zhang X, Wang J, Sun D, Chen F, Bai J, Fu S. Scand J Gastroenterol. 2010;45(2):168-74. doi: 10.3109/00365520903414176.
     

    Abstract
    OBJECTIVE:
    It has been reported that some single-nucleotide polymorphisms (-13910C/T, -22018G/A, -13907C/G, -13915T/G, and -14010G/C) within the lactase gene are associated with lactase persistence. In our previous study, we found that -13910C/T is not a good predictor of lactase persistence in Chinese populations. To obtain a better understanding of the mechanism of lactase persistence, we examined the frequencies in Northern China of the four other alleles that are associated with lactase persistence.
    MATERIAL AND METHODS:
    We evaluated the allele frequencies of -22018G/A, -13907C/G, -13915T/G, and -14010G/C in six northern Chinese populations (Manchu, Mongol, Hezhen, Oroqen, Kazak, and northern Han) using the methods of polymerase chain reaction-restriction fragment length polymorphism and resequencing.
    RESULTS:
    By genotyping 1092 chromosomes, we found that the frequency of the -22018A allele was highest in the Kazak population and extremely low in the northern Han population. Although there are little available data about the frequency of lactase persistence in northern Chinese populations, we compared the allele frequencies with the phenotype frequencies that have been published previously. We found that the frequency of the -22018A allele was basically consistent with the reported frequencies of lactase persistence in Northern China. With respect to the -13907C/G, -13915T/G, and -14010G/C polymorphisms, we found no individuals with the derived allele.
    CONCLUSIONS:
    The frequency of the -22018A allele differed significantly among the six populations and the frequency reflected the frequency of lactase persistence. Taking into consideration the results of previous studies, we believe that the origins of lactase persistence-associated alleles are different in different pastoral populations.

    22018A is greatest in north China's Kazakh population and lowest in the Han, which, according to the study, perfectly compliments the reported occurrence of lactase persistence there. One intriguing comment came with regard to the 13910T mutation, which was found to "not [be] a good predictor of lactase persistence in Chinese populations". This is the first reported non-correlation between lactase persistence, 13910T and 22018A as a whole in any given population. It is tempting to speculate that demic events in north China resulted in 22018A (for what ever reason) being selected through the generations rather than 13910T.


    It appears 22018A is the "sister" mutation to 13910T and has a very similar distribution and lactose tolerance pattern to it in the Near-East, the Indian Subcontinent and north China. It is reasonable to presume the point of origin was similar to 13910T's, wherever that may be.

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    Is there an rs-number for the SNP (i.e. is it tested through 23andme)? If so it might be fun to see who is likely tolerant.
     

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    This is the main one - rs182549. See here (http://snpedia.com/index.php/Rs182549). The mutation is C->T, so those with any T alleles are going to be lactose tolerant.

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    Thanks! Among the kits I manage:

    AJL's grandfather (Near Eastern):
    rs182549:CT
    rs4988235:AG

    AJL's mother (West Euro):
    rs182549:TT
    rs4988235:AA

    AJL:
    rs182549:CT
    rs4988235:AG

    I'm not sure what to make of that, other than that none of us is intolerant.
     

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    I think 22018A predominates over 13910T in Asia and among Indo-Iranian speakers. Given lactose tolerance frequencies of 70-100% for South Asia (I believe Palisto posted the Pakistani studies on Molgen) and the lack of 13910T over frequencies of 30-40% this makes the most sense. Are there any independent mutations that originated in West Asia besides the ones found in Arabs?

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    Quote Originally Posted by newtoboard View Post
    I think 22018A predominates over 13910T in Asia and among Indo-Iranian speakers. Given lactose tolerance frequencies of 70-100% for South Asia (I believe Palisto posted the Pakistani studies on Molgen) and the lack of 13910T over frequencies of 30-40% this makes the most sense. Are there any independent mutations that originated in West Asia besides the ones found in Arabs?
    Yes, I also saw Palisto's link. I am quite certain Iranians and Kurds also have similar rates of lactose tolerance with one another. Palisto posted on another thread here showing the majority of Kurds he is sharing with on 23andMe are homozygous CC (technically "intolerant") for 22018A.

    All of this leads me to believe another lactase persistence gene is responsible for the Iranian and Kurdish consumption of milk. It probably also accounts for some of the lactose tolerance also seen in South Asia.

    That being said, as you stated, it's quite possible 22018A has a greater standing in South Asia than 13910T, much is the case in north China.

    (This post accompanies a 400ml mug of skimmed powdered milk tea.)

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    So you think there is another mutation that is local to West/Central/South Asia?
    What about 13910T in Iranians and Kurds?

    Is there any reason why either 22018A seems to dominate 13910T in Asia? I'm just guessing it dominates given the lactose tolerance of South Asians to be similar to that of Western Europeans without the high frequencies of 13910T of Western Europeans.

    That said I couldn't imagine a diet without dairy. Milk, ice cream, cheese, cream, yogurt consumption are an important part of most South Asian diets.

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    Quote Originally Posted by newtoboard View Post
    So you think there is another mutation that is local to West/Central/South Asia?
    What about 13910T in Iranians and Kurds?

    Is there any reason why either 22018A seems to dominate 13910T in Asia? I'm just guessing it dominates given the lactose tolerance of South Asians to be similar to that of Western Europeans without the high frequencies of 13910T of Western Europeans.

    That said I couldn't imagine a diet without dairy. Milk, ice cream, cheese, cream, yogurt consumption are an important part of most South Asian diets.
    13910T isn't very common among Iranians and Kurds I don't think. Palisto provided the information on that too IIRC.

    An educated guess would be there must be another mutation local to West-Central Asia. How else could dairy products make up such a large amount of Iranian, Kurdish and from the sound of it South Asian diets? It surely cannot be a multi-societal refusal to admit a population-wide issue with flatulence over generations!

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    Here's an article of interest, mainly for its maps: Global Geography of Milk Consumption and Lactose (In)Tolerance

    To North Americans and especially Europeans, both drinking and eating dairy products is very common, but this is far from the global norm, as can be seen in the map reposted on the left from FoodBeast.com. Nordic countries, such as Finland and Sweden, top the list of milk consumption per capita, with over 350 kg (770 lbs) of dairy per person per year. ... The highest ranking non-European country by dairy consumption is Kazakhstan, which ranks #13 with over 260 kg (573 lbs) of milk per capita. For centuries, Kazakhs were herders who raised fat-tailed sheep, Bactrian camels, and horses, relying on these animals for transportation, clothing, and food, in the form of both meat and dairy.

    ...As can be seen from some of these maps, in the U.S. the levels of lactose (in)tolerance differ by race, with Caucasians being most lactose tolerant, followed by Hispanics and African Americans; Native Americans are said to have the highest levels of lactose intolerance.
    Source: http://geocurrents.info/cultural-geo...se-intolerance

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    Quote Originally Posted by Jean M View Post
    Here's an article of interest, mainly for its maps: Global Geography of Milk Consumption and Lactose (In)Tolerance


    I'm also TT for rs182549 as well as AA on 13910T.
    Last edited by ADW_1981; 03-20-2013 at 03:10 AM.

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