JOBNAME: No Job Name PAGE: 1 SESS: 9 OUTPUT: Wed Oct 10 19:05:48 2012 /v2503/blackwell/journals/jgh_v0_i0/jgh_7259 GASTROENTEROLOGY Lactase persistence/non-persistence genetic variants in irritable bowel syndrome in an endemic area for lactose malabsorption Sunil Kumar,* Prabhat Ranjan,* Balraj Mittal, † Rajan Singh* and Uday C Ghoshal* Departments of *Gastroenterology and † Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Science, Lucknow, Uttar Pradesh, India Key words adult type hypolactasia, lactase, lactose intolerance, single nucleotide polymorphism. Accepted for publication 27 August 2012. Correspondence Dr Uday C Ghoshal, Department of Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow-226014, UP, India. Email: udayghoshal@gmail.com Conflict of interest Sunil Kumar, Prabhat Ranjan, Balraj Mittal, Rajan Singh and Uday C Ghoshal have no conflict of interest to disclose. Abstract Background and Aim: Lactase non-persistence is common in India. We evaluated: (i) frequency of lactase gene (C/T-13910 and G/A-22018) polymorphisms in irritable bowel syndrome (IBS) and healthy controls (HC), (ii) association between these polymorphisms and IBS-subtypes and symptoms. Methods: A total of 150 IBS patients (Rome-III criteria) and 252 age and gender-matched HC were evaluated for C/T-13910 and G/A-22018 genotypes polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). Results: Totals of 79 (52%), 52 (35%) and 19 (13%) patients had diarrhea-predominant IBS (D-IBS), constipation predominant IBS (C-IBS) and alternating diarrhea and consti- pation IBS (A-IBS), respectively (Rome-III). Frequency of C/T-13910 [genotypes: CC 102 (68%), CT 43 (29%), TT 5 (3%) vs CC 155 (61%), CT 83 (33%), TT 14 (6%), P > 0.05] and G/A-22018 [GG 97 (65%), GA 41 (27%), AA 12 (8%) vs GG 154 (61%), GA 78 (31%), AA 20 (8%), P > 0.05] were similar among IBS and HC. Patients with D-IBS more often had C/T-13910 and G/A-22018 genotypes than C-IBS (CC 71 [90%], CT 6 [8%], TT 2 [2%]) versus (24 [46%], 25 [48%], 3 [6%]), A-IBS (7 [39%], 12 [63%], 0, [0%]) and HC (155 [61%], 83 [33%], 14 [6%]), P < 0.0001 and (GG 69 [87%], GA 6 [8%], AA 4 [5%]) vs (22 [42%], 24 [46%], 6 [12%]) vs (6 [32%], 11 [58%], 2 [10%]), P < 0.0001. IBS with CC and GG genotypes more often had abdominal pain (P = 0.005), distension (P = 0.031) and higher stool frequency (P = 0.003) and reported symptoms following dairy products than non-CC (P < 0.0001). Conclusion: Though C/T-13910 and G/A-22018 polymorphisms were comparable among IBS and HC, these were more common among D-IBS and reported some symptoms like abdominal pain, bloating and exacerbation by dairy products. Introduction Lactose malabsorption (LM) is a clinical syndrome, which may manifest with variable combination of symptoms that include abdominal pain, diarrhea, nausea, flatulence and bloating after ingestion of lactose or lactose-containing food substances. 1 Primary adult-type hypolactasia is relative or absolute absence of lactase without another cause and is the most common cause of LM. 2 It occurs most commonly in certain ethnic groups like Asian, particularly Indian. 3 Adult-type hypolactasia is also referred as lactase non-persistence (LNP). 2,4 LNP is a common inherited con- dition caused by reduced activity of small intestinal enzyme lactase (Lactase phlorizin hydrolase; LPH), encoded by a gene located on the long arm of chromosome 2q21-22. 2,4 Expression of LPH gene is temporally regulated during gut development and maturation. 4 It is maximal in the small intestine of pre-weaned mammals and declines markedly during maturation. 2,5 The matu- rational decline in LPH activity makes many adult humans intol- erant to milk and other dairy products. 2,5 Two single nucleotide polymorphisms about 14 and 22 kb upstream of the LPH gene have been shown to be associated with LNP. 6 Enattah et al. reported identification of genetic variants located at -13910 and -22018 base pair upstream of the human LPH gene on chromosome 2q21-22, using linkage disequilibrium and haplotype analysis. 6,7 The C/T-13910 variant is a single nucle- otide polymorphism, C to T. Subjects with CT or a TT genotype had normal lactase levels (lactase persistence; LP) and those with homozygous state for the C allele (CC genotype) were found to be lactase deficient (LNP), as determined by lactase activity of intes- tinal biopsies. 6,7 A second variant (G/A-22018) has also been shown to be associated with the LNP. 6,7 Subjects homozygous for the G allele of G/A-22018 (GG genotype) were shown to develop doi:10.1111/j.1440-1746.2012.07259.x Toppan Best-set Premedia Limited Journal Code: JGH Proofreader: Emily Article No: JGH7259 Delivery date: 10 Oct 2012 Page Extent: 6 Copyeditor: Mildred 1 Journal of Gastroenterology and Hepatology (2012) © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 2324 2526 2728 2930 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79