rs4988235
mixedMag 7.0This is a regulatory region variant variant in the MCM6 gene.
Key Literature Trait Associations
Lactose Tolerance
The A allele (also known as -13910*T in European notation) maintains LCT gene expression into adulthood, enabling continued lactose digestion. This is the primary lactase persistence variant in European populations, arising ~7,500 years ago with dairy farming. Homozygous G/G individuals typically develop lactose intolerance after childhood.
LDL cholesterol
The T allele (lactase persistence allele) of rs4988235 is consistently associated with lower LDL cholesterol, total cholesterol, and HDL cholesterol in large-scale Mendelian randomization studies, mediated through increased dairy consumption. A two-sample MR study in up to 1.9 million individuals found T allele carriers had significantly lower LDL-C (p=2.08×10⁻²⁶) and total cholesterol (p=2.40×10⁻³⁶). The LDL-lowering effect is thought to reflect both calcium-induced fatty acid binding and specific fatty acid profiles in dairy. Despite lower LDL, this allele was also associated with lower HDL-C and slightly higher BMI, making the net cardiovascular risk complex.
Colorectal cancer
Higher genetically predicted lactase-phlorizin hydrolase (LPH) levels, instrumented by rs4988235-T, are associated with reduced colorectal cancer risk in Mendelian randomization analyses. A two-sample MR study meta-analyzing data from multiple large biobanks (Fenland Study, FinnGen, PLCO, Pan-UK Biobank) found an inverse association between genetically predicted LPH levels and colorectal cancer risk (OR 0.92, 95% CI 0.89–0.95), with similar protective effects for colon cancer (OR 0.92, 95% CI 0.89–0.96) and rectal cancer (OR 0.92, 95% CI 0.87–0.98). The mechanism may involve calcium in dairy binding to secondary bile acids and reducing colonic epithelial proliferation.
Body mass index
Lactase persistence (T allele) is paradoxically associated with slightly higher BMI and increased odds of overweight/obesity in Mendelian randomization analyses, despite common perceptions that dairy is associated with leanness in observational data. A meta-analysis of MR studies found T allele carriers had BMI approximately 0.17 kg/m² higher (95% CI 0.07–0.27) and 9% higher odds of overweight/obesity (OR 1.09, 95% CI 1.02–1.17). A large MR study (n up to 1.9 million) confirmed the T allele association with higher BMI (p=4.68×10⁻¹²) and greater total, leg, arm, and trunk fat. The effect is modest but consistent, suggesting increased dairy caloric intake among persistent individuals may offset any metabolic benefits.
Bone mineral density
The T allele (lactase persistence) is associated with modestly higher femoral neck bone mineral density (BMD), primarily in women, mediated through greater dairy and calcium intake. A study of 97,811 Danish individuals found T allele carriers had higher femoral neck BMD (SMD 0.10, 95% CI 0.02–0.18 g/cm²), but no significant difference in lumbar spine or total hip BMD. A large MR study (n=53,236) confirmed the association in women (OR 1.032, p=0.014) but not men. Despite higher milk intake and modest BMD gains, lactase persistence was not associated with reduced hip fracture risk (HR 1.01, 95% CI 0.94–1.09), suggesting the BMD advantage does not translate to clinically meaningful fracture protection.
Neural tube defects
Maternal rs4988235 CC genotype (lactase non-persistence) was associated with increased offspring neural tube defect (NTD) risk among non-Hispanic White women in the National Birth Defects Prevention Study (OR 1.37, 95% CI 1.02–1.82). The hypothesized mechanism involves impaired calcium and folate absorption secondary to lactose intolerance. Notably, the association was reversed in Hispanic women (OR 0.50, 95% CI 0.33–0.77), which the authors could not definitively explain. This finding is preliminary (single study, single population), the effect is ancestry-specific and requires replication, and should not be used in isolation for clinical counseling.
Hypertension
Despite observational associations between dairy consumption and lower blood pressure, Mendelian randomization using rs4988235 as a genetic instrument does not support a causal effect on systolic blood pressure or hypertension risk. A large MR study (n=171,213 for genetic analysis) found the T allele was not associated with systolic blood pressure (β=0.31 mmHg, 95% CI -0.05 to 0.68, p=0.09) or hypertension (OR 1.01, 95% CI 0.97–1.05, p=0.27). These null results were supported by a meta-analysis including 8 RCTs, suggesting beneficial observational dairy-blood pressure associations are confounded.
▶GWAS Catalog Trait Associations (27)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (27)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
▶Research that mentions this SNP (9)
▶Association of the matrix metalloproteinase 3 (MMP3) single nucleotide polymorphisms with tendinopathies: case-control study in high-level athletesCase reportNina Briški et al.(2021)· International Orthopaedics
This is a Turkish-language personalized nutrigenetics and epigenetics coaching report for individual Mehmet Efe Yildirim (Report No. 1332, dated 2023-11-21). The report analyzes the individual's genetic polymorphisms related to nutritional metabolism, food sensitivities, detoxification pathways, and other health-related traits, providing personalized dietary and lifestyle recommendations based on cited scientific literature. This is a direct-to-consumer genetic test report, not a peer-reviewed research study.
