AFFECTED SIB-PAIR ANALYSIS OF THE GLUT1 GLUCOSE-TRANSPORTER GENE LOCUS IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS (NIDDM) - EVIDENCE FOR NOLINKAGE

Despite the strong evidence for a major role played by genetic factors in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), the genes involved are still unknown. Association studies of candidate genes for the inheritance of NIDDM have so far yielded inconclusive r esults. Some evidence exists for an association between NIDDM and the glucose transporter gene GLUT1, involved in basal glucose transport, a lthough this has not been confirmed. In the present study we have test ed the hypothesis of linkage between NIDDM and the GLUT1 gene, using a ffected sib-pairs. With this method the concordance observed for a giv en gene marker is compared with that expected under the assumption of no linkage between that marker and the disease. Fifty-four pedigrees ( 22 Italians and 32 British), for a total of 82 sib-pairs were studied by the affected sib-pair method proposed by Weeks and Lange, using two restriction frag ment length polymorphisms (RFLPs) at the GLUT1 locus , the MspI RFLP, at an estimated 0.171 recombination frequency from th e GLUT1 gene, and the XbaI RFLP, located within the GLUT1 gene and pre viously shown to be associated with the disease. Results showed that t he MspI marker and NIDDM segregate independently; for the XbaI RFLP, l inkage could be shown only if the results were weighted by the allele frequency [f(p) = 1/p], and only in the Italian and the combined (Ital ian and British) sib-pair groups. Multilocus analysis with both marker s was also negative. We conclude that the GLUT1 gene is very unlikely to play a major role in the aetiology of NIDDM, although an accessory role cannot be excluded, and studies of the gene sequence should help to clarify this question.