Confirmation of the hypothesis that non-coding sequence variation in CAPN10 affects susceptibility to type 2 diabetes has implications for how we search for susceptibility variants and interpret results of positional cloning studies for complex disorders, and suggests a new pathway in glucose homeostasis.
Considering the relatively low frequency of haplotype 221 and that none of the haplotypes including 221 was associated with any of the diabetes-related quantitative traits tested, it is concluded that SNP-43, -56, and -63 of the CAPN10 gene variants may play a limited role in the risk of type 2 diabetes risks in this cohort of West Africans.
Current knowledge regarding the role of calpain-10 in the development of type 2 diabetes mellitus and diabetes-related diseases is additionally reviewed.
Cysteine protease Calpain 10 (CAPN10) has been associated with T2DM, hypertension, hypercholesterolemia, increased body mass index (BMI) and polycystic ovary syndrome (PCOS), a reproductive disorder of women in which isunlin resistance seems to play a pathogenic role.
Further studies have shown a number of non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease.
Further studies have shown a number of noncoding polymorphisms in CAPN10 to be functionally associated with T2DM while the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease.
Further, special features of the structure of calpain 10 that differ from those of typical micro - or m-calpain used in most studies are summarized together with discussion of the physiological function of calpain with respect to type 2 diabetes.
Given the epidemiological, physiological, and genetic overlap between type 2 diabetes and polycystic ovary syndrome (PCOS), CAPN10 represents a strong candidate gene for a role in PCOS susceptibility.
Given the physiological overlap between PCOS and type-2 diabetes (T2DM), and calpain 10 gene (CAPN10) being a strong candidate for T2DM, a number of studies have analyzed CAPN10 SNPs among PCOS women yielding contradictory results.
Haplotype combination 112/121 defined by three single nucleotide polymorphisms (SNPs) (UCSNP-43, -19 and -63) of CAPN 10 conferred the highest risk for T2DM in Mexican-Americans.
Here, we investigate this hypothesis by re-sequencing the CAPN10 region with unusual polymorphism levels in T2D cases and controls (n=91) from a Mexican American (MA) population, and by using networks to infer the evolutionary relationships between the major haplotypes.
However, the relative infrequency of the "at-risk" combinations in the South Indian population suggests that calpain 10 is not a common determinant of susceptibility to type 2 diabetes.
I illustrate many of the challenges in designing, conducting and interpreting these studies by reviewing recent research conducted on the calpain-10 gene, implicated in positional cloning studies as a candidate gene for type 2 diabetes.
In conclusion, in a relatively large study sample of whites we found no consistent evidence of association of the CAPN10 SNP43 or SNP44 with T2D, obesity, or related quantitative traits, although meta-analyses of these two CAPN10 SNPs demonstrated an association with T2D.
In conclusion, the frequency of the 112/121 at-risk haplotype of CAPN10 is low among Scandinavians and we were unable to demonstrate significant associations between the CAPN10 variants and type 2 diabetes, insulin resistance, or impaired insulin secretion.
In fact, we evaluated the effect of seven polymorphisms in the following genes-PPARg (Pro12Ala), TNFα (-308A/G), ENPP1(K121Q), TCF7L2(rs7903146°C/T), MTHFR(C677T), ACE(I/D), and CAPN10(3R/2R)-on T2D risk, through a meta-analysis combining data of previous studies performed on Tunisian populations originating from the north, center, or south of the country.
In this study involving the Tunisian population, we identified genetic variants within CAPN10 that are linked with T2DM and a novel haplotype combination, 121/221, associated with an increased susceptibility to T2DM.