▶World-wide distributions of lactase persistence alleles and the complex effects of recombination and selectionAssociationN=2,056Anke Liebert et al.(2017)· Human Genetics
This study examined the worldwide distribution and haplotype structure of five lactase persistence (LP)-associated variants (rs4988235, rs41525747, rs41380347, rs869051967, rs145946881) in the LCT/MCM6 region across 2056 individuals from 52 populations. The research confirmed extended haplotype homozygosity (EHH) for LP alleles consistent with positive selection, but revealed that one ancient ancestral B haplotype also shows marked EHH despite lacking functional LP variants. This extended EHH of the B haplotype corresponds exactly to a region of suppressed recombination, suggesting that recombination patterns rather than selection alone explain some haplotype signatures in this region.
▶Genetic variation in the lactase gene, dairy product intake and risk for prostate cancer in the European prospective investigation into cancer and nutritionAssociationN=1,503Travis RC et al.(2013)· International Journal of Cancer
This European Prospective Investigation into Cancer and Nutrition (EPIC) study examined the association between the lactase gene C/T-13910 polymorphism (rs4988235) and prostate cancer risk among 630 cases and 873 matched controls. The lactase T allele showed strong association with milk intake (44.4, 69.8, and 82.3 g/day for CC, CT, and TT genotypes respectively), but no significant association with prostate cancer risk (adjusted OR for TT vs. CC: 1.10, 95% CI: 0.76-1.59). Meta-analysis combining this study with prior findings showed combined OR of 1.12 (95% CI: 0.96-1.32) for T allele carriers, indicating no large effect on prostate cancer risk despite the strong genetic-dairy intake relationship.
▶Polymorphism in the protease‐activated receptor‐4 gene region associates with platelet activation and perioperative myocardial injuryAssociationN=934Jochen D. Muehlschlegel et al.(2012)· American Journal of Hematology
A genetic association study identified SNP rs773857 in the F2RL3 gene region as associated with perioperative myocardial injury (PMI) in 934 CABG surgery patients (OR 2.4, p=0.004). Risk allele homozygotes showed increased platelet counts and enhanced P-selectin release upon PAR4 activation, indicating increased platelet reactivity and α-granule degranulation.
▶Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of boneAssociationN=744Pui Yan Jenny Chung et al.(2010)· Journal of Bone and Mineral Research
This association study identifies genetic variants in the TNFRSF11A gene (encoding RANK) associated with susceptibility to sporadic Paget's disease of bone (PDB) in three European populations. Meta-analysis across Belgian, Dutch, and British cohorts shows rs1805034 (A192V, p=1.27×10⁻⁸, OR=1.627) and rs35211496 (H141Y, p=.002, OR=1.410) are significantly associated with PDB, with strongest effects observed in females. Haplotype analysis in Belgian females identified risk haplotypes CGACGAA and AAAGGG with ORs of 2.808 and 3.462 respectively, though functional studies did not identify a definitive causative variant.
▶The T-13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intakeAssociationN=7,211Koek WN et al.(2010)· Journal of Bone and Mineral Research
This association study of 6,367 individuals from the Rotterdam Study and 844 from LASA examined the T-13910C polymorphism (rs4988235) in the lactase phlorizin hydrolase gene, which causes lactose intolerance. The C allele was significantly associated with lower dietary calcium intake (8.1% lower in C-homozygotes, p=3.0×10⁻⁵) and lower serum ionized calcium (p=0.02), but not with bone mineral density or fracture risk. Associations with height and vertebral area were explained by population stratification effects.
▶Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish CohortAssociationN=944Lídia Agueda et al.(2010)· Calcified Tissue International
This replication study analyzed three functional polymorphisms (MTHFR Ala222Val, LRP6 Ile1062Val, and LCT -13910C>T) in 944 postmenopausal Spanish women. Only MTHFR c.677C>T showed a significant association with vertebral fractures (OR=2.27, 95% CI 1.17-4.38, P=0.018), while LCT -13910C>T was associated with height and weight. No significant associations were found with lumbar spine or femoral neck bone mineral density.
▶Variability in Ethanol Biodisposition in Whites Is Modulated by Polymorphisms in the Adh1b and Adh1c GenesReviewCarmen Martínez et al.(2010)· Hepatology
A comprehensive review of nutrigenetics and nutrigenomics examining how genetic variants influence individual responses to nutrients and dietary interventions. The paper discusses associations between numerous SNPs (rs9939609 in FTO, rs2287019 in GIPR, rs7903146 in TCF7L2, rs5219 in KCNJ11, and many others) and metabolic traits including obesity, type 2 diabetes, and other chronic diseases, along with epigenetic mechanisms by which phytochemicals (curcumin, resveratrol, lycopene) modulate gene expression. The review synthesizes current evidence for precision nutrition approaches tailored to individual genetic profiles.
▶GJB2 mutations: Passage through IranAssociationN=1,021Hossein Najmabadi et al.(2005)· American Journal of Medical Genetics Part A
This population genetic study characterized genome-wide genetic diversity of 1021 individuals from 11 Iranian ethnic groups using the Axiom Precision Medicine Research Array (903,000 markers, 829,779 autosomal markers after QC). The authors identified a Central Iranian Cluster of genetically overlapping groups, substantial genetic heterogeneity, varying consanguinity levels, and evidence for language adoption events rather than demic replacement in Iranian history.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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