Mitochondrial insertion-deletion polymorphism: role in disease pathology.

AIM: Mitochondrial DNA (mtDNA) sequence variations are associated with a number of human diseases. The 9-bp repeat sequence, CCCCCTCTA, in the intergenic region of MTCO2 and MTTK genes of the mtDNA has been extensively used in phylogenic studies. The sequence has been reported to be polymorphic in south-east Asians in isolated cases of mt diseases. This is the first systemic study identifying the role of insertion-deletion polymorphism in human disease. RESULTS: A total of 241 patients including those with cardiomyopathy, ataxias, and idiopathic neurological disorders along with 100 controls were screened; 2.9% of patients showed a single repeat (deletion) and 4.14% had three repeats (insertion), whereas all the controls had two repeats (normal). CONCLUSION: This indicates that the 9-bp insertion-deletion repeat polymorphism plays a role in disease pathology, affecting the expression of the downstream genes of mtDNA and altering ATP generation.

Relationship of angiotensin-converting enzyme gene polymorphism with nephropathy associated with Type 2 diabetes mellitus in Asian Indians.

OBJECTIVE: Diabetic nephropathy (DN) has become the leading cause of end-stage renal disease, but the pathogenesis of this condition is not exactly understood. Several studies from different parts of the world have examined angiotensin-converting enzyme (ACE) gene polymorphism as a candidate for DN. Two studies yielding controversial results have been reported from India. To rule out this discrepancy, we carried out a hospital-based study on a cohort from our population to determine whether ACE gene polymorphism is associated with DN. RESEARCH DESIGN AND METHODS: ACE gene polymorphism was analyzed by polymerase chain reaction in 460 individuals consisting of 174 cases of DN, 175 cases of Type 2 diabetes mellitus (DM), and 111 controls. The DN cases included in the study were Type 2 DM cases with serum creatinine >1.5 mg/dl and serum albumin >30 mg/dl in a 24-h urine sample. RESULTS: ACE insertion/deletion genotyping analysis showed DD genotype in 22.75% of DN cases, 15.42% of Type 2 DM cases, and 21.62% of controls. Chi-square test between the DN group and the control group did not show a significant difference in D allele. However, the difference was significant at P<.05 between the DN group and the DM group. The odds ratio was 2.0953 (95% confidence interval=1.35-3.2522), indicating a significant association of DD genotype and D allele with DN. CONCLUSION: Our data enable us to conclude that Asian Indians with D allele and Type 2 DM are at greater risk for developing DN.

Molecular analysis of CAG repeats at five different spinocerebellar ataxia loci: correlation and alternative explanations for disease pathogenesis.

Spinocerebellar ataxias (SCAs) are caused by expansion of (CAG)n triplet repeats. These repeats occur as polymorphic forms in general population; however, beyond a threshold size they become pathogenic. The sizes and distributions of repeats at the SCA1, SCA2, SCA3, SCA7 and DRPLA loci were assessed by molecular analysis of 124 unrelated ataxia patients and 44 controls, and the association of larger normal (LN) alleles with disease prevalence was evaluated. Triplet repeat expansions in the disease range were detected in 8% (10/124) of the cases, with the majority having expansion at the SCA1 locus. Normal allele ranges in the cohort studied were similar to the Caucasian and North Indian populations but differed from the Korean and Japanese populations at various loci. The percentage of individuals with LN alleles at the SCA1 and SCA2 loci was higher than reported in Indians, Japanese and Caucasians. LN alleles showed a good correlation with the incidence of SCA1, indicating that SCA1 is the most prevalent ataxia in our population. The majority of cases with clinical symptoms of SCA could not be diagnosed by established CAG repeat criteria, suggesting that there may be an alternative basis for disease pathogenesis: (i) Repeats lower than the normal range may also result in abnormal phenotypes (ii) LN alleles at different loci in the same individual may contribute to symptoms (iii) Exogenous factors may play a role in triggering disease symptoms in individuals with LN alleles (iv) Triplet repeats may reach the disease range in the brain but not in the blood.