Sib-pair linkage analysis for susceptibility genes for microvascular complications among Pima Indians with type 2 diabetes. Pima Diabetes Genes Group.

Abstract

The aim of this study was to identify loci influencing susceptibility to microvascular complications (nephropathy and retinopathy) in Pima Indians with type 2 diabetes. Affected sib-pair linkage analyses were performed on 98 diabetic sibling pairs with nephropathy in both members and on 103 sibling pairs with retinopathy in both members. Four chromosomal regions with some evidence of linkage (P < 0.01; logarithm of odds [LOD] >1.18) with nephropathy were identified. The strongest evidence for linkage with nephropathy was on chromosome 7, where two adjacent markers, D7S500 and D7S1804, were linked both by two-point analysis (LOD = 2.73 and LOD = 2.28; respectively) and by multipoint analysis (LOD = 2.04). Additional loci potentially linked to nephropathy were found on chromosome 3, near D3S3053 (multipoint LOD = 1.48); on chromosome 9, near D9S910 (multipoint LOD = 1.12) and D9S302 (two-point LOD = 1.28); and on chromosome 20, near D20S115 (multipoint LOD = 1.83) and GATA65E01 (two-point LOD = 1.89). Multipoint analyses showed two regions with some evidence for linkage to retinopathy: chromosome 3 between D3S3053 and D3S2427 (LOD = 1.36), and chromosome 9 between D9S1120 and D9S910 (LOD = 1.46). These linkage analyses suggest that a genetic element on chromosome 7 and possibly one on chromosome 20 influence susceptibility to diabetic nephropathy but not retinopathy. Genetic elements on chromosome 3 and 9 may determine susceptibility to both these complications. These loci could presumably influence susceptibility to the complications by influencing the microvasculature directly, by influencing the severity of hyperglycemia, or by other unknown mechanisms.

Genetic risk factors for diabetic nephropathy on chromosomes 6p and 7q identified by the set-association approach

“…NOS3 is a well-documented functional candidate for DN susceptibility because of the involvement of nitric oxide in DN pathogenesis [39,40]. One of the first indications that genes within chromosome 7q35 (including NOS3) could influence genetic susceptibility to DN came from the nonparametric linkage study in Pima Indians [16]. Several positive associations of some of the numerous NOS3 SNPs with renal disease were documented in type 1 [41] and type 2 diabetes [42], as well as in non-diabetic subjects [43,44], while other studies did not find an association [45].…”

“…Ethnic differences in prevalence, uneven incidence over the time-course of the disease (culminating in the second decade of diabetes duration) [4], familial clustering in different populations for both type 1 and 2 diabetes [5][6][7][8][9][10][11][12][13], and the results of segregation analyses [14,15] suggest the existence of susceptibility genes for DN in addition to those leading to diabetes. Linkage analyses have thus far been inconclusive [16][17][18][19]. Nevertheless, results indicate that DN has the characteristics of a complex trait.…”

Molecular genetics of microvascular disease in diabetic retinopathy

“…There were indications that elements on chromosomes 3 and 9 influenced both nephropathy and retinopathy, but no clear genomic region was designated for retinopathy alone. 9 Candidate genes for retinopathy Association between genetic variability and retinopathy may be because of increased frequency or increased severity of retinopathy within the population of interest. A large number of candidate genes have been examined in subjects with diabetes, but few groups have identified a strong association between a gene and the frequency or severity of retinopathy.…”

The Finland–United States Investigation of Non–Insulin‐Dependent Diabetes Mellitus Genetics (FUSION) Study. II. An Autosomal Genome Scan for Diabetes‐Related Quantitative‐Trait Loci

“…Several groups have performed genome scans for type 2 diabetes, in attempts to identify disease-susceptibility loci (Hanis et al 1996;Mahtani et al 1996;Hanson et al 1998;Imperatore et al 1998;Pratley et al 1998;Duggirala et al 1999;Elbein et al 1999;Ghosh et al 1999;Ehm et al 2000). Although evidence has been reported for chromosomal regions that may contain type 2 diabetes-susceptibility genes, until recently only genes for specific subtypes of type 2 diabetes, such as maturity-onset diabetes of the young (MODY), have appeared in the literature (Bell et al 1991;Vaxillaire et al 1995;Horikawa et al 1997;Stoffers et al 1997).…”